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CEFADROXIL

• Molecular FormulaC₁₆H₁₇N₃O₅S
• Average mass363.388 Da

(6R,7R)-7-{[(2R)-2-Amino-2-(4-hydroxyphenyl)acetyl]amino}-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
256-555-6[EINECS]
50370-12-2[RN]
5-Thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, 7-(((2R)-amino(4-hydroxyphenyl)acetyl)amino)-3-methyl-8-oxo-, (6R,7R)-
5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]amino]-3-methyl-8-oxo-, (6R,7R)-
цефадроксил [Russian] [INN]
سيفادروكسيل [Arabic] [INN]
头孢羟氨苄 [Chinese] [INN]

Cephos

• Molecular FormulaC₁₆H₁₉N₃O₆S
• Average mass381.404 Da

5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]amino]-3-methyl-8-oxo-, (6R,7R)-, monohydrate
66592-87-8[RN]
(6R,7R)-7-{[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]amino}-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid hydrate
(6R,7R)-7-{[(2R)-2-Amino-2-(4-hydroxyphenyl)acetyl]amino}-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid hydrate (1:1)

Product Ingredients

CefadroxilCAS Registry Number: 66592-87-8 
CAS Name: (6R,7R)-7-[[(2R)-Amino-(4-hydroxyphenyl)acetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monohydrate 
Additional Names: 7-[D-(-)-a-amino-a-(4-hydroxyphenyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid monohydrate; p-hydroxycephalexine monohydrate 
Manufacturers’ Codes: BL-S578; MJF-11567-3 
Trademarks: Baxan (BMS); Bidocef (BMS); Cefa-Drops (Fort Dodge); Cefamox (BMS); Ceforal (Farmoffer); Cephos (CT); Duracef (BMS); Duricef (BMS); Kefroxil (Torre); Oracéfal (BMS); Sedral (BMS); Ultracef (BMS) 
Molecular Formula: C16H17N3O5S.H2O 
Molecular Weight: 381.40 
Percent Composition: C 50.39%, H 5.02%, N 11.02%, O 25.17%, S 8.41% 
Literature References: Semi-synthetic cephalosporin antibiotic. Prepn: NL6812382; L. B. Crast, Jr., US3489752 (1969, 1970 both to Bristol-Myers); T. Takahashi et al.,DE2216113; eidem,US3816253 (1972, 1974, both to Takeda). Prepn of crystalline monohydrate: D. Bouzard et al.,US4504657 (1985 to Bristol-Myers). Antimicrobial activity: R. E. Buck, K. E. Price, Antimicrob. Agents Chemother.11, 324 (1977). Pharmacology: M. Pfeffer et al.,ibid. 331; A. I. Hartstein et al.,ibid.12, 93 (1977). Review:J. Antimicrob. Chemother.10, Suppl. B, 1-162 (1982). Series of articles on clinical trials in respiratory tract infections: Drugs32, Suppl. 3, 1-56 (1986).Properties: White crystals, mp 197° (dec). 
Melting point: mp 197° (dec) 
Therap-Cat: Antibacterial. 
Therap-Cat-Vet: Antibacterial. 
Keywords: Antibacterial (Antibiotics); ?Lactams; Cephalosporins.

Cefadroxil is a cephalosporin antibiotic used in the treatment of various bacterial infections, such as urinary tract infections, skin and skin structure infections, and tonsillitis.

Cefadroxil (formerly trademarked as Duricef) is a broad-spectrum antibiotic of the cephalosporin type, effective in Gram-positive and Gram-negative bacterial infections. It is a bactericidal antibiotic.

It was patented in 1967 and approved for medical use in 1978.^[1]

DURICEF (cefadroxil) is a semisynthetic cephalosporin antibiotic intended for oral administration. It is a white to yellowish-white crystalline powder. It is soluble in water and it is acid- stable. It is chemically designated as 5-Thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[[amino(4-hydroxyphenyl)acetyl]amino]-3-methyl-8-oxo-, monohydrate[6R- [6α,7β(R*)]]-. It has the formula C₁₆H₁₇N₃O₅S•H₂0 and the molecular weight of 381.40. It has the following structural formula:

DURICEF (cefadroxil) film-coated tablets, 1 g, contain the following inactive ingredients: microcrystalline cellulose, hydroxypropyl methylcellulose, magnesium stearate, polyethylene glycol, polysorbate 80, simethicone emulsion, and titanium dioxide.

DURICEF (cefadroxil) for Oral Suspension contains the following inactive ingredients: FD&C Yellow No. 6, flavors (natural and artificial), polysorbate 80, sodium benzoate, sucrose, and xanthan gum.

DURICEF (cefadroxil) capsules contain the following inactive ingredients: D&C Red No. 28, FD&C Blue No. 1, FD&C Red No. 40, gelatin, magnesium stearate, and titanium dioxide.

SYN

IR spectrum of pure cefadroxil drug.

Synthesis Reference

Leonardo Marsili, “Substantially anhydrous crystalline cefadroxil and method for producing it.” U.S. Patent US5329001, issued April, 1978.

US5329001

SYN

Antibiotics

R.S. Vardanyan, V.J. Hruby, in Synthesis of Essential Drugs, 2006

Cefadroxil

Cefadroxil, [6R-[6α,7β(R)]]-3-methyl-8-oxo-7-[[amino(4-hydroxyphenyl) acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid (32.1.2.14), is an analog of cephalexin and differs only in the presence of a hydroxyl group in the fourth position of the phenyl ring of phenylglycine, and is synthesized by a scheme analogous to the scheme of cephradin synthesis [90–96].

Cefadroxil has a broad spectrum of antimicrobial action; it is active with respect to Gram-positive and Gram-negative microorganisms. Like all of the other drugs described above, it acts as a bactericide by disrupting the process of restoring the membranes of bacteria. Synonyms of this drug are bidocef, cefadril, duracef, ultracef, and others.SYN

Cefadroxil

• ATC:J01DA09

• MW:363.39 g/mol
• CAS-RN:50370-12-2
• InChI Key:BOEGTKLJZSQCCD-UEKVPHQBSA-N
• InChI:InChI=1S/C16H17N3O5S/c1-7-6-25-15-11(14(22)19(15)12(7)16(23)24)18-13(21)10(17)8-2-4-9(20)5-3-8/h2-5,10-11,15,20H,6,17H2,1H3,(H,18,21)(H,23,24)/t10-,11-,15-/m1/s1
• EINECS:256-555-6
• LD₅₀:>1.5 g/kg (M, i.v.); >10 g/kg (M, p.o.);
  >1 g/kg (R, i.v.); >10 g/kg (R, p.o.);
  >2 g/kg (dog, p.o.)

Synthesis

Substances

PATENT

 Seo, Dae-Won; WO 2005042543

https://patents.google.com/patent/WO2005042543A1/enOral cephalosporin antibiotics, including cefprozil, cefatrizine, and cefadroxii, commonly have a 4-hydroxyphenylglycine group, as represented by the following formula:

The compound of the above formula is cefprozil when A is -C=CH-CH₃, cefatrizine when A is 1 H-1 ,2,3-triazole-4-yl-thiomethyl, and cefadroxii when A is -CH₃. Conventionally, there have been known various processes for preparing oral cephalosporin antibiotics, such as cefprozil, cefatrizine, and cefadroxii, by reacting reactive derivatives of 4-hydroxyphenylglycine with 3-cephem compounds. For example, U.S. Patent No. 3,985,741 discloses a process for preparing a cefadroxii, which includes reacting 4-hydroxyphenylglycine and ethylchloroformate inN-methylmorpholine to obtain an anhydride, followed by reaction with7-amino-deacetoxy-cephalosporanic acid (7-ADCA). However, the yield and quality of the product are poor. U.S. Patent Nos. 4,520,022, 4,591 ,641 , and 4,661 ,590 disclose a condensation reaction between 4-hydroxyphenylglycine with a protected amino group and a cephem compound in the presence of Λ/.Λ/’-dicyclohexylcarbodimide. However,Λ/,Λ/’-dicyclohexylurea produced after the condensation reaction is not easily removed, which restricts industrial applications. U.S. Patent No. 4,336,376 discloses a process for preparing a cefadroxii, which includes reacting a 4-hydroxyphenylglycine salt having a protected amino group with trimethylsilyl-2-oxazolidinone to protect a 4-hydroxyl group followed by reaction with acylchloride to obtain a 4-hydroxyphenylglycine anhydride and then reaction with 7-ADCA. However, silylation is prerequisite and these reactions are annoying, and thus, this process is not suitable for industrial application. U.S. Patent No. 4,708,825 discloses a technique of reacting4-hydroxyphenylglycine having a substituted amino group with thionyl chloride using a gaseous hydrogen chloride to obtain a 4-hydroxyphenylglycyl chloride hydrochloride followed by reaction with a cephem compound. However, handling property of the thionyl chloride and the gaseous hydrogen chloride is poor, and thus, this technique is not suitable for industrial application. U.S. Patent Nos. 3,925,418, 4,243,819, and 4,464,307 disclose a process for producing 4-hydroxyphenylglycine using excess phosgene. However, difficulty in handling of highly toxic phosgene, removal of excess residual phosgene, and control of reaction conditions renders mass production difficult. As a process for preparing a reactive anhydride of 4-hydroxyphenylglycine, there are reported a method for the preparation of acid chloride using phosphorus pentachloride, phosphorus oxychloride, or thionyl chloride, and a method for the preparation of active ester using imidazole, mercaptobenzothiazole, or hydroxybenzotriazole. However, an acid chloride of 4-hydroxyphenylglycine has poor reactivity due to a hydroxyl group and an active ester of 4-hydroxyphenylglycine has poor reactivity and involves a side reaction. In addition, Korean Patent Laid-Open Publication Nos. 2002-69431 , 2002-69432, 2002-69437, and 2002-69440 disclose a process for preparing a pivaloyl or succinimide derivative of 4-hydroxyphenylglycine and a process for preparing a cephem compound such as cefprozil using the pivaloyl or succinimide derivative of 4-hydroxyphenylglycine. Meanwhile, there have been known various preparation processes for 3-(Z)-propenyl cephem derivative which is a compound useful as an intermediate for preparation of cefprozil which is an oral cephalosporin antibiotic. WO93/16084 discloses a process of selectively separating a 3-(Z)-propenyl cephem compound by means of a hydrochloride, metal, or tertiary amine salt of7-amino-3-(1-propen-1-yl)-3-cephem-carboxylic acid or by adsorption chromatography. However, there is a disadvantage in that separation and purification are cost-ineffective. U.K. Patent No. 2,135,305 discloses a process for preparing cefprozil from a4-hydroxyphenylglycine compound with a t-butoxycarbonyl-protected amino group and a cephem compound with a benzhydryl-protected carboxyl group. However, incorporation of a 3-propenyl group after acylation lowers reaction efficiency and high-performance liquid chromatography is required for isomer separation, which render industrial application difficult. U.S. Patent No. 4,727,070 discloses a technique of removing an E-isomer cefprozil from a mixture of 27E cefprozil, which includes incorporating an active group such as sodium imidazolidinone into the mixture of 2VE cefprozil by reaction of the mixture of 27E cefprozil with acetone followed by deprotection. However, purification by chromatography incurs enormous costs. In view of the above problems, Korean Patent Laid-Open Publication No.2002-80838 discloses a process for preparing a 3-(Z)-propenyl cephem compound by reacting a phosphoranylidene cephem compound with acetaldehyde in a mixed solvent essentially consisting of ether in the presence of a base. According to a disclosure in this patent document, ether is essentially used. In this respect, in the case of using methylenechloride or tetrahydrofuran, even when other reaction conditions, for example, reaction temperature, reaction duration, base, catalyst, and the like are adjusted, it is very difficult to adjust the content of the Z-isomer to more than 83%.DETAILED DESCRIPTION OF THE INVENTION Technical Goal of the Invention The present invention provides a process for simply preparing a cephalosporin antibiotic in high yield and purity using a novel reactive intermediate, i.e., a 4-hydroxyphenylglycine derivative. The present invention also provides a novel reactive intermediate, i.e., a 4-hydroxyphenylglycine derivative which is used in simply preparing a cephalosphorin antibiotic in high yield and purity, and a preparation process thereof. While searching for a process for stereospecifically preparing a novel3-(Z)-propenyl cephem derivative, the present inventors found that use of a mixed solvent including methylenechloride, isopropylalcohol, and water in a predetermined ratio can stereospecifically and efficiently produce the 3-(Z)-propenyl cephem derivative, which is in contrary to the disclosure in Korean Patent Laid-Open Publication No. 2002-80838. Therefore, the present invention also provides a process for stereospecifically preparing a 3-(Z)-propenyl cephem derivative using a mixed solvent including methylenechloride, isopropylalcohol, and water in a predetermined ratio.

 Example 9 Preparation of7-r2-amino-2-(4-hvdroxyphenyl)acetamido1-3-methyl-3-cephem-4-carboxylic acid(cefadroxii) The reaction solution obtained in step A of Example 1 was cooled to -40 ^°C and a solution obtained by dissolving 6.21 g (0.029mol) of 7-amino-3-methyl-3-cephem-4-carboxylic acid in 40 ml of methylenechloride, 10 ml of water, and 6.5 g of triethylamine was gradually dropwise added thereto for 1 hour. Then, the reaction mixture was incubated at the same temperature for 2 hours and cooled to 0^°C to obtain an insoluble solid. The insoluble solid was filtered. A filtrate was sent to a reactor and then stirred for 1 hour after addition of 20 ml of 6N HCI. The reaction solution was adjusted to pH of 3.2 by addition of 10% NaOH, stirred at0^°C for 2 hours, and filtered to give 9.1g (83%) of the titled compound as a white solid. H-NMR( δ , D₂0-d₂) : 1.79(3H, d, 8.6Hz, -CH₃), 3.22(1 H, d, 18Hz, 2-H),3.55(1 H. d. 18Hz, 2-H), 5.15(1 H, d, 4.6Hz, 6-H), 5.66(1 H, d, 4.6Hz, 7-H), 6.91 (2H, d,8.0Hz, phenyl-H), 7.38(2H, d, 8.0Hz, phenyl-H)

PAPER

Deshmukh, J. H.; Asian Journal of Chemistry 2010, V22(3), P1760-1768 

Journal of the Chinese Chemical Society (Weinheim, Germany), 66(12), 1649-1657; 2019

Journal of the Indian Chemical Society, 93(6), 593-598; 2016

 Biotechnology Letters, 34(9), 1719-1724; 2012

PATENT

WO 2011113486

By Gupta, Niranjan Lal et alFrom Indian, 184842, 30 Sep 2000

PAPER

European Journal of Organic Chemistry, (10), 1817-1820; 2001

PAPER

 Organic Letters, 2(18), 2829-2831; 2000

The cephalosporin antibiotic Cefadroxil can be epimerized at the α-carbon of its amino acid side chain using pyridoxal as the mediator. By clathration with 2,7-dihydroxynaphthalene, the desired diastereomer can be selectively withdrawn from the equilibrating mixture of epimers. In this way, an asymmetric transformation of Cefadroxil can be accomplished. This opens the possibility of the production of Cefadroxil starting from racemic p-hydroxyphenylglycine, in contrast to the current industrial synthesis that employs the d-amino acid in enantiopure form.

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Medical use

Cefadroxil is a first-generation cephalosporin antibacterial drug that is the para-hydroxy derivative of cephalexin, and is used similarly in the treatment of mild to moderate susceptible infections such as the bacterium Streptococcus pyogenes, causing the disease popularly called strep throat or streptococcal tonsillitis, urinary tract infection, reproductive tract infection, and skin infections.

Cefadroxil is used as an antibiotic prophylaxis before dental procedures, for patients allergic to penicillins.

Spectrum of bacterial resistance and susceptibility

Cefadroxil has a broad spectrum of activity and has been effective in treating bacteria responsible for causing tonsillitis, and infections of the skin and urinary tract. The following represents MIC susceptibility data for a few medically significant microorganisms.^[2]

• Escherichia coli: 8 μg/ml
• Staphylococcus aureus: 1 – 2 μg/ml
• Streptococcus pneumoniae: ≤1 – >16 μg/ml

Side effects

The most common side effects of cefadroxil are diarrhea (which, less commonly, may be bloody), nausea, upset stomach, and vomiting. Other side effects include^[3] rashes, hives, and itching.

Pharmacokinetics

Cefadroxil is almost completely absorbed from the gastrointestinal tract. After doses of 500 mg and 1 g by mouth, peak plasma concentrations of about 16 and 30 micrograms/ml, respectively, are obtained after 1.5 to 2.0 hours. Although peak concentrations are similar to those of cefalexin, plasma concentrations are more sustained. Dosage with food does not appear to affect the absorption of cefadroxil. About 20% of cefadroxil is reported to be bound to plasma proteins. Its plasma half-life is about 1.5 hours and is prolonged in patients with renal impairment.

Cefadroxil is widely distributed to body tissues and fluids. It crosses the placenta and appears in breast milk. More than 90% of a dose of cefadroxil may be excreted unchanged in the urine within 24 hours by glomerular filtration and tubular secretion; peak urinary concentrations of 1.8 mg/ml have been reported after a dose of 500 mg. Cefadroxil is removed by haemodialysis.

Dosage

Cefadroxil is given by mouth, and doses are expressed in terms of the anhydrous substance; 1.04 g of cefadroxil monohydrate is equivalent to about 1 g of anhydrous cefadroxil.

Veterinary use

It can be used for treating infected wounds on animals. Usually in powder form mixed with water, it has a color and smell similar to Tang. Given orally to animals, the amount is dependent on their weight and severity of infection.

References

1. ^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 493. ISBN 9783527607495.
2. ^ “Cefadroxil, Free Acid Susceptibility and Minimum Inhibitory Concentration (MIC) Data” (PDF).
3. ^ “Cefadroxil side effects”. Drugs.

////////////CEFADROXIL, цефадроксил , سيفادروكسيل , 头孢羟氨苄 , BL-S578; MJF-11567-3, BL S578, MJF 11567-3

[H][C@]12SCC(C)=C(N1C(=O)[C@H]2NC(=O)[C@H](N)C1=CC=C(O)C=C1)C(O)=O

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Racecadotril

• Molecular FormulaC₂₁H₂₃NO₄S
• Average mass385.477 Da

(±)-Acetorphan
(RS)-Benzyl N-[3-(acetylthio)-2-benzylpropanoyl]glycinate
2-{[2-[(acetylthio)methyl]-1-oxo-3-phenylpropyl]amino}acetic acid (phenylmethyl) ester7378
76K53XP4TO
81110-73-8[RN]
Benzyl N-[3-(acetylsulfanyl)-2-benzylpropanoyl]glycinate [ACD/IUPAC Name] 
Cadotril
Dexecadotril[INN]
Glycine, N-[3-(acetylthio)-1-oxo-2-(phenylmethyl)propyl]-, phenylmethyl ester
Hidrasec [Trade name] 
рацекадотрил[Russian][INN]
راسيكادوتريل[Arabic][INN]
消旋卡多曲[Chinese][INN]
RacecadotrilCAS Registry Number: 81110-73-8 
CAS Name:N-[2-[(Acetylthio)methyl]-1-oxo-3-phenylpropyl]glycine phenylmethyl ester 
Additional Names:N-[(R,S)-3-acetylthio-2-benzylpropanoyl]glycine benzyl ester; acetorphan 
Trademarks: Hidrasec (GSK); Tiorfan (Bioprojet) 
Molecular Formula: C21H23NO4S, Molecular Weight: 385.48 
Percent Composition: C 65.43%, H 6.01%, N 3.63%, O 16.60%, S 8.32% 
Literature References: Antisecretory enkephalinase inhibitor. Prepn: B. Roques et al.,EP38758 (1981); eidem,US4513009 (1985 to Bioprojet). Pharmacology: J.-M. Lecomte et al.,J. Pharmacol. Exp. Ther.237, 937 (1986). Effect on intestinal transit: J. F. Bergmann et al.,Aliment. Pharmacol. Ther.6, 305 (1992). Clinical trial in acute diarrhea: P. Baumer et al.,Gut33, 753 (1992); in children: E. Salazar-Lindo et al.,N. Engl. J. Med.343, 463 (2000). Symposium on pharmacology and clinical experience: Aliment. Pharmacol. Ther.13, Suppl. 6, 1-32 (1999). Review of clinical development: J.-C. Schwartz, Int. J. Antimicrob. Agents14, 75-79 (2000); J. M. Lecomte, ibid. 81-87. 
Properties: White crystals from ether mp 89°., Melting point: mp 89° 
Derivative Type: (S)-Form 
CAS Registry Number: 112573-73-6 
Additional Names: Ecadotril; sinorphan 
Manufacturers’ Codes: Bay-y-7432 
Molecular Formula: C21H23NO4S, Molecular Weight: 385.48 
Percent Composition: C 65.43%, H 6.01%, N 3.63%, O 16.60%, S 8.32% 
Literature References: Prepn: P. Duhamel et al.,EP318377; eidem,US5208255 (1989, 1993 both to Bioprojet); and pharmacology: B. Giros et al.,J. Pharmacol. Exp. Ther.243, 666 (1987). Clinical effect on plasma ANP levels in CHF: J. C. Kahn et al.,Lancet335, 118 (1990); on renal function: F. Schmitt et al.,Am. J. Physiol.267, F20 (1994). Clinical trial in heart failure: C. M. O’Connor et al.,Am. Heart J.138, 1140 (1999); J. G. F. Cleland, K. Swedberg, Lancet351, 1657 (1998). 
Properties: mp 71°. [a]D25 -24.1° (c = 1.3 in methanol). LD50 i.v. in mice: >100 mg/kg (Duhamel, 1993). 
Melting point: mp 71° 
Optical Rotation: [a]D25 -24.1° (c = 1.3 in methanol) 
Toxicity data: LD50 i.v. in mice: >100 mg/kg (Duhamel, 1993) 
Therap-Cat: Antidiarrheal. 
Keywords: Antidiarrheal; Neutral Endopeptidase Inhibitor.

Racecadotril is an anti-secretory enkephalinase inhibitor useful in the treatment of diarrhea.Racecadotril has been investigated for the basic science and treatment of Diarrhea, Acute Diarrhea, and Acute Gastroenteritis.

Racecadotril, also known as acetorphan, is an antidiarrheal medication which acts as a peripheral enkephalinase inhibitor.^[3] Unlike other opioid medications used to treat diarrhea, which reduce intestinal motility, racecadotril has an antisecretory effect — it reduces the secretion of water and electrolytes into the intestine.^[3] It is available in France (where it was first introduced in ~1990) and other European countries (including Germany, Italy, the United Kingdom, Spain, Portugal, Poland, Finland, Russia and the Czech Republic) as well as most of South America and some South East Asian countries (including China, India and Thailand), but not in the United States. It is sold under the tradename Hidrasec, among others.^[4] Thiorphan is the active metabolite of racecadotril, which exerts the bulk of its inhibitory actions on enkephalinases.^[5]

Medical uses

Racecadotril is used for the treatment of acute diarrhea in children and adults and has better tolerability than loperamide, as it causes less constipation and flatulence.^[6][7] Several guidelines have recommended racecadotril use in addition to oral rehydration treatment in children with acute diarrhea.^[8]

Contraindications

Racecadotril has no contraindications apart from known hypersensitivity to the substance.^[9][10]

There is insufficient data for the therapy of chronic diarrhea, for patients with renal or hepatic failure, and for children under three months. Additional contraindications for the children’s formulation are hereditary fructose intolerance, glucose-galactose malabsorption and saccharase deficiency, as it contains sugar.^[7][9]

Racecadotril (CAS NO.: 81110-73-8), with its systematic name of Glycine, N-(2-((acetylthio)methyl)-1-oxo-3-phenylpropyl)-, phenylmethyl ester, (+-)-, could be produced through many synthetic methods.

Following is one of the synthesis routes: 2-Benzylacrylic acid (I) reacts with SOCl₂ in hot toluene to afford the acyl chloride (II), which is condensed with N-tosylglycine benzyl ester (III) in the presence of TEA in toluene to yield the corresponding amide (IV). Finally, this compound is condensed with thioacetic acid by heating at 80 °C to afford the target acylthio compound.

Racecadotril is a neutral endopeptidase inhibitor used as antidiarrheal in the treatment of chronic cardiac insufficiency and is available under the brand names Hidrasec and Tiorfan. Racecadotril is chemically known as N-[2-[(acetylthio) methyl]- l-oxo-3-phenylpropyl] glycine phenyl methyl ester, (herein after referred by its generic name racecadotril) and represented by the formula (I).

U.S. Patent No. US 4,513,009 describes amino acid derivatives including racecadotril, a pharmaceutical composition and a method of treatment.

The US’009 patent also discloses a process for the preparation of racecadotril which is illustrated by below scheme:

U.S. Patent No. US 6,835,851 B2 discloses a process for the preparation of racecadotril which is illustrated by scheme below:

European Patent No. EP 0501870B 1 discloses a process for the preparation of racec

Racecadotril

The use of coupling agents like hydroxyl benzotriazole (HOBT) and dicyclohexyl amine carbodiimide (DCC) generally induces the formation of side products such as dicyclohexylurea. These side products do lead to major problems, wherein purification by chromatography may be contemplated, but the side products are extremely difficult to remove on an industrial scale.

Consequently, efforts have been made to replace the peptidic coupling step

so as to avoid the formation of side products associated with the use of the coupling agents. Thus, it appears that, even if the preparation of N-(mercaptoacyl)amino acid derivatives from .alpha.-substituted acrylic acids by Michael addition of a thio acid and conversion of acid to acid chloride by using thionyl chloride and then coupling of an amino ester may be advantageous on a laboratory scale, such reactions are difficult to adapt on an industrial use.

The aforementioned processes described above involves expensive reagents such as hydroxyl benzotriazole (HOBT) and dicyclohexyl amine carbodiimide (DCC) and hazardous reagent like thionyl chloride thus rendering the processes expensive and not feasible on industrial scale.

SYNTHESIS BY WORLDDRUGTRACKER

Patent

https://www.google.com/patents/WO2013098826A1?cl=en

EXAMPLES

Example-1: Preparation of Racecadotril (I):

Step A) Preparation of 2-acetyIsulfanyI methyI-3-phenyI propionic acid (IV)

16.2 g of 2-benzylacrylic acid and 12.3 ml of thioacetic acid were were charged into a clean and dry R.B.flask and stirred at about 30°C for about 1 hour. The reaction mixture was heated to about 60°C and stirred for about 4 hours.The excess of thioacetic acid was distilled off completely to afford the title compound as residue. Yield: 23.8 g. Step B) Preparation of Racecadotril crude (la)

23.8 g. of 2-acetyl sulfanylmethyl-3-phenyl-propionic acid (IV), 200ml of methylene chloride and 16.7 ml of triethylamine were charged into a clean and dry R.B.flask. 10. 5 ml of ethylchloroformate was added at about -5°C. The resultant reaction mixture was stirred at about 0°C for about 30 min. 33.7 g of glycine benzyl ester p-tosyalte (II), 14 ml of triethylamine and 100ml of methylene chloride was added as a mixture to the reaction mass at about 0°C. Then the resultant reaction mixture was stirred at about 0°C for about 1 hr. followed by at about 30°C for about 30 min. After completion of the reaction as determined by TLC, the reaction mass was washed with 65 ml of distilled water, 65 ml 4% sodium bicarbonate solution and followed by 65 ml distilled water. The organic and aqueous phases were separated and the solvent was distilled completely, 2 x 50 ml Isopropyl alcohol was charged and again distilled off the solvent completely to give residue. The residue

obtained was triturated with a mixture of isopropyl alcohol 4 ml) and n-hexane (94 ml) at about 5°C to the title compound as crude. Yield: 34 g.

ExampIe-2: Purification of Racecadotril (Crude):

34 g. of crude Racecadotril and 35 ml of 20 % v/v aqueous .methanol were charged in a clean and dry R.B.flask and heated to about 65°C. 3g. of SP.carbon was charged and stirred at about 65°C for about 10 min. The reaction suspension was stirred at about 65°C for about 10 min. The reaction suspension was filtered on hyflow bed (diatomous earth) and washed the hyflow bed with 30 ml of aqueous methanol. The filtrate obtained was cooled to about 0°C for about 30 min. The solid separated was filtered and the solid obtained washed with 60 ml of precooled aqueous methanol to afford the pure racecadotril (I).

Yield: 29 g.; Purity by HPLC: 99.5 area %; The overall yield is 75.3%.

PATENT

https://www.google.com/patents/CN104356036A?cl=en

Example 1

The 40. 0g Racecadotril dissolved in 200ml of absolute ethanol and water bath heated to 40 ° C, and stir until the whole solution, stirring was stopped, the solution was placed in 15 ° C water bath was allowed to stand, when starting When there is precipitation of crystals, and then placed under the 0 ° C crystallization, after filtration, to 45 ° C under hot air drying cycle 6 hours to obtain 29. 2g, purity 99.6% of Racecadotril a polymorph crystals.

  reflection angle X-ray powder diffraction pattern 20 at 4.3 °, 8.7 °, 13.2 °, 16.8 °, 17.8 ° and 20.0 ° at the show X-ray powder diffraction peaks. In 1135. 19CHT1,1551. 46CHT1,1644. 73CHT1,1687. 57CHT1, 1731. 35CHT1 and 3289. 20CHT1 displayed at an infrared absorption peak.

Clips

US 20020055645

PATENT

CN 104356036 A

Racecadotril, chemical name N_ [(R, S) -3- acetyl-mercapto-2-benzyl-propionyl)] glycine benzyl ester, is a neprilysin inhibitor, selectively, reversible inhibition of neprilysin, so that the inner protection from degradation of endogenous enkephalins, prolong the physiological activity of endogenous enkephalins in the digestive tract, mainly used in clinical treatment of children and adults with acute diarrhea. Its structural formula is as follows:

 Racecadotril as enkephalinase inhibitors, developed in France in 1993 Bioprojet listed acute diarrhea treatment, trade name Tiorfan.

In W02011116490A1, US5945548 and CN101768095A and other documents, documented racecadotril the synthesis process, but did not report the crystal form; therefore the present inventors have not reported Racecadotril crystalline polymorph conduct further

Example 1

[0032] The 40. 0g Racecadotril dissolved in 200ml of absolute ethanol and water bath heated to 40 ° C, and stir until the whole solution, stirring was stopped, the solution was placed in 15 ° C water bath was allowed to stand, when starting When there is precipitation of crystals, and then placed under the 0 ° C crystallization, after filtration, to 45 ° C under hot air drying cycle 6 hours to obtain 29. 2g, purity 99.6% of Racecadotril a polymorph crystals.

[0033] reflection angle X-ray powder diffraction pattern 20 at 4.3 °, 8.7 °, 13.2 °, 16.8 °, 17.8 ° and 20.0 ° at the show X-ray powder diffraction peaks. In 1135. 19CHT1,1551. 46CHT1,1644. 73CHT1,1687. 57CHT1, 1731. 35CHT1 and 3289. 20CHT1 displayed at an infrared absorption peak.

SYN

EP 0038758

Alternatively, the condensation of dimethyl malonate (VI) with benzaldehyde (VII) by means of piperidine in refluxing toluene gives dimethyl benzylidenemalonate (VIII), which is reduced with H2 over Pd/C in toluene to yield the corresponding benzyl derivative (IX). The hydrolysis of (IX) with NaOH in water affords the benzylmalonic acid (X). Alternatively, intermediate (X) can also be obtained starting from diethyl malonate (XI), which is condensed with with benzaldehyde (VII) by means of piperidine in refluxing toluene to give diethyl benzylidenemalonate (XII). Reduction of (XII) with H2 over Pd/C in toluene yields the corresponding benzyl derivative (XIII), which is then hydrolized with NaOH in water. The monodecarboxylation of (X) and its condensation with paraformaldehyde and diethylamine in refluxing ethyl acetate provides 2-benzylacrylic acid (XIV), which is condensed with thioacetic acid (V) by heating at 70 C to afford 2-(acetylsulfanylmethyl)-3-phenylpropionic acid (XV). Finally, this compound is condensed with N-tosylglycine benzyl ester (XVI) by means of HOBt, DCC and TEA in THF.

SYN

Reaction of benzaldehyde (I) with dimethyl malonate (II) in refluxing toluene in the presence of piperidine and HOAc provides dimethyl benzylidene malonate (III), which is then hydrogenated over Pd/C to afford dimethyl benzyl malonate (IV). Reduction of (IV) with LiAlH4 in refluxing THF furnishes 2-benzyl-1,3-propanediol (V), which is then subjected to reaction with vinyl acetate (VI) by means of Novozym 435 enzyme to yield diacetate (VII). Enantioselective removal of one acetyl group from (VII) by treatment with Pseudomonas fluorescens Lipase in acetone/phosphate buffer (pH = 7) at 30 C gives 3-acetoxy-2(S)-benzyl-propanol (S)-(VIII), which is then oxidized by means of Jones reagent in acetone/isopropanol to provide carboxylic acid (R)-(IX). The hydrolysis of (IX) with LiOH in THF/H2O gives 2(R)-benzyl-3-hydroxypropanoic acid (R)-(X). Alternatively, intermediate (X) can also be synthesized as follows: Condensation of benzaldehyde (I) with methyl acrylate (XV) by means of diaza-1,4-bicyclo[2.2.2.]octane affords methyl beta-hydroxy-alpha-methylene-benzenepropanoate (XVI), which is then subjected to hydrolysis with KOH in MeOH/H2O to yield carboxylic acid (XVII). Treatment of (XVII) with p-toluenesulfonic acid in refluxing HOAc gives (E)-2-(acetoxymethyl)-3-phenylpropionic acid (XVIII), which is finally converted into (X) by enantioselective hydrogenation in the presence of S-Binap and ruthenium catalyst [CodRu(all)2]. Derivative (R)-(X) is then converted into 3-(acetylsulfanyl)-2(S)-benzylpropionic acid (XI) by means of a Mitsunobu reaction with thioacetic acid, diisopropyl azodicarboxylate (DIAD) and triphenylphosphine (PPh3). Compound (XI) is then subjected to optical purification by formation and isolation of the corresponding salt with (-)-ephedrine and subsequent hydrolysis with HCl to furnish enantiomerically pure (S)-(XII). Finally, carboxylic acid (S)-(XII) is converted into ecadotril by its coupling with benzyl glycinate (XIV), either by means of Et3N, DCC and HOBt in CHCl3, or by first reaction with thionyl chloride to give acid chloride (S)-(XIII) and subsequent coupling with glycinate (XIV) by means of Et3N in CH2Cl2.

SYN

The reaction of 2-benzylacrylic acid (I) with SOCl2 in hot toluene gives the acyl chloride (II), which is condensed with N-tosylglycine benzyl ester (III) by means of TEA in toluene to yield the corresponding amide (IV). Finally, this compound is condensed with thioacetic acid by heating at 80 C to afford the target acylthio compound.

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Side effects

The most common adverse effect is headache, which occurs in 1–2% of patients.^[7] Rashes occur in fewer than 1% of patients. Other described skin reactions include itching, urticaria, angioedema, erythema multiforme, and erythema nodosum.^[9][10]

Overdose

No cases of overdose are known. Adults have tolerated 20-fold therapeutic doses without ill effects.^[10]

Interactions

No interactions in humans have been described. Combining racecadotril with an ACE inhibitor can theoretically increase the risk for angioedema.^[9][10]

Racecadotril and its main metabolites neither inhibit nor induce the liver enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. They also do not induce UGT enzymes.^[10] This means that racecadotril has a low potential for pharmacokinetic interactions.

Pharmacology

Mechanism of action

Enkephalins are peptides produced by the body that act on opioid receptors with preference for the δ subtype.^[11] Activation of δ receptors inhibits the enzyme adenylyl cyclase, decreasing intracellular levels of the messenger molecule cAMP.^[7]

The active metabolite of racecadotril, thiorphan, inhibits enkephalinase enzymes in the intestinal epithelium with an IC₅₀ of 6.1 nM, protecting enkephalins from being broken down by these enzymes. (Racecadotril itself is much less potent at 4500 nM.)^[7][8] This reduces diarrhea related hypersecretion in the small intestine without influencing basal secretion. Racecadotril also has no influence on the time substances, bacteria or virus particles stay in the intestine.^[10]

Pharmacokinetics

Some metabolites of racecadotril.
top left: precursor to the active metabolite
top right: active metabolite
bottom row: inactive metabolites

Racecadotril is rapidly absorbed after oral administration and reaches C_max within 60 minutes. Food delays C_max by 60 to 90 minutes but does not affect the overall bioavailability. Racecadotril is rapidly and effectively metabolized to the moderately active S-acetylthiorphan the main active metabolite thiorphan, of which 90% are bound to blood plasma proteins. In therapeutic doses, racecadotril does not pass the blood–brain barrier. Inhibition of enkephalinases starts 30 minutes after administration, reaches its maximum (75–90% inhibition with a therapeutic dose) two hours after administration, and lasts for eight hours. The elimination half-life, measured from enkephalinase inhibition, is three hours.^[7][8][9]

Thiorphan is further metabolized to inactive metabolites such as the methyl thioether and the methyl sulfoxide. Both active and inactive metabolites are excreted, mostly via the kidney (81.4%), and to a lesser extent via the feces (8%).^[10]

Society and culture

Brand names

In both France and Portugal it is sold as Tiorfan and in Italy as Tiorfix. In India it is available as Redotril and Enuff.^[4]

See also

• Ecadotril, the (S)-enantiomer of racecadotril
• D/DL-Phenylalanine
• RB-101

References

1. ^ https://www.ema.europa.eu/documents/psusa/racecadotril-list-nationally-authorised-medicinal-products-psusa/00002602/202003_en.pdf
2. ^ Jump up to:^a b c d “SPC-DOC_PL 39418-0003.PDF” (PDF). Medicines and Healthcare Products Regulatory Agency. Bioprojet Europe Ltd. 26 December 2012. Retrieved 7 May 2014.
3. ^ Jump up to:^a b Matheson AJ, Noble S (April 2000). “Racecadotril”. Drugs. 59 (4): 829–35, discussion 836–7. doi:10.2165/00003495-200059040-00010. PMID 10804038.
4. ^ Jump up to:^a b Brayfield, A, ed. (13 December 2013). “Racecadotril”. Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. Retrieved 6 May 2014.
5. ^ Spillantini MG, Geppetti P, Fanciullacci M, Michelacci S, Lecomte JM, Sicuteri F (June 1986). “In vivo ‘enkephalinase’ inhibition by acetorphan in human plasma and CSF”. European Journal of Pharmacology. 125 (1): 147–50. doi:10.1016/0014-2999(86)90094-4. PMID 3015640.
6. ^ Fischbach, Wolfgang; Andresen, Viola; Eberlin, Marion; Mueck, Tobias; Layer, Peter (2016). “A Comprehensive Comparison of the Efficacy and Tolerability of Racecadotril with Other Treatments of Acute Diarrhea in Adults”. Frontiers in Medicine. 3: 44. doi:10.3389/fmed.2016.00044. ISSN 2296-858X. PMC 5064048. PMID 27790616.
7. ^ Jump up to:^{a b c d e f} Dinnendahl, V; Fricke, U, eds. (1982). Arzneistoff-Profile (in German). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3.
8. ^ Jump up to:^a b c Eberlin, Marion; Mück, Thomas; Michel, Martin C. (2012). “A Comprehensive Review of the Pharmacodynamics, Pharmacokinetics, and Clinical Effects of the Neutral Endopeptidase Inhibitor Racecadotril”. Frontiers in Pharmacology. 3: 93. doi:10.3389/fphar.2012.00093. ISSN 1663-9812. PMC 3362754. PMID 22661949.
9. ^ Jump up to:^{a b c d e} Mediq.ch: racecadotril. Accessed 2019-12-30.
10. ^ Jump up to:^{a b c d e f g} Haberfeld, H, ed. (2019). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Hidrasec 100 mg-Hartkapseln.
11. ^ Cumming, P (2019). “A Survey of Molecular Imaging of Opioid Receptors”. Molecules. 24 (22): 4190. doi:10.3390/molecules24224190. PMC 6891617. PMID 31752279.

External links

• “Racecadotril”. Drug Information Portal. U.S. National Library of Medicine.

///////////Racecadotril, рацекадотрил , راسيكادوتريل , 消旋卡多曲 , Antidiarrheal, Neutral Endopeptidase Inhibitor, Cadotril, Dexecadotril , 

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Dipyridamole

• Molecular FormulaC₂₄H₄₀N₈O₄
• Average mass504.626 Da

2,2′,2”,2”’-{[4,8-Di(piperidin-1-yl)pyrimido[5,4-d]pyrimidine-2,6-diyl]dinitrilo}tetraethanol
200-374-7[EINECS]
58-32-2[RN]
Ethanol, 2,2′,2”,2”’-[(4,8-di-1-piperidinylpyrimido[5,4-d]pyrimidine-2,6-diyl)dinitrilo]tetrakis-
дипиридамол [Russian] [INN]
ديبيريدامول [Arabic] [INN]
双嘧达莫 [Chinese] [INN]
0068373 [Beilstein]
DipyridamoleCAS Registry Number: 58-32-2 
CAS Name: 2,2¢,2¢¢,2¢¢¢-[(4,8-Di-1-piperidinylpyrimido[5,4-d]pyrimidine-2,6-diyl)dinitrilo]tetrakisethanol 
Additional Names: 2,6-bis(diethanolamino)-4,8-dipiperidinopyrimido-[5,4-d]pyrimidine 
Manufacturers’ Codes: NSC-515776; RA-8 
Trademarks: Anginal (Yamanouchi); Cardoxin (RAFA); Cleridium (Marcofina); Coridil (Delalande); Coronarine (NEGMA); Curantyl (Berlin-Chemie); Dipyridan (Hokuriku); Gulliostin (Taiyo); Natyl (Interdelta); Peridamol (Boehringer, Ing.); Persantine (Boehringer, Ing.); Piroan (Towa Yakuhin); Prandiol (Bottu); Protangix (Lefrancq) 
Molecular Formula: C24H40N8O4 
Molecular Weight: 504.63 
Percent Composition: C 57.12%, H 7.99%, N 22.21%, O 12.68% 
Literature References: Phosphodiesterase inhibitor that reduces platelet aggregation; also acts as a coronary vasodilator. Prepn: GB807826; F. G. Fischer, et al.,US3031450 (1959, 1962 both to Thomae). Activity studies: Saraf, Seth, Indian J. Physiol. Pharmacol.15, 135 (1971). Toxicological study: F. Takenaka et al.,Arzneim.-Forsch.22, 892 (1972). Symposium on pharmacology and clinical experience as antithrombotic: Thromb. Res.60, Suppl. 12, 1-99 (1990). Review of use as pharmacological stress agent in echocardiography: M. B. Buchalter et al.,Postgrad. Med. J.66, 531-535 (1990); in 201Tl cardiac imaging: S. G. Beer et al.,Am. J. Cardiol.67, Suppl., 18D-26D (1991). 
Properties: Deep yellow needles from ethyl acetate, mp 163°. Bitter taste. Slightly sol in H2O; sol in dil acid having a pH of 3.3 or below; very sol in methanol, ethanol, chloroform; not too sol in acetone, benzene, ethyl acetate. Solns are yellow and show strong blue-green fluorescence. LD50 in rats: 8.4 g/kg orally; 208 mg/kg i.v. (Takenaka).Melting point: mp 163° 
Toxicity data: LD50 in rats: 8.4 g/kg orally; 208 mg/kg i.v. (Takenaka) 
Derivative Type: Combination with aspirin 
Trademarks: Aggrenox (Boehringer, Ing.) 
Literature References: Review of pharmacology and clinical efficacy in secondary prevention of stroke: P. S. Hervey, K. L. Goa, Drugs58, 469-475 (1999). 
Therap-Cat: Antithrombotic; diagnostic aid (cardiac stress testing). 
Keywords: Antithrombotic; Diagnostic Aid; Phosphodiesterase Inhibitor.

Dipyridamole (trademarked as Persantine and others) is a nucleoside transport inhibitor and a PDE3 inhibitor medication that inhibits blood clot formation^[3] when given chronically and causes blood vessel dilation when given at high doses over a short time.

PATENT

https://patents.google.com/patent/WO2011151640A1/enDipyridamole, represented by structural formula (I), possesses platelet aggregation inhibiting, anti-thrombotic and vasodilator properties and it is marketed as an anti-platelet therapy for the treatment and prevention of disorders such as thrombo-embolisms.

A process for the preparation of dipyridamole, disclosed in patent US 3031450, involves the reaction of 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine with diethanolamine (see Scheme 1). The preparation of 2,6-dichloro-4,8-dipiperidino- pyrimido(5,4-d)pyrimidine is also reported in US 3031450 and is incorporated herein by reference. The reaction to prepare dipyridamole does not employ an additional reaction solvent and is a neat mixture of the two reactants carried out at a very high temperature of 190 to 195°C. The process also involves a cumbersome work-up to isolate dipyridamole, since the crude product obtained is a pasty mass which needs decantation of the mother liquor and further purification. This decantation process is not practical on commercial scale.

2,6-dichloro-4,8-dipiperidino- dipyridamole (Ί) pyflmido(5,4-d)pyrimidineScheme 1A similar process for the production of dipyridamole is described in patent DD 117456 wherein the reaction conditions exemplified are heating 2,6-dichloro-4,8-dipiperidino- pyrimido(5,4-d)pyrimidine and diethanolamine at 155 to 160°C under vacuum. However, this process again requires a high temperature which leads to the formation of impurities.A process for the preparation and purification of dipyridamole is disclosed in patent DE 1812918, wherein 2,6-dicMoro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine and diethanolamine are heated to 150 to 200°C. After completion of the reaction, the reaction mixture is dissolved in chloroform, which is further separated into an upper layer of diethanolamine and its hydrochloride and a chloroform solution. The chloroform solution obtained is separated and reduced to dryness after stirring with water. This process also requires a high temperature which can lead to the formation of impurities. In addition, the solvent used for the isolation of dipyridamole, chloroform, is inconvenient as it is a restricted solvent and its permitted limit in the final marketed dipyridamole is very low.A similar process, wherein dipyridamole is manufactured by the reaction of diethanolamine with 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine is disclosed in patent RO 104718. However, this process again requires high temperatures of 180 to 200°C which leads to the formation of impurities and, consequently, the yield of the final product is very low (58%) with a purity of less than 98%.A process is disclosed in patent DD 115670, wherein the purification of dipyridamole involves refluxing it in butyl acetate, AcOBu, for 2 hours in the presence of an equal amount of silica gel or column chromatography on silica gel at 60-100°C. However, purification by column chromatography is not economical and not feasible on industrial scale. Moreover, this purification process only removes one specific impurity, 2,4,6-tris- (diethanolamino) – 8 -pip eridino-pyrimido (5,4-d)pyrimidine .The processes described above to prepare dipyridamole do not employ an additional reaction solvent but involve neat mixtures of the two reactants, 2,6-dichloro-4,8- dipiperidino-pyrimido(5,4-d)pyrimidine and diethanolamine, which are heated at very high temperatures. The use of neat reaction mixtures and/ or high temperatures means that it is very difficult to control the levels of impurities formed.Another process for the preparation of dipyridamole, disclosed in patent application WO 2007/080463, involves reacting diethanolamine with 2,6-dichloro-4,8-dipiperidino- pyrimido(5,4-d)pyrimidine in a solvent selected from the group consisting of l-methyl-2- pyrrolidinone, sulpholane and polyethylene glycol. However, the exemplified reaction temperatures are very high at 190 to 200°C and the HPLC purity of the crude dipyridamole is reported to be only 90-94%. A purification method is disclosed using first a ketonic solvent and then an alcohol and water. Even though the process disclosed in this patent application uses a solvent in the reaction, the temperature of reaction is still very high and the purification in ketonic solvent is reported at high temperature (100 to 120°C). The HPLC purity after purification is reported as only 99.0-99.5%.As discussed above, all the processes disclosed in the prior art for the preparation of dipyridamole suffer from serious disadvantages with respect to commercial production. The prior art synthetic and purification processes employ high temperatures in the preparation of dipyridamole which leads to inefficiency and high processing costs. The high temperatures also lead to higher levels of impurities being formed during manufacture with the consequence that further cumbersome and expensive purification procedures are required.The high quality dipyridamole prepared by the processes according to the present invention can be used for the preparation of a pharmaceutical composition to use in the manufacture of a medicament for anti-platelet therapy. A preferred embodiment of the present invention, illustrated in Scheme 2, provides a process for the preparation of dipyridamole comprising reacting 2,6-dichloro-4,8- dipiperidino-pyrimido(5,4-d)pyrimidine with diethanolamine at 113-115°C. This reaction temperature is significantly lower than that used in the prior art processes to prepare dipyridamole.

Another preferred embodiment of the present invention, illustrated in Scheme 3, also provides a process for the preparation of dipyridamole by the reaction of 2,6-dichloro-4,8- dipiperidino-pyrimido(5,4-d)pyrimidine with diethanolamine in dimethylsulfoxide at 120- 125°C to afford the mono-substituted intermediate, 2-chloro-6-diethanolamino-4,8- dipiperidino-pyrimido(5,4-d)pyrimidine, which is isolated and then further converted to dipyridamole by heating in diethanolamine at 113-115°C.Although the solvent used in this preferred embodiment of the present invention is preferably dimethylsulfoxide (DMSO), other solvents can alternatively be used. Preferred alternative solvents are other polar aprotic solvents, such as dimethylformamide (DMF), dimethylacetamide (DMA) or N-methyl-2-pyrrolidinone (NMP). Alternatively, hydrocarbon solvents can be used. Preferred hydrocarbon solvents are aromatic hydrocarbon solvents such as toluene or xylene.

Example 1Preparation of crude dipyridamoleDiethanolamine (10 vol) and 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine (1 eq) were mixed at 25-30°C, stirred for 10 minutes and then heated at 113-115°C for 45-48 hours. After completion of the reaction, the mixture was cooled to 75-80°C. Ethanol (5 vol) was added at 75-80°C and the mixture was stirred at 75-80°C for 10 minutes. Toluene (10 vol) was added at 70-75°C and the mixture was stirred at 70-75°C for 15 minutes. Purified water (15 vol) was added at 70-75°C and the mixture was stirred at 60-65°C for 30 minutes. The mixture was then cooled and stirred at 25-30°C for 30 minutes. The precipitated solid was filtered and washed with purified water (2 x 5 vol) before drying at 75-80°C under reduced pressure afforded crude dipyridamole as a yellow crystalline solid. Yield (w/w) = 80-85%Yield (molar) = 58-62%HPLC purity > 98%Example 2Stage 1: Preparation of 2-chloro-6-diemanolamino-4,8-dipiperidino-pyrimido(5,4-d) pyrimidineDiethanolamine (3 eq) and 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine (1 eq) were added to dimefhylsulfoxide (10 vol) at 25-30°C, stirred for 10 minutes and then heated at 120-125°C for 4-5 hours. After completion of the reaction, the reaction mixture was cooled to 55-60°C. Acetone (5 vol) was added at 55-60°C and the mixture was stirred at 55-60°C for 10 minutes. Purified water (15 vol) was added at 55-60°C and the mixture was stirred at 50-55°C for 15 minutes. The mixture was cooled to 25-30°C and stirred at 25-30°C for 30 minutes. The precipitated solid was filtered, washed with purified water (2 x 5 vol) and dried at 75-80°C under reduced pressure to afford crude 2-chloro-6- diethanolamino-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine as a yellow crystalline solid. Yield (w/w) = 110-120%Yield (molar) = 93-100%HPLC purity > 96%Stage 2: Preparation of crude dipyridamoleDiethanolamine (10 vol) and 2-chloro-6-diemanolamino-4,8-dipiperidino-pyrimido(5,4-d) pyrimidine (1 eq) were mixed at 25-30°C, stirred for 10 minutes and then heated at 113- 115°C for 45-48 hours. After completion of the reaction, the mixture was cooled to 75- 80°C. Ethanol (5 vol) was added and the mixture was stirred at 75-80°C for 10 minutes. Toluene (10 vol) was added and the mixture was stirred at 70-75°C for 15 minutes. Purified water (15 vol) was added and the mixture was stirred at 60-65°C for 30 minutes. The mixture was then cooled to 25-30°C and stirred for 30 minutes. The precipitated solid was filtered, washed with purified water (2 x 5 vol) and dried at 75-80°C under reduced pressure to afford crude dipyridamole as a yellow crystalline solid.Yield (w/w) = 95-97%Yield (molar) = 82-84%HPLC purity > 98%Example 3Crystallization of crude dipyridamoleCrude dipyridamole (1 eq) and diefhanolamine (8 vol) were stirred together at 25-30°C for 10 minutes and then heated to about 80°C for 10 minutes. The clear solution was cooled to 75-80°C, ethanol (5 vol) was added and the mixture was stirred at 75-80°C for 10 minutes. Toluene (10 vol) was added and the mixture was stirred at 70-75°C for 15 minutes. The mixture was cooled to 25-30°C, stirred at 25-30°C for 10 minutes and filtered. The filtrate was heated to 70-75°C for 10 minutes, purified water (15 vol) was added and the mixture was stirred at 60-65°C for 30 minutes before cooling to 25-30°C with stirring for 30 minutes. The precipitated solid was filtered, washed with purified water (2 x 5 vol) and dried at 75-80°C under reduced pressure to afford dipyridamole as a yellow crystalline solid.Yield (w/w and molar) = 90-95%HPLC purity > 99.9% 
PATENT 
https://patents.google.com/patent/WO2007080463A1/enDipyridamole which is chemically known as 4,8-Bis(piperidino)-N,N,N’,N’- tetra(2-hydroxyethyl)pyrimido[5,4-d]pyrimidine-2,6-diamine is a platelet adhesion inhibitor. It is useful in anti-platelet therapy and it is marketed as Persantin ^® by Boehringer Ingelheim.The platelet aggregation inhibiting properties, anti-thrombotic and vasodilator properties of Dipyridamole is reported in US patent 3031450 which also describe a process for its preparation by reacting 2-chloro-6-diethanolamino-4, 8-dipiperidyl- pyrimido-pyrimidine with diethanolamine.German patent 117456 describes the process for the production of Dipyridamole from 2,6-dichloro-4,8-dipiperidinopyrimido[5,4-d]pyrimidine and diethanolamine at 130 to 200° C under vacuum. German patent 1812918 describes the process for the preparation and purification of Dipyridamole. According to this patent 2,6-dichloro-4,8,- dipiperidinopyrimido[5,4-d]pyrimidine and diethanolamine are heated to 150 to 200⁰C to obtain Dipyridamole. This is characterized by the fact that after the completion of the reaction, the reaction mixture is dissolved in chloroform, which is further separated into the upper layer of diethanolamine and its hydrochloride and the chloroform solution. Thus obtained chloroform solution is reduced to dryness after stirring with water.RO 104718 Bl describes a process where Dipyridamole is manufactured and purified by reaction of diethanolamine with 2,6-dichloro-4,8-dipiperidinopyrimido[5,4- d]pyrimidine. In this process the yield is very low (58%) and purity is only 98%.Another patent DDl 15670 Z describes a process for the purification of Dipyridamole by refluxing it in AcOBu for 2 h in the presence of an equal amount of silica gel or by column chromatography on silica gel at 60-100⁰C. The purification by column chromatography is not economical and feasible at industrial scale.All the above mentioned prior art are neat reaction in which it is difficult to control the impurity and is not easy to scale up. In the prior art process the obtained product is pasty which needs decanting the mother liquor and further purification.We focused our research to develop an improved and efficient process for the preparation and purification of Dipyridamole of formula (I) which will overcome the above mentioned prior art problems and will produce Dipyridamole in substantially good yield, high purity and with no mixture of solvents.Objectives of the InventionThe main objective of the present invention is to provide an improved process for the preparation and purification of compound of formula (I), which gives better purity and high yield of the product. Another objective of the present invention is to provide a process for the preparation and purification of compound of formula (I), which would be easy to scale up and implement at industrial level.Yet another objective of the present invention is to provide a process for the preparation and purification of compound of formula (I), which avoids, use of hazardous gas (SO₂) and corrosive chemicals like HCl, H₂SO₄, acetic acid, NaOH, NH₃ etc.Summary of the InventionAccordingly, the present invention provides a process for the preparation ofDipyridamole of formula (I) comprising reacting 2,6-Dichloro-4,8- dipiperidinopyrimido- (5,4-d)pyrimidine (DDH) of formula (II) with Diethanolamine (DEA) of formula (III) using a solvent. This process can be represented by the scheme given below:

(II) (III) (I)The obtained wet or optionally dried crude Dipyridamole is purified by using ketonic solvent and aqueous alcoholic solvent or mixture thereof.Description of the InventionIn an embodiment of the present invention the solvent is selected from the group consisting of l-Methyl-2-pyrrolidinone, Sulpholane and Polyethylene glycol, preferably l-Methyl-2-pyrrolidinone (NMP). In another embodiment of the present invention, the polyethylene glycol used is PEG-20Q or PEG-400, preferably PEG-400.In yet another embodiment of the present invention, the reaction is carried out at a temperature of about 25° C to reflux temperature, preferably at a temperature of about 150° C to 200⁰C.In still another embodiment of the present invention the starting material of this invention is prepared according to the literature available in the prior art.In yet another embodiment the ketonic solvent is acetone, methyl ethyl ketone, methyl vinyl ketone or methyl isobutyl ketone (MIBK), preferably MIBK.In yet another embodiment the alcoholic solvent is selected from the group having Ci to C₄ alkanol preferably isopropyl alcohol (IPA) or methanol.The present invention is illustrated with the following examples, which should not be construed for limiting the scope of the invention.Example 1Preparation of Dipyridamole (Crude)250 mL of l-Methyl-2-pyrrolidinone (NMP), 50g of 2,6-Dichloro-4,8 dipiperidinopyrimido(5,4-d)pyrimidine (DDH) and 136g of Diethanolamine (DEA) were charged into a 2.0 L four-necked RBF at 25-35 ⁰C. The reaction mass was heated to 190 – 200⁰C and maintained for 1.5 to 2.5 hrs under stirring. The reaction mass was cooled to 25-35⁰C and 450 mL of purified water was charged slowly into it and stirred for lhr. The solid reaction mass was filtered and washed with 500ml-purified water and dried the solid under vacuum at 50-55⁰C for 8 to 10 hrs to get 55-60 g of crude Dipyridamole of 90-94% HPLC purity.Purification Of DipyridamoleMethyl isobutyl ketone (750 ml) and 50 g of Dipyridamole (crude) were charged into a clean 2.0 L four-necked RBF at 25-3O⁰C and heated to 100-120⁰C. It was stirred to dissolve and cooled to 25-35⁰C and stirred for 30-60 min. The solid was Filtered and washed with 100 ml MIBK. The product was dried at 45-50 ⁰C under vacuum. The obtained material was further purified as follows:Isopropyl alcohol (200 mL) and 40-45 g of Dipyridamole were charged into a clean 1.0 lit four-necked RBF at 25-35⁰C. It was heated to 60-65⁰C. Carbon (Ig) was added at 30-35⁰C and filtered through celite and washed with 50 mL IPA. Water (500 mL) was charged slowly and stirred for 30 min. The solid was filtered and washed with a mixture of IPA : Water (1 :2) and dried the product at 45-50 ⁰C under vacuum to obtain 43-5Og of Dipyridamole having HPLC purity 99.0 – 99.5%Example 2Sulpholane (15 mL), 5.0g of 2,6-Dichloro-4,8-dipiperidinopyrimido(5,4-d) pyrimidine (DDH) and 8.6g Diethanolamine (DEA) were charged into 100 mL four- necked RBF at 25-35°C. It was heated to 190-200⁰C and stirred for 2-3 hrs. The reaction mass was cooled to 25-35°C and 45 mL of water was added into it. The reaction mass was stirred. The solid was filtered and washed with water. The solid was purified with MIBK,IPA-Water as given in example 1.Example 3Polyethylene glycol-400 (15 mL), 5g of 2,6-Dichloro-4,8-dipiperidinopyrimido (5,4-d) pyrimidine (DDH) and 8.6 gm Diethanolamine (DEA) were charged into 10OmL four necked RBF at 25-35°C. The reaction mass was heated to 190-200⁰C and maintained for 2-3 hrs. The mixture was cooled to 25-35⁰C. Water (45 mL) was added to the reaction mixture and stirred. The solid was filtered and washed with water. The solid was purified with MIBK,IPA- Water as given in example 1.Example 4 (Azeotrophic removal of water in MIBK purification)Preparation of Dipyridamole (Crude^*) l-Methyl-2-pyrrolidinone (150 mL), 50g of 2,6-Dichloro-4,8-dipiperidinopyrimido(5,4-d)pyrimidine (DDH) and 136g Diethanolamine (DEA) was charged into a 2.0 L four-necked RBF at 25-35 ⁰C. The reaction mass was stirred & heated to 190 – 200⁰C and stirring was continued for 1.5 to 2.5 hrs. The reaction mass was cooled to 25-35⁰C and 450 mL of purified water was charged slowly into it and stirred for lhr. The solid reaction mass was filtered and washed with 500ml-purified water to obtain 110-13Og of wet crude Dipyridamole.Purification Of DipyridamoleMethyl isobutyl ketone (750 ml) and 65 g of Dipyridamole (wet crude) were charged into a clean 2.0 L four-necked RBF at 25-3O⁰C and heated to 100-120⁰C followed by azeotrophic separation of water. It was cooled to 25-35⁰C and stirred for30-60 min. The solid was filtered and washed with 100 ml MIBK. The product was dried at 45-50 ⁰C under vacuum. The obtained material was further purified as follows:Isopropyl alcohol (200 mL) and 45-48 g of Dipyridamole were charged into a clean 1.0 L four-necked RBF at 25-35⁰C. It was heated to 60-65⁰C and stirred to dissolve. Carbon (Ig) was added at 30-35⁰C and filtered through celite and washed with 50 mL IPA. Water (500 mL) was charged slowly and stirred for 30 min. The solid was filtered and washed with a mixture of IPA : Water (1:2) and dried the product at 45-50 ⁰C under vacuum to obtain 43-5Og of Dipyridamole having HPLC purity 99.0-99.5%Purification with Methaanol-waterMethanol (200 mL) and 45-48 g of Dipyridamole were charged into a clean 1.0 L four-necked RBF at 25-35⁰C. It was heated to 60-65⁰C and stirred to dissolve. Carbon (Ig) was added at 30-35⁰C and filtered through celite and washed with 50 mL methanol. Water (500 mL) was charged slowly and stirred for 30 min. The solid was filtered and washed with a mixture of methanol : Water (1 :2) and dried the product at 45-50 ⁰C under vacuum to obtain 45g of Dipyridamole having HPLC purity 99%. 
PATENThttps://patents.google.com/patent/CN108069972A/enEmbodiment 1Weigh urea 120g（2mol）, ethylene glycol 62g（1mol）120 DEG C are heated in a kettle, in Catalyzed by p-Toluenesulfonic Acid Effect is lower to carry out step（1）Reaction, generate compound 3；Then 2,3- diamino succinic acid 37g is weighed（0.25mol）With step The compound 3 generated in rapid 1 carries out the reaction generation compound 5 of step 2,220 DEG C, reaction time 3h of reaction temperature, catalyst For the nickel-base catalyst of support type, catalyst is filtered out after the completion of reaction；Exist in phosphorus oxychloride, phosphorus trichloride and lead to chlorine In the case of, compound 5 carries out chlorination reaction generation compound 6,110 DEG C of reaction temperature, reaction time 30h；Weigh piperidines 85g （1mol）Step is carried out with compound（4）Reaction, after reaction liquid hydrolysis, cooling filtering, be dried to obtain compound 9；Claim Take 105g（1mol）Diethanol amine and compound 9 carry out step（6）Reaction, 220 DEG C of reaction temperature, reaction time 3h fills 1.5 MPa of Hydrogen Vapor Pressure, catalyst are the crude product of the nickel-base catalyst, after reaction cold filtration of support type, and crude product passes through It is refining to obtain Dipyridamole finished product, quality 62.10g, purity 99.21%, product yield 48.74%（Yield is with 2,3- diamino fourths Diacid is calculating benchmark）.Embodiment 2Weigh urea 120g（2mol）, ethylene glycol 62g（1mol）120 DEG C are heated in a kettle, in Catalyzed by p-Toluenesulfonic Acid Effect is lower to carry out step（1）Reaction, generate compound 3；Then 2,3- diamino succinic acid 30g is weighed（0.2mol）With step The compound 3 generated in rapid 1 carries out the reaction generation compound 5 of step 2,220 DEG C, reaction time 3h of reaction temperature, catalyst For the nickel-base catalyst of support type, catalyst is filtered out after the completion of reaction；Exist in phosphorus oxychloride, phosphorus trichloride and lead to chlorine In the case of, compound 5 carries out chlorination reaction generation compound 6,110 DEG C of reaction temperature, reaction time 30h；Weigh piperidines 85g （1mol）Step is carried out with compound（4）Reaction, after reaction liquid hydrolysis, cooling filtering, be dried to obtain compound 9；Claim Take 105g（1mol）Diethanol amine and compound 9 carry out step（6）Reaction, 220 DEG C of reaction temperature, reaction time 3h fills 1.5 MPa of Hydrogen Vapor Pressure, catalyst are the crude product of the nickel-base catalyst, after reaction cold filtration of support type, and crude product passes through It is refining to obtain Dipyridamole finished product, quality 50.34g, purity 99.3%, product yield 49.53%（Yield is with 2,3- diamino fourth two Acid is calculating benchmark）.Embodiment 3Other steps are the same as embodiment 2, step（6）In reaction temperature for 240 DEG C, product yield 50.31%.Comparative example 1Weigh urea 36g（0.6mol）, ethyl acetoacetate 26g（0.2mol）, add in ethanol-hydrogen chloride liquid（30% hydrochloric acid：95% second Alcohol=1:4）Then 200ml, drying and dehydrating after stirring add in sodium hydroxide solution and are warming up to 95 DEG C, then cool to 75 DEG C, add Hydrochloric acid adjusts PH=1, cold filtration, the 6- methyluracils of washing filtering；Nitric acid is added in reaction pot, is cooled to less than 10 DEG C, Stirring adds in 6- methyluracils, be warming up to 30 DEG C of heat preservations 1 it is small when the nitro whey liquid that filters；Take a policy powder in water, stirring After dissolving plus nitro whey liquid, temperature control keep the temperature 30min at 35 DEG C, add the static 3h of hydrochloric acid, stir 2h, filtration drying obtains amino breast Clear liquid；Again weigh urea 36g and add in reaction kettle with amino whey liquid, stirring is warming up to 100 DEG C of heat preservation 20min, cools to 90 DEG C add in 2mol/L sodium hydroxide solution, be warming up to 100 DEG C heat preservation dissolving 1h.Cool to 40 DEG C, filter tetrahydroxy pyrimidine- [4,5d] and pyrimidine sodium salt, adds water, 60 DEG C of heat preservation 30min add hydrochloric acid to adjust PH=4, is cooled to 15 DEG C of filterings, washing, dries 2,4,6,8- tetrahydroxys pyrimidine-[4,5d] and pyrimidine；Tetrahydroxy object, phosphorus oxychloride, phosphorus trichloride are added in reaction kettle, is stirred, 10 DEG C of similarly hereinafter chlorine are warming up to 110 DEG C of reflux for 24 hours, be cooled to 15 DEG C of filterings, washing, dry 2,4,6,8- tetrachloro-pyrimidines- [4,5d] and pyrimidine；Acetone, tetrachloride are sequentially added, piperidines-acetone mixture, 30 DEG C of heat preservations are added dropwise in 20 DEG C of heat preservation 30min 1h, adds water to stir 1h, and filtration drying obtains 2,6- bis- chloro- 4,8 ,-two piperidines-pyrimidine（Dichloride）；Weigh diethanol amine 63g with Dichloride is mixed, and is warming up to 200 DEG C of heat preservation 15min, is cooled to less than 25 DEG C plus acetone and stirs 30min, then 30 DEG C 4h is kept the temperature, filtration drying obtains Dipyridamole crude product, then carries out refined Dipyridamole finished product 13.53, purity 98.5%, yield 13.21%（Using ethyl acetoacetate as calculating standard）.It is found by being compared with comparative example：The method of the production Dipyridamole of the present invention is short with synthetic route, into The characteristics of product high income, production cost is low. 

SYN

GB 807826 U.S. Patent 3,031,450

SYN

SYN

R.S. Vardanyan, V.J. Hruby, in Synthesis of Essential Drugs, 2006

Dipyridamole

Dipyridamole, 2,2′,2″,2′″-[(4,8-dipiperidinopirimido[5,4-d]pirimidin-2,6-diyl)-diimino]-tetraethanol (19.4.13), is easily synthesized from 5-nitroorotic acid (19.4.8), easily obtained, in turn, by nitrating of 2,4-dihydroxy-6-methylpyrimidine, which is usually synthesized by the condensation of urea with acetoacetic ether. Reduction of the nitro group in 5-nitroorotic acid by various reducing agents gives 5-aminoorotic acid (19.4.9), which is reacted with urea or with potassium cyanide to give 2,4,6,8-tetrahydroxypyrimido[5,4-d]pyrimidine (19.4.10). This undergoes a reaction with a mixture of phosphorous oxychloride and phosphorous pentachloride, which forms 2,4,6,8- tetra-chloropyrimido[5,4-d]pyrimidine (19.4.11). Reacting the resulting tetrachloride with piperidine replaces the chlorine atoms at C₄ and C₈ of the heterocyclic system with piperidine, giving 2,6-dichloropyrimido-4,8-dipiperidino[5,4-d]pyrimidine (19.4.12). Reacting the resulting product with diethanolamine gives dipyridamole (19.4.13) [32,33].

Dipyridamole increases coronary blood circulation, increases oxygen flow to the myocardium, potentiates adenosine activity, and impedes its metabolization. It inhibits aggregation of thrombocytes, blocks phosphodiesterase, increases microcirculation, and inhibits the formation of thrombocytes.

It is used for chronic coronary insufficiency, as well as for preventing and treating thrombosis. Synonyms of this drug are anginal, curantyl, stenocor, thrompresantin, and many others.SYN

Chemical Synthesis

Dipyridamole, 2,2′,2”,2”’-[(4,8-dipiperidinopirimido[5,4-d]pirimidin-2,6- diyl)-diimino]-tetraethanol (19.4.13), is easily synthesized from 5-nitroorotic acid (19.4.8), easily obtained, in turn, by nitrating of 2,4-dihydroxy-6-methylpyrimidine, which is usually synthesized by the condensation of urea with acetoacetic ether. Reduction of the nitro group in 5-nitroorotic acid by various reducing agents gives 5-aminoorotic acid (19.4.9), which is reacted with urea or with potassium cyanide to give 2,4,6,8- tetrahydroxypyrimido[5,4-d]pyrimidine (19.4.10). This undergoes a reaction with a mixture of phosphorous oxychloride and phosphorous pentachloride, which forms 2,4,6,8- tetrachloropyrimido[ 5,4-d]pyrimidine (19.4.11). Reacting the resulting tetrachloride with piperidine replaces the chlorine atoms at C4 and C8 of the heterocyclic system with piperidine, giving 2,6-dichloropyrimido-4,8-dipiperidino[5,4-d]pyrimidine (19.4.12). Reacting the resulting product with diethanolamine gives dipyridamole (19.4.13).

 clipA general outline of the procedure for synthesizing dipyridamole is shown in Scheme 1. Reaction of the pyrimidino pyrimidine-2,4,6,8- tetraol (1) with a mixture of phosphorous oxychloride and phosphorous pentachloride gives the tetrachloro derivative (2). The halogens at the peri positions 4 and 8 are more reactive to substitution than are the remaining halogen pairs 2 and 6, which are in effect the two positions of the pyrimidines. Thus, reaction with piperidine at ambient temperature gives the 4, 8 diamine (3). Subsequent reaction with bis-2-hydroxy ethylamine under more strenuous conditions gives dipyridamole (4) [12, 13].12. F.G. Fischer, J. Roch, and A. Kottler, U.S. Patent 3, 031, 450 (1962). 13. D. Lednicer and L.A. Mitscher, The Organic Chemistry of Drug Synthessis Volume 1, John Wiley and Sons, New York, p. 428 (1977). 

set 2

set 3 

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Medical uses

• Dipyridamole is used to dilate blood vessels in people with peripheral arterial disease and coronary artery disease^[4]
• Dipyridamole has been shown to lower pulmonary hypertension without significant drop of systemic blood pressure
• It inhibits formation of pro-inflammatory cytokines (MCP-1, MMP-9) in vitro and results in reduction of hsCRP^{[clarification needed]} in patients.
• It inhibits proliferation of smooth muscle cells in vivo and modestly increases unassisted patency of synthetic arteriovenous hemodialysis grafts.^[5]
• It increases the release of tissue plasminogen activator from brain microvascular endothelial cells.
• It results in an increase of 13-hydroxyoctadecadienoic acid and decrease of 12-hydroxyeicosatetraenoic acid in the subendothelial matrix and reduced thrombogenicity of the subendothelial matrix.
• Pretreatment it reduced reperfusion injury in volunteers.
• It has been shown to increase myocardial perfusion and left ventricular function in patients with ischemic cardiomyopathy.
• It results in a reduction of the number of thrombin and PECAM-1 receptors on platelets in stroke patients.
• Cyclic adenosine monophosphate impairs platelet aggregation and also causes arteriolar smooth muscle relaxation. Chronic therapy did not show significant drop of systemic blood pressure.
• It inhibits the replication of mengovirus RNA.^[6]
• It can be used for myocardial stress testing as an alternative to exercise-induced stress methods such as treadmills.

Stroke

A combination of dipyridamole and aspirin (acetylsalicylic acid/dipyridamole) is FDA-approved for the secondary prevention of stroke and has a bleeding risk equal to that of aspirin use alone.^[4] Dipyridamole absorption is pH-dependent and concomitant treatment with gastric acid suppressors (such as a proton pump inhibitor) will inhibit the absorption of liquid and plain tablets.^[7][8] Modified release preparations are buffered and absorption is not affected.^[9][10]

However, it is not licensed as monotherapy for stroke prophylaxis, although a Cochrane review suggested that dipyridamole may reduce the risk of further vascular events in patients presenting after cerebral ischemia.^[11]

A triple therapy of aspirin, clopidogrel, and dipyridamole has been investigated, but this combination led to an increase in adverse bleeding events.^[12]

• Vasodilation occurs in healthy arteries, whereas stenosed arteries remain narrowed. This creates a “steal” phenomenon where the coronary blood supply will increase to the dilated healthy vessels compared to the stenosed arteries which can then be detected by clinical symptoms of chest pain, electrocardiogram and echocardiography when it causes ischemia.
• Flow heterogeneity (a necessary precursor to ischemia) can be detected with gamma cameras and SPECT using nuclear imaging agents such as Thallium-201, Tc99m–Tetrofosmin and Tc99m–Sestamibi. However, relative differences in perfusion do not necessarily imply any absolute decrease in blood supply in the tissue supplied by a stenosed artery.

Other uses

Dipyridamole also has non-medicinal uses in a laboratory context, such as the inhibition of cardiovirus growth in cell culture.^{[citation needed]}

Drug interactions

Due to its action as a phosphodiesterase inhibitor, dipyridamole is likely to potentiate the effects of adenosine. This occurs by blocking the nucleoside transporter (ENT1) through which adenosine enters erythrocyte and endothelial cells.^[13]

According to Association of Anaesthetists of Great Britain and Ireland 2016 guidelines, dipyridamole is considered to not cause risk of bleeding when receiving neuroaxial anaesthesia and deep nerve blocks. It does not therefore require cessation prior to anaesthesia with these techniques, and can continue to be taken with nerve block catheters in place.^[14]

Overdose

Dipyridamole overdose can be treated with aminophylline^[2]: 6 or caffeine which reverses its dilating effect on the blood vessels. Symptomatic treatment is recommended, possibly including a vasopressor drug. Gastric lavage should be considered. Since dipyridamole is highly protein bound, dialysis is not likely to be of benefit.

Mechanisms of action

Dipyridamole has two known effects, acting via different mechanisms of action:

• Dipyridamole inhibits the phosphodiesterase enzymes that normally break down cAMP (increasing cellular cAMP levels and blocking the platelet aggregation, response^[4] to ADP) and/or cGMP.
• Dipyridamole inhibits the cellular reuptake of adenosine into platelets, red blood cells, and endothelial cells, leading to increased extracellular concentrations of adenosine.

Experimental studies[

Dipyridamole is currently undergoing repurposing for treatment of ocular surface disorders. These include pterygium and dry eye disease. The first report of topical dipyridamole’s benefit in treating pterygium was published in 2014.^[15] A subsequent report of outcomes in 25 patients using topical dipyridamole was presented in 2016.^[16]

See also

• Acetylsalicylic acid/dipyridamole
• Cilostazol

References

1. ^ Nielsen-Kudsk, F; Pedersen, AK (May 1979). “Pharmacokinetics of Dipyridamole”. Acta Pharmacologica et Toxicologica. 44 (5): 391–9. doi:10.1111/j.1600-0773.1979.tb02350.x. PMID 474151.
2. ^ Jump up to:^a b “Aggrenox (aspirin/extended-release dipyridamole) Capsules. Full Prescribing Information” (PDF). Boehringer Ingelheim Pharmaceuticals, Inc. Retrieved 1 December 2016.
3. ^ “Dipyridamole” at Dorland’s Medical Dictionary
4. ^ Jump up to:^a b c Brown DG, Wilkerson EC, Love WE (March 2015). “A review of traditional and novel oral anticoagulant and antiplatelet therapy for dermatologists and dermatologic surgeons”. Journal of the American Academy of Dermatology. 72 (3): 524–34. doi:10.1016/j.jaad.2014.10.027. PMID 25486915.
5. ^ Dixon BS, Beck GJ, Vazquez MA, et al. (2009). “Effect of dipyridamole plus aspirin on hemodialysis graft patency”. N Engl J Med. 360 (21): 2191–2201. doi:10.1056/nejmoa0805840. PMC 3929400. PMID 19458364.
6. ^ Dipyridamole in the laboratory: Fata-Hartley, Cori L.; Ann C. Palmenberg (2005). “Dipyridamole reversibly inhibits mengovirus RNA replication”. Journal of Virology. 79 (17): 11062–11070. doi:10.1128/JVI.79.17.11062-11070.2005. PMC 1193570. PMID 16103157.
7. ^ Russell TL, Berardi RR, Barnett JL, O’Sullivan TL, Wagner JG, Dressman JB. pH-related changes in the absorption of “dipyridamole” in the elderly. Pharm Res (1994) 11 136–43.
8. ^ Derendorf H, VanderMaelen CP, Brickl R-S, MacGregor TR, Eisert W. “Dipyridamole” bioavailability in subjects with reduced gastric acidity. J Clin Pharmacol (2005) 45, 845–50.
9. ^ “Archived copy”. Archived from the original on 2009-07-05. Retrieved 2010-02-06.
10. ^ Stockley, Ivan (2009). Stockley’s Drug Interactions. The Pharmaceutical Press. ISBN 978-0-85369-424-3.
11. ^ De Schryver EL, Algra A, van Gijn J (2007). Algra A (ed.). “Dipyridamole for preventing stroke and other vascular events in patients with vascular disease”. Cochrane Database of Systematic Reviews (2): CD001820. doi:10.1002/14651858.CD001820.pub3. PMID 17636684.
12. ^ Sprigg N, Gray LJ, England T, et al. (2008). Berger JS (ed.). “A randomised controlled trial of triple antiplatelet therapy (aspirin, clopidogrel and dipyridamole) in the secondary prevention of stroke: safety, tolerability and feasibility”. PLOS ONE. 3 (8): e2852. Bibcode:2008PLoSO…3.2852S. doi:10.1371/journal.pone.0002852. PMC 2481397. PMID 18682741.
13. ^ Gamboa A, Abraham R, Diedrich A, Shibao C, Paranjape SY, Farley G, et al. Role of adenosine and nitric oxide on the mechanisms of action of dipyridamole. Stroke. 2005;36(10):2170-2175.
14. ^ AAGBI Guidelines Neuraxial and Coagulation June 2016
15. ^ Carlock, Beth H.; Bienstock, Carol A.; Rogosnitzky, Moshe (2014-03-25). “Pterygium: Nonsurgical Treatment Using Topical Dipyridamole – A Case Report”. Case Reports in Ophthalmology. 5 (1): 98–103. doi:10.1159/000362113. ISSN 1663-2699. PMC 3995373. PMID 24761148.
16. ^ “Topical Dipyridamole for Treatment of Pterygium and Associated Dry Eye Symptoms: Analysis of User-Reported Outcomes”. ResearchGate. Retrieved 2019-05-19.

Patent

Publication numberPriority datePublication dateAssigneeTitleUS3031450A1959-04-301962-04-24Thomae Gmbh Dr KSubstituted pyrimido-[5, 4-d]-pyrimidinesDE1812918A11968-04-251969-11-06Dresden Arzneimittel2,6-Bis (diethanolamino-4,8-dipiperidino-pyrimido (5,4-d)-pyrimidine – purification by simple procedure giving good yieldsDD115670A11974-02-191975-10-12DD117456A11975-02-131976-01-12DE2927539A1 *1979-07-071981-01-08Margineanu Dan Axente Dipl IngBis:di:ethanol-amino-di:piperidino-pyrimido-pyrimidine prepn. – from methyl acetoacetate and urea via amino-orotic acidRO104718B11989-08-091994-09-30Medicamente DePRODUCTION METHOD OF PURE 2,6-bis-(DIETHANOL AMIDE)-4,8-DI- PIPERIDINE-PYRIMIDO-(5,4-d)-PYRIMIDINEWO2007080463A12006-01-122007-07-19Orchid Chemicals & Pharmaceuticals LimitedAn improved process for the preparation of dipyridamoleFamily To Family CitationsDE115670C *JPS5191295A *1975-02-051976-08-10Jipiridamooruno kairyoseizohoJPS5757038B2 *1977-09-301982-12-02Yamanouchi Pharma Co LtdJPS57209291A *1981-06-171982-12-22Kyowa Hakko Kogyo Co LtdPurification of dipyridamoleUS6232312B1 *1995-06-072001-05-15Cell Pathways, Inc.Method for treating patient having precancerous lesions with a combination of pyrimidopyrimidine derivatives and esters and amides of substituted indenyl acetic acidesCN1425461A *2003-01-032003-06-25贵州益佰制药股份有限公司Injection preparation for resisting platelet aggregation and its producing methodCN1634085A *2004-11-242005-07-06崔晓廷Injectio of aspirin and dipyridamole and its preparing process 

Non-Patent

TitleCURTIN, NICOLA J. ET AL: “Resistance-Modifying Agents of Pyrimido[5,4-d]pyrimidine Modulators of Antitumor Drug Activity. Synthesis and Structure-Activity Relationships for Nucleoside Transport Inhibition and Binding to .alpha.1-Acid Glycoprotein”, JOURNAL OF MEDICINAL CHEMISTRY , 47(20), 4905-4922 CODEN: JMCMAR; ISSN: 0022-2623, 26 August 2004 (2004-08-26), XP002651697 * 

CN104710431B *2015-03-182017-03-01常州康普药业有限公司A kind of purifying process of dipyridamoleCN107782805B *2016-08-252021-02-02亚宝药业集团股份有限公司HPLC analysis method for key intermediate impurity synthesized by dipyridamoleCN106380471B *2016-08-312018-11-06广州市桐晖药业有限公司A kind of preparation method of DipyridamoleCN108069972A *2016-11-162018-05-25湖南尔康制药股份有限公司A kind of production method of Dipyridamole bulk pharmaceutical chemicalsCN106946887B *2017-03-242019-05-28大连万福制药有限公司A kind of preparation method introducing catalyst optimization synthesis Dipyridamole

/////////////////Dipyridamole, дипиридамол , ديبيريدامول , 双嘧达莫 , 0068373 , NSC-515776, RA-8

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TAUROLIDINE

• Molecular FormulaC₇H₁₆N₄O₄S₂
• Average mass284.356 Da

19388-87-5[RN]
243-016-5[EINECS]
2H-1,2,4-Thiadiazine, 4,4′-methylenebis[tetrahydro-, 1,1,1′,1′-tetraoxide
4,4′-methanediylbis(1,2,4-thiadiazinane) 1,1,1′,1′-tetraoxide
UNII-8OBZ1M4V3V 
тауролидин 
توروليدين 
牛磺利定 
NMR https://www.apexbt.com/downloader/document/C4559/NMR-2.pdf
MS https://www.apexbt.com/downloader/document/C4559/MS-2.pdf
Taurolidine 
CAS Registry Number: 19388-87-5 
CAS Name: 4,4¢-Methylenebis(tetrahydro-1,2,4-thiadiazine) 1,1,1¢,1¢-tetraoxide 
Additional Names: 4,4¢-methylenebis(perhydro-1,2,4-thiadiazine 1,1-dioxide); bis(1,1-dioxoperhydro-1,2,4-thiadiazin-4-yl)methane 
Trademarks: Drainasept (Geistlich); Taurolin (HMR); Tauroflex (Geistlich) 
Molecular Formula: C7H16N4O4S2, Molecular Weight: 284.36 
Percent Composition: C 29.57%, H 5.67%, N 19.70%, O 22.51%, S 22.55% 
Literature References: Broad spectrum, synthetic formaldehyde carrier formed by the condensation of two molecules of taurine and three molecules of formaldehyde. Prepn: FR1458701; R. W. Pfirrmann, US3423408 (1966, 1969 both to Ed. Geistlich Söhne). Antibacterial activity in mice: M. K. Browne et al.,J. Appl. Bacteriol.41, 363 (1976). Anti-endotoxin activity in lab animals: R. W. Pfirrmann, G. B. Leslie, ibid.46, 97 (1979). Mechanism of action: E. Myers et al.,ibid.48, 89 (1980). HPLC determn of metabolites in plasma: A. D. Woolfson et al.,Int. J. Pharm.49, 135 (1989). Pharmacokinetics: C. Steinbach-Lebbin et al.,Arzneim.-Forsch.32, 1542 (1982). Metabolism in humans: B. I. Knight et al.,Br. J. Clin. Pharmacol.12, 695 (1981). Clinical trials in peritonitis: M. K. Browne et al.,Surg. Gynecol. Obstet.146, 721 (1978); G. Wesch et al.,Fortschr. Med.101, 545 (1983); in wound sepsis: A. K. Halsall et al.,Pharmatherapeutica2, 673 (1981); in pleural infection: A. A. Conlan et al.,S. Afr. Med. J.64, 653 (1983). 
Properties: White crystals, mp 154-158°. Sol in water. 
Melting point: mp 154-158° 
Therap-Cat: Antibacterial. 
Keywords: Antibacterial (Synthetic).

Taurolidine is an antimicrobial that is used to try to prevent infections in catheters.^[1] Side effects and the induction of bacterial resistance is uncommon.^[1] It is also being studied as a treatment for cancer.^[2]

It is derived from the endogenous amino acid taurine. Taurolidine’s putative mechanism of action is based on a chemical reaction. During the metabolism of taurolidine to taurinamide and ultimately taurine and water, methylol groups are liberated that chemically react with the mureins in the bacterial cell wall and with the amino and hydroxyl groups of endotoxins and exotoxins. This results in denaturing of the complex polysaccharide and lipopolysaccharide components of the bacterial cell wall and of the endotoxin and in the inactivation of susceptible exotoxins.^[3]

PATENT

https://patents.google.com/patent/WO2012070066A1/en

Taurolidine is an antibacterial drug and also has antiendotoxic substance, which is used as an antiseptic solution in surgery for washing out the abdominal cavity and it also prevents septic shock. It is commercially sold as Taurolidine (Formula I). The present invention relates to a process for the preparation of Taurolidine which provides significant advantages over the existing processes.

Formula I

The current process for the preparation of Taurolidine is depicted in Scheme 1

Formula II

Formula IVFormula IThe present inventors thus propose an industrially viable procedure for isolation of Taurolidine in substantially pure form.Taurolidine is dissolved in a suitable solvent to obtain a clear solution. The product starts to precipitate and an anti solvent is added optionally to maximize the precipitation procedure. The solvents employed for the purification are non -aqueous aprotic solvents comprising DMSO, DMAc, DMF, Acetonitirle, DMSO being the most preferred solvent. The antisolvents employed are toluene, ethyl acetate, dichloromethane, ether; toluene being the most preferred.Taurolidine obtained by the instant procedure has purity greater than or equal to 99.5 %. The process of the invention is illustrated by the following examples to obtain Taurolidine. Example ICbz-Taurine sodium salt (Formula II)To 1000ml of water in the RBF charge 192gm of (3.0 eq) of sodium hydroxide under cooling followed by 200gm of Taurine and dissolve it until clear solution is obtained. Cool to 0°C to 5°C, and Charge 50% CBZ-C1 in toluene at 0°C to 5°C. After completion of addition, maintain at room temperature for 14h. Separate the toluene layer and wash the aqueous layer with 2x200ml of ethyl acetate. Add slowly 27gm of sodium hydroxide in 60ml of water to the aqueous layer and adjust pH to 12- 14. Cool to 0°C to 5°C and a white solid separates from the solution. Filter the solid and dry the solid at 60 -70 °C. Weight of the solid: 320 gExample 2Cbz-Taurinamide (Formula III)To a clean dry flask charge 1500ml of toluene and charge 320gm of Formula II and cool to 0°C to 5°C. Charge 308 gm of PC1₅ slowly at 0°C to 5°C for 2hrs. Maintain at 0°C to 5°C up to completion of reaction. Quench the RM into another flask containing 2 ltr of water at 0°C to 5°C. Separate the organic layer, wash and extract the aqueous layer with toluene. Dry the organic layer with sodium sulphate and cool to 0°C to 5°C. Purge ammonia gas into the reaction mass till the reaction is complete. Filter the solid and dissolve the solid in 21tr of water and extract the aqueous layer with 2x600ml of ethyl acetate. Dry the organic layer with sodium sulphate and concentrate it under reduced pressure to obtain a white solid. Weight of the solid: 150 gExample 3Taurinamide Succinate (Formula IV)Take a suspension of 100 g of Cbz-Taurinamide in 1000 ml methanol, and 10% Pd/C (1 .0 g) and subject to hydrogenation at 45-50 psi. Upon completion of the reaction filter the catalyst and add succinic acid (1 .0 eq) to the solvent and distill off the solvent under vacuum to provide the title compound in about 90% yield as a white solid.Example 4Taurolidine (Formula I)To a solution of 100 g Taurinamide succinate in water is added sat sodium bicarbonate solution and pH adjusted to 7-8. To the solution was added formaldehyde (50 ml) and allowed to stir for 4 h. The solid obtained was filtered and washed with water to give Taurolidine. The title compound was obtained in about 70% yield and about 98% purity.Example 5Purification of TaurolidineTaurolidine (100 g) was dissolved in DMSO (400 ml) and a clear solution is obtained and a precipitate is obtained immediately. The solid is filtered and washed with toluene and dried to give a white solid in 40 % yield. The product obtained was >99.5% pure.Example 6Purification of TaurolidineTaurolidine (100 g) was dissolved in DMSO (400 ml) and a clear solution is obtained and a precipitate is obtained immediately. To the solution, toluene (1000 ml) is added. The solid is filtered and washed with toluene and dried to give a white solid in 70 % yield. The product obtained was >99.5% pure by HPLC and passed elemental analysis within 0.4% of the theoretical values.Example 7Purification of TaurolidineTaurolidine (100 g) was dissolved in DMAc (800 ml) and to the solution, toluene (1000 ml) is added. The solid is filtered and washed with toluene and dried to give a white solid in 70% yield.

PATENT

WO/2022/007713

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022007713&_cid=P12-KYJIDL-52672-1Taurolidine (English name Taurolidine, chemical name is 4,4′-methylenebis[tetrahydro-2H-1,2,4-thiadiazine] 1,1,1′,1′-tetraoxide , the molecular formula is C ₇ H ₁₆ N ₄ O ₄ S ₂ ) is a derivative of the amino acid taurine, and its structure is as follows:

Taurolidine has anti-endotoxin, anti-bacterial and anti-adherent properties. In terms of bacteria, taurolidine can chemically react with cell walls, endotoxins and exotoxins to inhibit microbial adhesion and play an antibacterial role. In addition, in terms of anti-tumor, taurolidine can induce cytotoxicity of tumor cells by inducing apoptosis, autophagy and necrosis. The extent to which these processes are involved may vary with the type of tumor cell. Until July 2020, there were more than 260 foreign literature searches on taurolidine research reports, most of which focused on the exploration of the effect of taurolidine on tumor-related signaling pathways, while the application of taurolidine in antiviral activity was not yet available. See research reports. 
PATENThttps://patents.google.com/patent/CN101274921B/en
Taurolidine synthetic operation step:1. the preparation of tauryl villaumite hydrochlorate 
In being housed, ventpipe, escape pipe, thermometer and churned mechanically 300ml four-necked bottle add Mercaptamine 25g, 200ml methylene dichloride and 32ml dehydrated alcohol, under ice-water bath (below the 10 ℃) mechanical stirring, feed dry appropriate chlorine, reaction begins and heat release immediately, the thick solid of adularescent generates, and temperature remains on below 50 ℃ and stirs, reaction 5h.The whole process HCl gas and the monochloroethane gas of alkali lye absorption reaction process.Stop logical chlorine after reacting end, get yellow mercury oxide, suction filtration is used washed with dichloromethane four times, and vacuum-drying gets white solid 50g, 152～154 ℃ of fusing points.2. the preparation of tauryl azide salt hydrochlorate 
The reaction flask ice-water bath of containing 45ml water is cooled to-15 ℃, adds NaN ₃(2g), after stirring is molten entirely, add slightly pinkiness of tauryl villaumite hydrochlorate (9g) solution in batches, the water-bath of 20 minutes recession deicings, room temperature continues stirring 60 minutes.3. the preparation of tauryl amine hydrochlorate 
Above-mentioned reaction solution is joined in the 500ml autoclave, add 0.5g 5%Pd/C, feed hydrogen, pressure is 7Mpa, stirring at room 6h.Turn off hydrogen, pour out reaction solution, elimination Pd/C gets colourless reaction solution.The reaction solution that takes a morsel adds in the nuclear-magnetism pipe, adds deuterated reagent D ₂O, with ¹HNMR determines the transformation efficiency of hydrogenation reaction.Two kinds of CH of tauryl amine hydrochlorate ₂D ¹The HNMR peak is 3.29～3.31 and 3.40～3.42ppm place, and two kinds of CH of reactant tauryl azide salt hydrochlorate ₂D ¹The HNMR peak is 3.37～3.38 and 3.82～3.84ppm place.Determine that with the peak height ratio of two kinds of compounds the 4th step added the amount of formaldehyde.4. the preparation of taurolidine 
With the above-mentioned reaction solution that removes by filter Pd/C, add 5g NaHCO ₃, be stirred to molten entirely, frozen water cooling, stir slowly splash into down formaldehyde solution (37%, 2ml), have milky white precipitate to produce after 30 minutes, continue to stir 1h, suction filtration, filter cake is washed 3 times with frozen water.Vacuum-drying gets white powdery solid 2.3g, 170～174 ℃ of fusing points.Embodiment 2:Making with extra care of taurolidine:The above-mentioned taurolidine white powder 5～10g that obtains adds 50～200ml acetonitrile, and heating for dissolving removes by filter a small amount of insolubles, concentrates, and cooling below 10 ℃ gets white powder 5～10g, 172～174 ℃ of fusing points.Embodiment 3:Proton nmr spectra ( ¹H-NMR) data are as follows:¹HNMR(DMSO-D6，TMS7.26-7.28(t，2H，NH)，4.09-4.10(d，4H，N-CH ₂)，3.53(s，2H，N-CH ₂-N)，3.28-3.29(t，4H，N-CH ₂-CH ₂)，2.96-2.97(t，4H，S-CH ₂-CH ₂)。The infrared absorption spectrum data are as follows:IR (KBr compressing tablet cm ^-1): 3425,3263,1633,1450,1404,1317,1278,1228,1160,1134,1073,1026,993,958,924,830,757,667,532,511.See Fig. 3.The ultimate analysis analytical value:C, 29.04%, N, 18.55%, H, 5.85%; Calculated value: C, 29.57%, N, 19.71%, H, 5.67%Embodiment 4:Taurolidine formulation optimizing injection type of the present invention, as: infusion solution, injection liquid, freeze-dried powder injection or powder ampoule agent for injection etc., more preferably infusion solution.The preparation of infusion solution[prescription 1] taurolidine 10.0～30.0gPVP 40.0～80.0gNaCl 2～5gAdd water to 1000ml[method for making] takes by weighing taurolidine, is dissolved in water, and stirs, and adds the PVP dissolving, and adjust pH to 7.0 is crossed the moisture film of 0.22 μ m, packing, and 121 ℃ of sterilizations 20 minutes, promptly.[prescription 2] taurolidine 10.0～30.0gCitric acid 0.1～1.0gLemon enzyme sodium 10.0～20.0gAdd water to 1000ml[method for making] takes by weighing taurolidine, is dissolved in water, stir, and the dissolving of adding citric acid sodium, adjust pH to 7.0, the moisture film of mistake 0.22 μ m, packing was sterilized 20 minutes for 121 ℃, promptly. 
PATENThttps://patents.google.com/patent/US8952148B2/en

Example ICbz-Taurine Sodium Salt (Formula II)To 1000 ml of water in the RBF charge 192 gm of (3.0 eq) of sodium hydroxide under cooling followed by 200 gm of Taurine and dissolve it until clear solution is obtained. Cool to 0° C. to 5° C., and Charge 50% CBZ-Cl in toluene at 0° C. to 5° C. After completion of addition, maintain at room temperature for 14 h. Separate the toluene layer and wash the aqueous layer with 2×200 ml of ethyl acetate. Add slowly 27 gm of sodium hydroxide in 60 ml of water to the aqueous layer and adjust pH to 12-14. Cool to 0° C. to 5° C. and a white solid separates from the solution. Filter the solid and dry the solid at 60-70° C. Weight of the solid: 320 g

Example 2Cbz-Taurinamide (Formula III)To a clean dry flask charge 1500 ml of toluene and charge 320 gm of Formula II and cool to 0° C. to 5° C. Charge 308 gm of PCl₅ slowly at 0° C. to 5° C. for 2 hrs. Maintain at 0° C. to 5° C. up to completion of reaction. Quench the RM into another flask containing 2 ltr of water at 0° C. to 5° C. Separate the organic layer, wash and extract the aqueous layer with toluene. Dry the organic layer with sodium sulphate and cool to 0° C. to 5° C. Purge ammonia gas into the reaction mass till the reaction is complete. Filter the solid and dissolve the solid in 2 ltr of water and extract the aqueous layer with 2×600 ml of ethyl acetate. Dry the organic layer with sodium sulphate and concentrate it under reduced pressure to obtain a white solid. Weight of the solid: 150 g

Example 3Taurinamide Succinate (Formula IV)Take a suspension of 100 g of Cbz-Taurinamide in 1000 ml methanol, and 10% Pd/C (1.0 g) and subject to hydrogenation at 45-50 psi. Upon completion of the reaction filter the catalyst and add succinic acid (1.0 eq) to the solvent and distill off the solvent under vacuum to provide the title compound in about 90% yield as a white solid.

Example 4Taurolidine (Formula I)To a solution of 100 g Taurinamide succinate in water is added sat sodium bicarbonate solution and pH adjusted to 7-8. To the solution was added formaldehyde (50 ml) and allowed to stir for 4 h. The solid obtained was filtered and washed with water to give Taurolidine. The title compound was obtained in about 70% yield and about 98% purity.

Example 5Purification of TaurolidineTaurolidine (100 g) was dissolved in DMSO (400 ml) and a clear solution is obtained and a precipitate is obtained immediately. The solid is filtered and washed with toluene and dried to give a white solid in 40% yield. The product obtained was >99.5% pure.

Example 6Purification of TaurolidineTaurolidine (100 g) was dissolved in DMSO (400 ml) and a clear solution is obtained and a precipitate is obtained immediately. To the solution, toluene (1000 ml) is added. The solid is filtered and washed with toluene and dried to give a white solid in 70% yield. The product obtained was >99.5% pure by HPLC and passed elemental analysis within 0.4% of the theoretical values.

Example 7Purification of TaurolidineTaurolidine (100 g) was dissolved in DMAc (800 ml) and to the solution, toluene (1000 ml) is added. The solid is filtered and washed with toluene and dried to give a white solid in 70% yield. 

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Medical uses

Taurolidine is an antimicrobial agent used in an effort to prevent catheter infections. It however is not approved for this use in the United States as of 2011.^[4]

• Catheter lock solution in home parenteral nutrition (HPN) or total parenteral nutrition (TPN): catheter-related blood stream infections (CRBSI) remains the most common serious complication associated with long-term parenteral nutrition. The use of taurolidine as a catheter lock solution shows a reduction of CRBSI.^[1][5] The overall quality of the evidence however is not strong enough to justify routine use.^[1][5]
• Catheter lock solution: Taurolidine decreases the adherence of bacteria and fungi to host cells by destructing the fimbriae and flagella and thus prevent the biofilm formation.^[6][7] Taurolidine is the active ingredient of antimicrobial catheter lock solutions for the prevention and treatment of catheter related bloodstream infections (CRBSIs) and is suitable for use in all catheter based vascular access devices.^[8][1] Bacterial resistance against taurolidine has never been observed in various studies.^[9][10]
• The use of a taurolidine lock solution may decrease the risk of catheter infection in children with cancer but the evidence is tentative.^[11]

Side effects

No systemic side effects have been identified. The safety of taurolidine has also been confirmed in clinical studies with long-term intravenous administration of high doses (up to 20 grams daily). In the body, taurolidine is metabolized rapidly via the metabolites taurultam and methylol taurinamide, which also have a bactericidal action, to taurine, an endogenous aminosulphonic acid, carbon dioxide and water. Therefore, no toxic effects are known or expected in the event of accidental injection. Burning sensation while instilling, numbness, erythema, facial flushing, headache, epistaxis, and nausea have been reported.^[12]

Toxicology

Taurolidine has a relatively low acute and subacute toxicity.^[1] Intravenous injection of 5 grams taurolidine into humans over 0.5–2 hours produce only burning sensation while instilling, numbness, and erythema at the injection sites.^[12] For treatment of peritonitis, taurolidine was administered by peritoneal lavage, intraperitoneal instillation or intravenous infusion, or by a combination thereof. The total daily dose ranged widely from 0.5 to 50 g. The total cumulative dose ranged from 0.5 to 721 g. In those patients who received intravenous taurolidine, the daily intravenous dose was usually 15 to 30 g but several patients received up to 40 g/day. Total daily doses of up to 40 g and total cumulative doses exceeding 300 g were safe and well tolerated.^{[12][13][14][15][16]}

Pharmacology

• Metabolism: Taurolidine and taurultam are quickly metabolized to taurinamide, taurine, carbon dioxide and water. Taurolidine exists in equilibrium with taurultam and N-methylol-taurultam in aqueous solution.^[17]
• Pharmacokinetic (elimination): The half-life of the terminal elimination phase of taurultam is about 1.5 hours, and of the taurinamide metabolite about 6 hours. 25% of the taurolidine dose applied is renally eliminated as taurinamide and/or taurine.^[13][14][18]

Mechanism of action

Following administration of taurolidine, the antimicrobial and antiendotoxin activity of the taurolidine molecule is conferred by the release of three active methylol (hydroxymethyl) groups as taurolidine is rapidly metabolized by hydrolysis via methylol taurultam to methylol taurinamide and taurine. These labile N-methylol derivatives of taurultam and taurinamide react with the bacterial cell-wall resulting in lysis of the bacteria, and by inter- and intramolecular cross-linking of the lipopolysaccharide-protein complex, neutralization of the bacterial endotoxins which is enhanced by enzymatic activation. This mechanism of action is accelerated and maximised when taurolidine is pre-warmed to 37 °C (99 °F). Microbes are killed and the resulting toxins are inactivated; the destruction time in vitro is 30 minutes.^[19]

The chemical mode of action of taurolidine via its reactive methylol groups confers greater potency in vivo than indicated by in vitro minimum inhibitory concentration (MIC) values, and also appears to preclude susceptibility to resistance mechanisms.^[14]

Taurolidine binding to lipopolysaccharides (LPS) prevents microbial adherence to host epithelial cells, thereby prevents microbial invasion of uninfected host cells. Although the mechanism underlying its antineoplastic activity has not been fully elucidated, it may be related to this agent’s anti-adherence property.^[6][7] Taurolidine has been shown to block interleukin 1 (IL-1) and tumour necrosis factor (TNF) in human peripheral blood mononuclear cells (PBMC).^[20] In addition, taurolidine also promotes apoptosis by inducing various apoptotic factors and suppresses the production of vascular endothelial growth factor (VEGF), a protein that plays an important role in angiogenesis.^[21]

Taurolidine is highly active against the common infecting pathogens associated with peritonitis and catheter sepsis, this activity extends across a wide-spectrum of aerobic and anaerobic bacteria and fungi (with no diminution of effect in the presence of biological fluids, e.g. blood, serum, pus).^[15][16][22]

• Gram-positive bacteria (MIC of 1–2 mg/mL): Staphylococcus (including multiple-antibiotic resistant coagulase negative strains, methicillin-resistant S. aureus), Streptococcus, Enterococcus.
• Gram-negative bacteria (MIC of 0.5–5 mg/mL): Aerobacter species, Citrobacter species, Enterobacter species, Escherichia coli, Proteus species (indole negative), Proteus mirabilis, Pseudomonas species (including P. aeruginosa), Salmonella species, Serratia marcescans, Klebsiella species.
• Anaerobes (MIC 0.03–0.3 mg/mL): Bacteroides species (including B. fragilis), Fusobacteria, Clostridium species, Peptostreptococcus anaerobius.
• Fungi (MIC 0.3–5 mg/mL): Candida albicans, Cryptococcus neoformans, Aspergillus species, Trichophyton rubrum, Epidermophyton floccosum, Pityrosporum ovale.^[10][17][22]

Chemical properties

The chemical name for taurolidine is 4,4′-Methylene-bis(1,2,4-thiadiazinane)-1,1,1’,1′-tetraoxide.

It is a white to off white odourless crystalline powder. It is practically insoluble in chloroform, slightly soluble in boiling acetone, ethanol, methanol, and ethyl acetate, sparingly soluble in water 8 at 20° and ethyl alcohol, soluble in dilute hydrochloric acid, and dilute sodium hydroxide, and freely soluble in N,N-dimethylformamide (at 60 °C).

History

Taurolidine was first synthesized in the laboratories of Geistlich Pharma AG, Switzerland in 1972. Clinical trials begun in 1975 in patients with severe peritonitis.

Research

Taurolidine demonstrates some anti-tumor properties, with positive results seen in early-stage clinical investigations using the drug to treat gastrointestinal malignancies and tumors of the central nervous system.^[23] More recently, it has been found to exert antineoplastic activity. Taurolidine induces cancer cell death through a variety of mechanisms. Even now, all the antineoplastic pathways it employs are not completely elucidated. It has been shown to enhance apoptosis, inhibit angiogenesis, reduce tumor adherence, downregulate pro-inflammatory cytokine release, and stimulate anticancer immune regulation following surgical trauma. Apoptosis is activated through both a mitochondrial cytochrome-c-dependent mechanism and an extrinsic direct pathway. A lot of in vitro and animal data support taurolidine’s tumoricidal action.^[24][25][26] Taurolidine has been used as an antimicrobial agent in the clinical setting since the 1970s and thus far appears nontoxic. The nontoxic nature of taurolidine makes it a favorable option compared with current chemotherapeutic regimens. Few published clinical studies exist evaluating the role of taurolidine as a chemotherapeutic agent. The literature lacks a gold-standard level 1 randomized clinical trial to evaluate taurolidine’s potential antineoplastic benefits. However, these trials are currently underway. Such randomized control studies are vital to clarify the role of taurolidine in modern cancer treatment.^[21][2]

References

1. ^ Jump up to:^{a b c d e f} Liu Y, Zhang AQ, Cao L, Xia HT, Ma JJ (2013). “Taurolidine lock solutions for the prevention of catheter-related bloodstream infections: a systematic review and meta-analysis of randomized controlled trials”. PLOS ONE. 8 (11): e79417. Bibcode:2013PLoSO…879417L. doi:10.1371/journal.pone.0079417. PMC 3836857. PMID 24278133.
2. ^ Jump up to:^a b Neary PM, Hallihan P, Wang JH, Pfirrmann RW, Bouchier-Hayes DJ, Redmond HP (April 2010). “The evolving role of taurolidine in cancer therapy”. Annals of Surgical Oncology. 17 (4): 1135–43. doi:10.1245/s10434-009-0867-9. PMID 20039217. S2CID 23807182.
3. ^ Waser PG, Sibler E (1986). “Taurolidine: A new concept in antimicrobial chemotherapy”. In Harms AF (ed.). Innovative Approaches in Drug Research. Elsevier Science Publishers. pp. 155–169.
4. ^ O’Grady NP, Alexander M, Burns LA, Dellinger EP, Garland J, Heard SO, et al. (May 2011). “Guidelines for the prevention of intravascular catheter-related infections”. Clinical Infectious Diseases. 52 (9): e162-93. doi:10.1093/cid/cir257. PMC 3106269. PMID 21460264.
5. ^ Jump up to:^a b Bradshaw JH, Puntis JW (August 2008). “Taurolidine and catheter-related bloodstream infection: a systematic review of the literature”. Journal of Pediatric Gastroenterology and Nutrition. 47 (2): 179–86. doi:10.1097/MPG.0b013e318162c428. PMID 18664870. S2CID 19136945.
6. ^ Jump up to:^a b Gorman SP, McCafferty DF, Woolfson AD, Jones DS (April 1987). “Reduced adherence of micro-organisms to human mucosal epithelial cells following treatment with Taurolin, a novel antimicrobial agent”. The Journal of Applied Bacteriology. 62 (4): 315–20. doi:10.1111/j.1365-2672.1987.tb04926.x. PMID 3298185.
7. ^ Jump up to:^a b Blenkharn JI (July 1989). “Anti-adherence properties of taurolidine and noxythiolin”. Journal of Chemotherapy. 1 (4 Suppl): 233–4. PMID 16312382.
8. ^ Liu H, Liu H, Deng J, Chen L, Yuan L, Wu Y (2014). “Preventing catheter-related bacteremia with taurolidine-citrate catheter locks: a systematic review and meta-analysis”. Blood Purification. 37 (3): 179–87. doi:10.1159/000360271. PMID 24777144.
9. ^ Olthof ED, Rentenaar RJ, Rijs AJ, Wanten GJ (August 2013). “Absence of microbial adaptation to taurolidine in patients on home parenteral nutrition who develop catheter related bloodstream infections and use taurolidine locks”. Clinical Nutrition. 32 (4): 538–42. doi:10.1016/j.clnu.2012.11.014. PMID 23267744.
10. ^ Jump up to:^a b Torres-Viera C, Thauvin-Eliopoulos C, Souli M, DeGirolami P, Farris MG, Wennersten CB, et al. (June 2000). “Activities of taurolidine in vitro and in experimental enterococcal endocarditis”. Antimicrobial Agents and Chemotherapy. 44 (6): 1720–4. doi:10.1128/aac.44.6.1720-1724.2000. PMC 89943. PMID 10817739.
11. ^ Simon A, Bode U, Beutel K (July 2006). “Diagnosis and treatment of catheter-related infections in paediatric oncology: an update”. Clinical Microbiology and Infection. 12 (7): 606–20. doi:10.1111/j.1469-0691.2006.01416.x. PMID 16774556.
12. ^ Jump up to:^a b c Gong L, Greenberg HE, Perhach JL, Waldman SA, Kraft WK (June 2007). “The pharmacokinetics of taurolidine metabolites in healthy volunteers”. Journal of Clinical Pharmacology. 47 (6): 697–703. doi:10.1177/0091270007299929. PMID 17395893. S2CID 31059736.
13. ^ Jump up to:^a b Knight BI, Skellern GG, Browne MK, Pfirrmann RW (November 1981). “Peritoneal absorption of the antibacterial and antiendotoxin taurolin in peritonitis”. British Journal of Clinical Pharmacology. 12 (5): 695–9. doi:10.1111/j.1365-2125.1981.tb01292.x. PMC 1401955. PMID 7332737.
14. ^ Jump up to:^a b c Stendel R, Scheurer L, Schlatterer K, Stalder U, Pfirrmann RW, Fiss I, et al. (2007). “Pharmacokinetics of taurolidine following repeated intravenous infusions measured by HPLC-ESI-MS/MS of the derivatives taurultame and taurinamide in glioblastoma patients”. Clinical Pharmacokinetics. 46 (6): 513–24. doi:10.2165/00003088-200746060-00005. PMID 17518510. S2CID 33321671.
15. ^ Jump up to:^a b Browne MK, MacKenzie M, Doyle PJ (May 1978). “C controlled trial of taurolin in established bacterial peritonitis”. Surgery, Gynecology & Obstetrics. 146 (5): 721–4. PMID 347606.
16. ^ Jump up to:^a b Browne MK (1981). “The treatment of peritonitis by an antiseptic – taurolin”. Pharmatherapeutica. 2 (8): 517–22. PMID 7255507.
17. ^ Jump up to:^a b Knight BI, Skellern GG, Browne MK, Pfirrmann RW (September 1981). “The characterisation and quantitation by high-performance liquid chromatography of the metabolites of taurolin”. British Journal of Clinical Pharmacology. 12 (3): 439–40. doi:10.1111/j.1365-2125.1981.tb01245.x. PMC 1401804. PMID 7295478.
18. ^ Browne MK, Leslie GB, Pfirrmann RW (December 1976). “Taurolin, a new chemotherapeutic agent”. The Journal of Applied Bacteriology. 41 (3): 363–8. doi:10.1111/j.1365-2672.1976.tb00647.x. PMID 828157.
19. ^ Braumann C, Pfirrman RW, et al. (2013). “Taurolidine, an Effective Multimodal Antimicrobial Drug Versus Traditional Antiseptics and Antibiotics”. In Willy C (ed.). Antiseptics in Surgery – Update 2013. Lindqvist Book Publishing. pp. 119–125.
20. ^ Bedrosian I, Sofia RD, Wolff SM, Dinarello CA (November 1991). “Taurolidine, an analogue of the amino acid taurine, suppresses interleukin 1 and tumor necrosis factor synthesis in human peripheral blood mononuclear cells”. Cytokine. 3 (6): 568–75. doi:10.1016/1043-4666(91)90483-t. PMID 1790304.
21. ^ Jump up to:^a b Jacobi CA, Menenakos C, Braumann C (October 2005). “Taurolidine–a new drug with anti-tumor and anti-angiogenic effects”. Anti-Cancer Drugs. 16 (9): 917–21. doi:10.1097/01.cad.0000176502.40810.b0. PMID 16162968. S2CID 33876185.
22. ^ Jump up to:^a b Nösner K, Focht J (1994). “In-vitro Wirksamkeit von Taurolidin und 9 Antibiotika gegen klinische Isolate aus chirurgischem Einsendegut sowie gegen Pilze”. Chirurgische Gastroenterologie. 10 (Suppl 2): 10.
23. ^ Stendel R, Picht T, Schilling A, Heidenreich J, Loddenkemper C, Jänisch W, Brock M (2004-04-01). “Treatment of glioblastoma with intravenous taurolidine. First clinical experience”. Anticancer Research. 24 (2C): 1143–7. PMID 15154639.
24. ^ Calabresi P, Goulette FA, Darnowski JW (September 2001). “Taurolidine: cytotoxic and mechanistic evaluation of a novel antineoplastic agent”. Cancer Research. 61 (18): 6816–21. PMID 11559556.
25. ^ Clarke NW, Wang JH, et al. (2005). “Taurolidine inhibits colorectal adenocarcinoma metastases in vivo and in vitro by inducing apoptosis”. Ir J Med Sci. 174 (Supplement 3): 1.
26. ^ Stendel R, Scheurer L, Stoltenburg-Didinger G, Brock M, Möhler H (2003-06-01). “Enhancement of Fas-ligand-mediated programmed cell death by taurolidine”. Anticancer Research. 23 (3B): 2309–14. PMID 12894508.

////////////////////TAUROLIDINE, UNII-8OBZ1M4V3V, тауролидин  ,توروليدين , 牛磺利定  ,

C1CS(=O)(=O)NCN1CN2CCS(=O)(=O)NC2

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Daridorexant

• Molecular FormulaC₂₃H₂₃ClN₆O₂
• Average mass450.921 Da

[(2S)-2-(5-Chloro-4-methyl-1H-benzimidazol-2-yl)-2-methyl-1-pyrrolidinyl][5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone
1505484-82-1[RN]
Methanone, [(2S)-2-(5-chloro-4-methyl-1H-benzimidazol-2-yl)-2-methyl-1-pyrrolidinyl][5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]-
ACT-541468, , Nemorexant

FDA APPROVED 2022, 1/7/2022, To treat insomnia,

Daridorexant HCl
CAS#: 1792993-84-0 (HCl)
Chemical Formula: C23H24Cl2N6O2
Molecular Weight: 487.39
Elemental Analysis: C, 56.68; H, 4.96; Cl, 14.55; N, 17.24; O, 6.57

 Methanone, ((2S)-2-(6-chloro-7-methyl-1H-benzimidazol-2-yl)-2-methyl-1-pyrrolidinyl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)-, hydrochloride (1:1)

Daridorexant HCl; Daridorexant hydrochloride; ACT541468A; ACT 541468A; ACT-541468A; ACT541468 hydrochloride; ACT 541468 hydrochloride; ACT-541468 hydrochloride

Daridorexant HCl is used in the treat of Insomnia Disorder in Adult Patients

Daridorexant, sold under the brand name Quviviq, is a medication used for the treatment of insomnia.^[1] Daridorexant is a dual orexin receptor antagonist (DORA) which was originated by Actelion Pharmaceuticals and is under development by Idorsia Pharmaceuticals.^[3][4] It acts as a selective dual antagonist of the orexin receptors OX₁ and OX₂.^[3][4] The medication has a relatively short elimination half-life of 6 to 10 hours.^[2] As of April 2020, daridorexant has passed its first phase III clinical trial for the treatment of insomnia.^[3]Daridorexant was approved for medical use in the United States in January 2022.^[1][5][6]

Daridorexant, formerly known as nemorexant, is a selective dual orexin receptor antagonist used to treat insomnia. Insomnia is characterized by difficulties with sleep onset and/or sleep maintenance and impairment of daytime functioning. It chronically affects the person’s daily functioning and long-term health effects, as insomnia is often associated with comorbidities such as hypertension, diabetes, and depression. Conventional treatments for insomnia include drugs targeting gamma-aminobutyric acid type-A (GABA-A), serotonin, histamine, or melatonin receptors; however, undesirable side effects are frequently reported, such as next-morning residual sleepiness, motor incoordination, falls, memory and cognitive impairment. Novel drugs that target orexin receptors gained increasing attention after discovering the role of orexin signalling pathway in wakefulness and almorexant, an orexin receptor antagonist that improved sleep. Daridorexant was designed via an intensive drug discovery program to improve the potency and maximize the duration of action while minimizing next-morning residual activity.¹

Daridorexant works on orexin receptors OX1R and OX2R to block the binding of orexins, which are wake-promoting neuropeptides and endogenous ligands to these receptors. Daridorexant reduces overactive wakefulness: in the investigational trials, daridorexant reportedly improved sleep and daytime functioning in patients with insomnia.¹ It was approved by the FDA on January 10, 2022, under the name QUVIVIQ.⁶ as the second orexin receptor antagonist approved to treat insomnia following suvorexant.²

QUVIVIQ

• Generic Name: daridorexant tablets
• Brand Name: Quviviq

QUVIVIQ contains daridorexant, an orexin receptor antagonist. The chemical name of daridorexant hydrochloride is (S)-(2-(5-chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5- methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone hydrochloride. The molecular formula is C₂₃H₂₃N₆O₂Cl * HCl. The molecular weight is 487.38 g/mol.

The structural formula is:

Daridorexant hydrochloride is a white to light yellowish powder that is very slightly soluble in water.

QUVIVIQ tablets are intended for oral administration. Each film-coated tablet contains 27 mg or 54 mg of daridorexant hydrochloride equivalent to 25 mg or 50 mg of daridorexant, respectively. The inactive ingredients are croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, povidone, and silicon dioxide.

In addition, the film coating contains the following inactive ingredients: glycerin, hypromellose, iron oxide black, iron oxide red, microcrystalline cellulose, talc, titanium dioxide, and, in the 50 mg tablet only, iron oxide yellow.

Dosage Forms And Strengths

QUVIVIQ (daridorexant) tablets are available as:

25 mg: light purple, arc-triangle shaped, film-coated tablet debossed with “25” on one side and “i” (Idorsia logo) on the other side, containing 25 mg daridorexant.

50 mg: light orange, arc-triangle shaped, film-coated tablet debossed with “50” on one side and “i” (Idorsia logo) on the other side, containing 50 mg daridorexant.

QUVIVIQ tablets are available as:

25 mg, light purple, arc-triangle shaped film-coated tablets debossed with “25” on one side, and “i” on the other side. NDC 80491-7825-3, bottle of 30 with child-resistant closure

50 mg: light orange, arc-triangle shaped film-coated tablets debossed with “50” on one side, and “i” on the other side. NDC 80491-7850-3, bottle of 30 with child-resistant closure

SYN

https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.202000453

Since its discovery in 1998, the orexin system has been of interest to the research community as a potential therapeutic target for the treatment of sleep/wake disorders. Herein we describe our efforts leading to the identification of daridorexant, which successfully finished two pivotal phase 3 clinical trials for the treatment of insomnia disorders.

Step 3. Amide (S7) (1000 g, 2.13 mmol) was dissolved in EtOH (5 L) and 32% aqueous HCl (500 mL) was added at 23 °C. The solution was filtered through a Whatman filter (5 µm). The filtrate was heated to 75 °C for 4h. The resulting suspension was cooled to 0 °C and filtered. The product was dried under reduced pressure to yield 93 x HCl (922 g, 89%) as a white solid.

LC-MS B: tR = 0.78 min; [M+H]+ = 451.19, mp 280 °C.

1H NMR (500 MHz, D6-DMSO) δ: 15.05- 15.65 (m, 1 H), 8.06 (s, 2 H), 7.79 (s, 1 H), 7.75 (d, J = 8.9 Hz, 2 H), 7.66 (m, 1 H), 7.57 (d, J = 8.7 Hz, 1 H), 7.15 (dd, J1 = 2.9 Hz, J2 = 8.9 Hz, 1 H), 4.06-4.10 (m, 1 H), 3.92 (s, 3 H), 3.35 (s, 1 H), 2.78 (s, 3 H), 2.54-2.67 (m, 1 H), 2.23-2.31 (m, 1 H), 2.06-2.20 (m, 2 H), 1.97 (s, 3 H),

13C NMR (125 MHz, D6-DMSO) δ: 166.2, 159.3, 158.6, 136.5, 132.7, 131.9, 130.4, 130.3, 129.4, 126.8, 124.5, 123.4, 116.4, 113.7, 113.0, 61.6, 56.8, 49.7, 41.1, 23.9, 20.2, 15.7.

SYN

https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.201900618

Abstract

DORA explorers: The orexin system plays an important role in regulating the sleep-wake cycle. Herein we report our optimization efforts toward a novel dual orexin receptor antagonist (DORA) with improved properties over compound 6. Replacing the oxadiazole by a triazole resulted in compounds (e. g. compound 33) with improved properties, such as higher intrinsic metabolic stability, lower plasma protein binding, higher brain free fraction, and increased solubility. Further optimization was needed to decrease the compounds P-glycoprotein susceptibility. Our work led to the identification of compound 42, a potent, brain-penetrating DORA with improved in vivo efficacy in dogs compared with compound 6.

Abstract

The orexin system is responsible for regulating the sleep-wake cycle. Suvorexant, a dual orexin receptor antagonist (DORA) is approved by the FDA for the treatment of insomnia disorders. Herein, we report the optimization efforts toward a DORA, where our starting point was (5-methoxy-4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-[5-(2-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrrolidin-1-yl}methanone (6), a compound which emerged from our in-house research program. Compound 6 was shown to be a potent, brain-penetrating DORA with in vivo efficacy similar to suvorexant in rats. However, shortcomings from low metabolic stability, high plasma protein binding (PPB), low brain free fraction (f_u brain), and low aqueous solubility, were identified and hence, compound 6 was not an ideal candidate for further development. Our optimization efforts addressing the above-mentioned shortcomings resulted in the identification of (4-chloro-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-methyl-2-[5-(2-trifluoromethoxy-phenyl)-4H-[1,2,4]triazol-3-yl]-pyrrolidin-1-yl}l-methanone (42), a DORA with improved in vivo efficacy compared to 6.

PAT

WO 2015083071

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015083071

Reference Example 1

1) Synthesis of 5-methoxy-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid

2-lodo-5-methoxy benzoic acid (15.0 g; 53.9 mmol) is dissolved in anhydrous DMF (45 ml) followed by the addition of 1 H-1 ,2,3-triazole (7.452 g; 108 mmol) and cesium carbonate (35.155 g; 108 mmol). By the addition of cesium carbonate the temperature of the reaction mixture increases to 40°C and gas evolved from the reaction mixture. Copper(l)iodide (514 mg; 2.7 mmol) is added. This triggers a strongly exothermic reaction and the temperature of the reaction mixture reaches 70°C within a few seconds. Stirring is continued for 30 minutes. Then the DMF is evaporated under reduced pressure followed by the addition of water (170 ml) and EtOAc (90 ml). The mixture is vigorously stirred and by the addition of citric acid monohydrate the pH is adjusted to 3-4. The precipitate is filtered off and washed with water and EtOAc and discarded. The filtrate is poured into a separation funnel and the phases are separated. The water phase is extracted again with EtOAc. The combined organic layers are dried over MgS0₄, filtered and the solvent is evaporated to give 7.1 g of 5-methoxy-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid as a white powder of 94% purity (6 % impurity is the regioisomerically N1-linked triazolo-derivative); t_R [min] = 0.60; [M+H]⁺ = 220.21

2) Synthesis of (S)-1 -(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid

2-Methyl-L-proline hydrochloride (99.7 g; 602 mmol) is dissolved in a 1/1-mixture of MeCN and water (800 ml) and triethylamine (254 ml; 1810 mmol) is added. The temperature of the reaction mixture slightly rises. The reaction mixture is cooled to 10°C to 15°C followed by careful addition of a solution of Boc₂0 (145 g; 662 mmol) in MeCN (200 ml) over 10 minutes.

Stirring at RT is continued for 2 hours. The MeCN is evaporated under reduced pressure and aq. NaOH solution (2M; 250 ml) is added to the residual aq. part of the reaction mixture. The water layer is washed with Et₂0 (2x 300 ml) then cooled to 0°C followed by slow and careful addition of aq. HCI (25%) to adjust the pH to 2. During this procedure a suspension forms.

The precipitate is filtered off and dried at HV to give 1 10.9 g of the title compound as a beige powder; t_R [min] = 0.68; [M+H]⁺ = 230.14

3) Synthesis of (S)-tert-butyl 2-((2-amino-4-chloro-3-methylphenyl)carbamoyl)-2-

(S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (60 g; 262 mmol) and HATU (100 g; 264 mmol) is suspended in DCM (600 ml) followed by the addition of DIPEA (84.6 g; 654 mmol) and 6-chloro-2,3-diaminotoluene (41 g; 262 mmol). The reaction mixture is stirred at rt for 14 hours then concentrated under reduced pressure and to the residue is added water followed by the extraction of the product with EtOAc (3x). The combined organic layers are washed with brine, dried over MgS0₄, filtered and the solvent is evaporated under

reduced pressure to give 185 g of the title compound as a dark brownish oil, which is used in the next step without further purification; t_R [min] = 0.89; [M+H]⁺ = 368.01

4) Synthesis of (S)-tert-butyl 2-(5-chloro-4-methyl-1 H-benzo[d]imidazol-2-yl)-2-methylpyrrolidine-1 -carboxylate

(S)-tert-butyl 2-((2-amino-4-chloro-3-methylphenyl)carbamoyl)-2-methylpyrrolidine-1-carboxylate (185 g; 427 mmol) are dissolved in AcOH (100%; 611 ml), heated to 100°C and stirring continued for 90 minutes. The AcOH is evaporated under reduced pressure and the residue is dissolved in DCM followed by careful addition of saturated sodium bicarbonate solution. The phases are separated, the aq. phase is extracted once more with DCM, the combined aq. phases are dried over MgS0₄, filtered and the solvent is evaporated under reduced pressure to give 142.92 g of the title compound as a dark brown oil which is used in the next step without further purification; t_R [min] = 0.69; [M+H]⁺ = 350.04

5) Synthesis of (S)-5-chloro-4-methyl-2-(2-methylpyrrolidin-2-yl)-1 H-benzo[d]imidazole hydrochloride

(S)-tert-butyl 2-(5-chloro-4-methyl-1 H-benzo[d]imidazol-2-yl)-2-methylpyrrolidine-1-carboxylate (355.53 g; 1.02 mol) are dissolved in dioxane (750 ml) followed by careful addition of HCI solution in dioxane (4M; 750 ml; 3.05 mol). The reaction mixture is stirred for 3 hours followed by the addition of Et₂0 (800 ml) which triggered precipitation of the product. The solid is filtered off and dried at high vacuum to give 298.84 g of the title compound as a redish powder; t_R [min] = 0.59; [M+H]⁺ = 250.23

6) Synthesis of [(S)-2-(5-chloro-4-methyl-1 H-benzoimidazol-2-yl)-2-methyl-pyrrolidin-1- -(5-methoxy-2-[1,2,3]triazol-2-yl-phenyl)-methanone

(S)-5-chloro-4-methyl-2-(2-methylpyrrolidin-2-yl)-1 H-benzo[d]imidazole hydrochloride (62.8 g; 121 mmol) is dissolved in DCM (750 ml) followed by the addition of 5-methoxy-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid (62.8 g; 121 mmol) and DIPEA (103 ml; 603 mmol). Stirring is continued for 10 minutes followed by the addition of HATU (47 g; 124 mmol). The reaction mixture is stirred for 16 hours at RT. The solvents are evaporated under reduced pressure and the residue is dissolved in EtOAc (1000 ml) and washed with water (3x 750 ml). The organic phase is dried over MgS0₄, filtered and the solvent is evaporated under reduced pressure. The residue is purified by CC with EtOAc / hexane = 2 / 1to give 36.68 g of the title compound as an amorphous white powder. t_R [min] = 0.73; [M+H]⁺ = 450.96

Table 1 : Characterisation data for COMPOUND as free base in amorphous form

II. Preparation of crystalline forms of COMPOUND

Example 1 :

Preparation of seeding material of COMPOUND hydrochloride in crystalline Form 1

10 mg COMPOUND is mixed with 0.2 mL 0.1 M aq. HCI and 0.8 mL EtOH. The solvent is fully evaporated and 0.05 mL isopropanol is added. Alternatively 0.05 mL methyl-isobutylketone can be added. The sample is stored closed at room temperature for 4 days and crystalline material of COMPOUND hydrochloride in crystalline Form 1 is obtained. This material can be used as seeding material for further crystallization of COMPOUND hydrochloride in crystalline Form 1.

Example 2: Preparation and characterization of COMPOUND hydrochloride in crystalline form 1

5g COMPOUND is mixed with 0.9 mL 1 M aq. HCI and 20 mL EtOH. The solvent is evaporated and 25 mL isopropanol is added. Seeds of COMPOUND hydrochloride are added and the sample is allowed to stand at room temperature. After about 2 days the suspension is filtered and the solid residue is dried at reduced pressure (2 mbar for 1 hour) and allowed to equilibrate open for 2 hours at 24°C/46% relative humidity. The obtained solid is COMPOUND hydrochloride in crystalline Form 1

Table 2: Characterisation data for COMPOUND hydrochloride in crystalline form 1

PAT

WO 2018202689

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018202689

Examples

Reference Example 1

Synthesis of 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid

4,5-dibromo-2-(4-methoxy-2-nitrophenyl)-2H-1,2,3-triazole

4- Fluoro-3-nitroanisole (3.44 g, 1 eq.), 4,5-dibromo-2/-/-1 ,2,3-triazole (4.56 g, 1 eq.)¹, K₂C0₃ (2.78 g, 1 eq.) and DMF (30 mL) are heated to 1 10 °C for 32 h. The reaction mixture is cooled to 22 °C and treated with water (70 mL). The resulting suspension is filtered, washed with water (15 mL). The product is slurried in isopropanol (40 mL), filtered and dried under reduced pressure to yield a white solid. Yield: 6.42 g, 84%. Purity: 100% a/a (LC-MS method 2). ¹H NMR (400 MHz, CDCI₃) δ: 7.71 (d, J = 8.9 Hz, 1 H), 7.47 (d, J = 2.8 Hz, 1 H), 7.25 (dd, Ji = 2.8 Hz, J₂ = 8.9 Hz, 1 H), 3.97 (s, 3 H).

¹ X. Wang, L. Zhang, D. Krishnamurthy, C. H. Senanayake, P. Wipf Organic Letters 2010 12 (20), 4632-4635.

5- methoxy-2-(2H-1 ,2,3-triazol-2-yl)aniline

4, 5-Dibromo-2-(4-methoxy-2-nitrophenyl)-2/-/-1 ,2,3-triazole (2 g, 1 eq.), sodium acetate (1.3 g, 3 eq.), and 10% Pd/C 50% water wet (0.3 g) is suspended in EtOAc (10 mL). The mixture is heated to 50 °C and set under hydrogen until conversion is complete. The reaction mixture is filtered over Celite. The filtrate is washed with 1 N NaOH (10 mL) and water (15 mL). The organic layer is concentrated under reduced pressure to yield an oil. Yield: 0.95 g, 94%. Purity: 96% a/a (LC-MS method 2). ¹H NMR (400 MHz, DMSO) <5: 8.05 (s, 2 H), 7.53 (d, J = 8.9 Hz, 1 H), 6.49 (d, J = 2.7 Hz, 1 H), 6.30 (dd, Ji = 2.7 Hz, J₂ = 8.9 Hz, 1 H), 5.94 (s, 2 H), 3.74 (s, 3 H).

5-methoxy-2-(2H-1,2,3-triazol-2-yl)aniline monosulfate

5-Methoxy-2-(2/-/-1 ,2,3-triazol-2-yl)aniline (455 g, 1 eq ) is dissolved in isopropanol (3 L). To the solution is added cone. H2SO4 (235 g, 1 eq.) below 40 °C. The suspension is cooled to

20 °C and filtered. The cake is washed with isopropanol (700 mL) and TBME (1.5 L). The product is dried to obtain a white solid. Yield: 627 g, 91 %. Purity: 100% a/a (LC-MS method 2).

2-(2-iodo-4-methoxyphenyl)-2H-1,2,3-triazole

5-Methoxy-2-(2/-/-1 ,2,3-triazol-2-yl)aniline monosulfate (200 g, 1 eq.) is dissolved in 2 M aq. H2SO4 soln. (1.4 L) and cooled to -5 °C. To the solution is added a solution of sodium nitrite (62 g, 1.3 eq.) in water (600 mL) at -5 to 0 °C. The mixture is stirred at 0 °C for 30 min and then added to a preheated mixture of Kl (161 g, 1.4 eq.) in water (700 mL) at 65 °C. The resulting solution is stirred at 60 °C for 20 min, cooled to 20 °C and treated with a soln. of sulfamic acid (27 g, 0.4 eq.) in water (120 mL). The mixture is extracted with isopropyl acetate (2 L). The organic layer is washed with a mixture of 2 N NaOH (500 mL) and 40% NaHS0₃ soln. (100 mL), and a mixture of 1 N HCI (50 mL) and water (500 mL). The organic layer is concentrated to dryness. The residue is dissolved in isopropanol (700 mL) and cooled to 0 °C. The resulting suspension is filtered. The solid is dried under reduced pressure. Yield: 164 g, 79%. Purity: 100% a/a (LC-MS method 2). ¹H NMR (400 MHz, DMSO) <5: 8.08 (s, 2 H), 7.57 (d, J = 2.8 Hz, 1 H), 7.43 (d, J = 8.8 Hz, 1 H), 7.13 (dd, Ji = 2.8 Hz, J₂ = 8.8 Hz, 1 H), 3.85 (s, 3 H).

5-methoxy-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid

2-(2-lodo-4-methoxyphenyl)-2/-/-1 ,2,3-triazole (200 g, 1 eq.) is dissolved in THF (2 L) and cooled to 0 °C. 2 M iPrMgCI soln. in THF (350 mL, 1.05 eq.) is added at 0 °C. The mixture is cooled to -20 °C and C0₂ (gas) is bubbled into the solution over 30 min until the exothermicity is ceased. To the mixture is added 2 N HCI (600 mL) at 8 °C and concentrated under reduced pressure to remove 2.4 L solvent. The residue is extracted with TBME (1.6 L). The organic layer is washed with 1 N HCI (200 mL) and extracted with 1 N NaOH (600 mL and 200 mL). The aq. layer is filtered over charcoal (15 g), diluted with water (200 mL) and treated with 32% HCI (160 mL). The resulting suspension is filtered and washed with water (200 mL). Yield: 127 g, 87%. Purity: 100% a/a (LC-MS method 2); MP: 130 °C (DSC goldpan). The obtained product may be re-crystallized from toluene (MP: 130.9 °C) or water (MP: 130 °C).

Table Ref 1 : Characterisation data for 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid in crystalline form 2 (recrystallization from toluene)

Technique Data Summary Remarks

XRPD Crystalline see Fig. 8

Reference Example 2

Synthesis of 4-methyl-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid

4,5-Dibromo-2-(5-methyl-2-nitrophenyl)-2H-1 ,2,3-triazole

3- Fluoro-4-nitrotoluene (1367 g, 1 eq.), 4,5-dibromo-2/-/-1 ,2,3-triazole (1999 g, 1 eq.), K₂C0₃ (1340 g, 1.1 eq.) and DMF (1 1 L) is heated to 75 °C for 15 h. The reaction mixture is cooled to 22 °C and treated with water (18 L). The resulting suspension is filtered, washed with water (4 L). The product is washed with isopropanol (5 L), and dried under reduced pressure to yield a white solid. Yield: 281 1 g, 88%. Purity: 100% a/a (LC-MS method 2). ¹H NMR (400 MHz, DMSO) <5: 8.10 (d, J = 8.3 Hz, 1 H), 7.86 (d, J = 1.0 Hz, 1 H), 7.66 (dd, J1 = 0.9 Hz, J2 = 8.3 Hz, 1 H), 2.51 (s, 3 H).

4- Methyl-2-(2H-1 ,2,3-triazol-2-yl)aniline

4, 5-Dibromo-2-(5-methyl-2-nitrophenyl)-2/-/-1 ,2,3-triazole (205 g, 1 eq.), sodium acetate (149 g, 3.2 eq.), and 5% Pd/C 50% water wet (37.8 g) is suspended in EtOAc (0.8 L). The mixture is heated to 40-50 °C and set under hydrogen (2 bar) until conversion is complete. The reaction mixture is filtered over Celite. The filtrate is washed with water (300 mL), 2N NaOH (300 ml_+250 mL) and water (300 mL). The organic layer is concentrated under reduced pressure to yield a yellow oil. Yield: 132 g, 90%. Purity: 100% a/a (LC-MS method 2). ¹H NMR (400 MHz, DMSO) <5: 8.09 (s, 2 H), 7.48 (d, J = 1.3 Hz, 1 H), 6.98 (dd, J1 = 1.8 Hz, J2 = 8.3 Hz, 1 H), 6.85 (d, J = 8.2 Hz, 1 H), 5.79 (s, 2 H), 2.23 (s, 3 H).

4-Methyl-2-(2H-1,2,3-triazol-2-yl)aniline monosulfate

4-Methyl-2-(2/-/-1 ,2,3-triazol-2-yl) aniline (199 g, 1 eq ) is dissolved in isopropanol (1.7 L). To the solution is added cone. H2SO4 (118 g, 1.05 eq.) below 40 °C. The suspension is cooled to 20 °C and filtered. The cake is washed with isopropanol (500 mL). The product is dried to obtain a white solid. Yield: 278 g, 89%. Purity: 100% a/a (LC-MS method 2). ¹H NMR (400 MHz, DMSO) <5: 8.21 (s, 2 H), 7.70 (s, 1 H), 7.23 (s, 2 H), 2.35 (s, 3 H).

2-(2-iodo-5-methylphenyl)-2H-1 ,2,3-triazole

4-Methyl-2-(2/-/-1 ,2,3-triazol-2-yl)aniline monosulfate (1553 g, 1 eq.) is dissolved in 1 M aq. H2S04 Soln. (1 1 L) and cooled to -5 °C. To the solution is added a solution of sodium nitrite (433 g, 1.1 eq.) in water (4 L) at -5 to 0 °C. The mixture is stirred at 0 °C for 30 min and then added to a preheated mixture of potassium iodide (1325 g, 1.4 eq.) in water (4 L) at 55-70 °C. The resulting solution is stirred at 60 °C for 20 min, cooled to 20 °C and treated with a soln. of sulfamic acid (220 g, 0.4 eq.) in water (900 mL). The mixture is extracted with isopropyl acetate (13 L). The organic layer is washed with a mixture of 2 N NaOH (3.5 L) and 40% NaHSOs soln. (330 g), and a mixture of 1 N HCI (280 mL) and water (3.5 L). The

organic layer is concentrated to dryness. Yield: 1580 g, 97%. Purity: 91 % a/a (LC-MS method 2). ¹ H NMR (400 MHz, CDCI3) <5: 7.90 (s, 2 H), 7.87 (d, J = 8.1 Hz, 1 H), 7.34 (d, J = 1 .6 Hz, 1 H), 7.03-7.06 (m, 1 H), 2.40 (s, 3 H).

The crude product, together with a second batch (141 1 g) is purified by distillation on a short path distillation equipment at 120 °C jacket temperature, feeding tank (70 °C), cooling finger (20 °C) and at a pressure of 0.004 mbar. Yield: 2544 g (78%), Purity: 100 % a/a ()LC-MS method 2).

4-Methyl-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid

2-(2-lodo-5-methylphenyl)-2/-/-1 ,2,3-triazole (1250 g, 1 eq.) is dissolved in THF (13 L) and cooled to 0 °C. 2 M iPrMgCI soln. in THF (2.2 L, 1 eq.) is added at 0 °C. The mixture is cooled to -25 °C and CO2 (gas) is bubbled into the solution over 60 min until the exothermicity is ceased. To the mixture is added 2 N HCI (5 L) at 4 °C and concentrated under reduced pressure to remove 14.5 L solvent. The residue is extracted with TBME (10 L). The organic layer is extracted with 1 N NaOH (6 L and 3 L). The aq. layer is filtered over charcoal (15 g), diluted with water (200 mL) and treated with 32% HCI (1 .23 L). The resulting suspension is filtered and washed with water (5 L). Yield: 796 g, 89%. Purity: 100% a/a (LC-MS method 2); MP: 125 °C (DSC goldpan).

The following examples illustrate the invention.

Example 1 :

Example 1.1: Crystalline 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid potassium salt (potassium 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoate)

2-Bromo-5-methoxybenzoic acid (21 .5 g, 0.093 mol, 1 eq.) copper (I) iodide (0.886 g, 0.05 eq.), and K2CO3 powder (32.2 g, 2.5 eq.) were suspended in dioxane (600 mL) and water (8.4 mL). To the mixture were added 1 H-1 ,2,3-triazole (10.8 mL, 2 eq.) and trans-/V,/V-dimethylcyclohexane-1 ,2-diamine (1 .32 g, 0.1 eq.). The mixture was heated at reflux for 3.5 h. IPC showed full conversion. The ratio of the desired N(2) to the regioisomeric Λ/(1 ) isomer was 84: 16. The mixture was cooled to 40 °C and filtered. The cake was washed with dioxane (100 mL). The solid was dried to obtain 50.6 g of a blue solid. The ratio of N{2) to Λ/(1 ) isomer of was 98.6: 1 .4.

Table 1 : Characterisation data for 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid potassium salt in crystalline form 1

Example 1.2: Crystalline 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid

The solid of Example 1.1 was dissolved in water (300 mL). TBME (200 mL) and 32% aq. HCI (35 mL) was added. The aq. layer was separated and discarded. The organic layer was washed with a mixture of 2N aq. HCI (100 mL) and 32% aq. HCI (20 mL). The organic layer was washed with 1 N aq. HCI (50 mL). The organic layer was extracted with 1 N aq. NaOH (200 mL). The aq. layer was heated to 45 °C and traces of TBME were removed under reduced pressure. To the aq. layer was added at 45 °C 32% aq. HCI (20 mL). At a pH of 6 optionally seed crystals were added. The resulting suspension was filtered at 40 °C. The cake was washed with water (30 mL). The product was dried at 60 °C and 5 mbar. Yield: 12.4 g, 61 %. Purity: 100% a/a, t_R 0.63 min. Seed crystals may be obtained by careful crystallization according to the above procedure.

MP: 80 °C (DSC).

¹H NMR (400 MHz, DMSO) & 3.87 (s, 3 H), 7.26 (m, 2 H), 7.64 (d, J = 8.7 Hz, 1 H), 8.02 (s, 2 H), 13.01-13.22 (br, 1 H).

Table 2: Characterisation data for 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid in crystalline form 1

Example 1.3: Crystalline 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid potassium salt

5-Methoxy-2-(2/-/-1 ,2,3-triazol-2-yl)benzoic acid, e.g. obtained according to the procedure of Reference Example 1 (5 g, 0.0228 mol) and KHCO3 (1.61 g, 0.7 eq) were suspended in dioxane (100 mL) and water (1 mL). The mixture was heated at reflux for 40 min. The mixture was cooled to 20 °C and filtered. Yield: 2.56 g, 44%. ¹H NMR (400 MHz, D20) & 3.80 (s, 3 H), 7.04 (m, 2 H), 7.46 (d, J = 8.7 Hz, 1 H), 7.82 (s, 2 H). MP: 279.5°C (DSC shows additionally a broad endothermic event at about 153 °C to 203 °C which may be attributed to endothermic desolvations; melting is immediately followed by exothermic degradation).

Table 3: Characterisation data for 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid potassium salt in crystalline form 2

Example 1.4: Crystalline 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid potassium salt

In an alternative procedure, 2-Bromo-5-methoxybenzoic acid (20 g, 0.086 mol, 1 eq.) copper (I) iodide (0.824 g, 0.05 eq.), and K₂C0₃ powder (26.9 g, 2.25 eq.) were suspended in dioxane (494 mL). To the mixture was added 1 H-1 ,2,3-triazole (12 g, 2 eq.). The mixture was heated at reflux for 1 h. To the mixture was added water (12.5 g, 8 eq.). The mixture was heated at reflux for 2 h. Solvent (100 mL) was removed by distillation. The residue was cooled to 45 °C in 8 min, filtered and washed with dioxane (50 mL).

XRPD corresponds to crystalline form 1 (see Fig. 1 , Example 1.1 ).

Example 1.5: Crystalline 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid

The solid of Example 1.4 was dissolved in water (200 mL). The mixture was heated to 50 °C and 20% aq. H2SO4 (40 mL) was added to adjust the pH to 5. The mixture was filtered over Celite. The filtrate was treated at 45 °C with 20% aq. H₂S0₄ (40 mL). At pH 3 seeds (obtained for example using the procedure of reference example 1 ) were added. The suspension was stirred at 45 °C and filtered. The product was washed with water (20 mL) and dried at 60 °C and 10 mbar to yield a white solid. Yield: 10.8 g, 57%. Purity: 100% a/a, t_R 0.63 min.

Characterisation of 5-methoxy-2-(2/-/-1 ,2,3-triazol-2-yl)benzoic acid obtained according to Example 1.5:

XRPD corresponds to crystalline form 1 (see Fig. 2, Example 1.2).

Example 2:

Example 2.1: Crystalline 4-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid potassium salt (potassium 4-methyl-2-(2H-1,2,3-triazol-2-yl)benzoate)

2-Bromo-4-methylbenzoic acid (20 g, 0.093 mol, 1 eq.) copper (I) iodide (0.886 g, 0.05 eq.), and K2CO3 powder (32.2 g, 2.5 eq.) were suspended in dioxane (300 mL) and water (10.1 mL). To the mixture was added 1 A7-1 ,2,3-triazole (10.8 mL, 2 eq.) and trans-Λ/,ΛΑ-

dimethylcyclohexane-1 ,2-diamine (1 .32 g, 0.1 eq.). The mixture was heated at reflux for 4 h. IPC showed a conversion of 98.5%. The ratio of the desired N(2) to the regioisomeric Λ/(1 ) isomer was 75:25. The mixture was concentrated at normal pressure and external temperature of 130 °C. Solvent (100 mL) was removed. To the residue was added dioxane (100 mL) and the mixture was cooled to 45 °C and filtered. The cake was washed with dioxane (80 mL). The solid was dried to obtain 48.8 g of a blue solid. The ratio of N(2) to Λ/(1 ) isomer was 98.7: 1 .3.

Table 4: Characterisation data for 4-methyl-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid potassium salt in crystalline form 1

Example 2.2: Crystalline 4-methyl-2-(2H-1,2,3-triazol-2-yl) benzoic acid

The solid of Example 2.1 was dissolved in water (300 mL) and filtered. To the filtrate were added TBME (200 mL) and 32% aq. HCI (30 mL). The aq. layer was separated and discarded. The organic layer was washed with a mixture of 2N aq. HCI (100 mL) and 32% aq. HCI (10 mL). The organic layer was washed with 1 N aq. HCI (50 mL). The organic layer was extracted with 1 N aq. NaOH (200 mL). The aq. layer was heated to 45 °C and traces of TBME were removed under reduced pressure. To the aq. layer was added at 45 °C 32% aq. HCI (20 mL). At a pH of 6 seed crystals (obtained for example using the procedure of reference example 2) were added. The resulting suspension was filtered at 40 °C. The cake was washed with water (30 mL). The product was dried at 60 °C and 5 mbar. Yield: 1 1 .7 g, 62%. Purity: 100% a/a. t_R 0.66 min.

MP: 125 °C (DSC).

¹H NMR (400 MHz, DMSO) & 2.44 (s, 3 H), 7.41 (d, J = 7.9 Hz, 1 H), 7.56 (s, 1 H), 7.68 (d, J = 7.9 Hz, 1 H), 8.06 (s, 2 H), 12.53-13.26 (br, 1 H)

Table 5: Characterisation data for 4-methyl-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid in crystalline form 1

Technique Data Summary Remarks

XRPD Crystalline see Fig. 5

Example 2.3: Crystalline 4-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid potassium salt

4-Methyl-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid (5 g, 0.0246 mol) and KHC0₃ (1 .74 g , 0.7 eq) were suspended in dioxane ( 100 mL) and water (1 mL). The mixture was heated at reflux for 40 min. The mixture was cooled to 20 °C and filtered. Yield: 2.47 g, 42% . MP: 277 °C (DSC Alupan) ¹ H NMR (400 MHz, D20) & 2.32 (s, 3 H), 7.28 (d, J = 7.9 Hz, 1 H), 7.39 (m, 2 H), 7.84 (s, 2 H).

MP: 276.8 °C (DSC shows additionally a broad endothermic event at about 140 °C to 208 °C which may be attributed to endothermic desolvations; melting is immediately followed by exothermic degradation).

XRPD corresponds to crystalline form 1 (see Fig. 4, Example 2.1 ).

Reference Example 3:

Reference Example 3.1: Crystalline 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid sodium salt (sodium 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoate)

2-Bromo-5-methylbenzoic acid (20 g, 0.093 mol, 1 eq. ) copper (I) iodide (0.886 g, 0.05 eq.), Na2CC>3 powder (24.6 g, 2.5 eq.) were suspended in dioxane (300 mL) and water (10.1 mL). To the mixture was added 1 /-/-1 ,2,3-triazole ( 10.8 mL, 2 eq.) and 8-hydroxy quinoline ( 1 .35 g, 0.1 eq.). The mixture was heated at reflux for 5 h. IPC showed a conversion of >99%. The ratio of the desired N(2) to the regioisomeric Λ/(1 ) isomer was 78:22. The mixture was concentrated at normal pressure and external temperature of 135 °C. Solvent (100 mL) was removed. To the residue was added dioxane (100 mL) and the mixture was cooled to 45 °C and filtered. The cake was washed with dioxane (80 mL). The solid was dried to obtain 36.2 g of a yellow solid. The ratio of N(2) to Λ/( 1 ) isomer of was 99: 1 .

Table 6: Characterisation data for 5-methyl-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid sodium salt in crystalline form 1

Reference Example 3.2: Crystalline 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid

The solid obtaind in Reference Example 3.1 was dissolved in water (300 mL) and filtered. To the filtrate was added TBME (200 mL) and 32% aq. HCI (30 mL) was added. The aq. layer was separated and discarded. The organic layer was washed with 1 N aq. HCI ( 100 mL). The organic layer was washed with 1 N aq. HCI (50 mL). The organic layer was extracted with 1 N aq. NaOH (200 mL). The aq. layer was heated to 45 °C and traces of TBME were removed

under reduced pressure. To the aq. layer was added at 45 °C 32% aq. HCI (20 mL). At a pH of 6 seed crystals (obtained for example using the procedure of Reference example 2) were added. The resulting suspension was filtered at 40 °C. The cake was washed with water (30 mL). The product was dried at 60 °C and 5 mbar. Yield: 12.1 g, 64%. Purity: 100% a/a. t_R 0.67 min.

MP: 173 °C (DSC)

¹ H NMR (400 MHz, DMSO) & 2.42 (s, 3 H), 7.50-7.52 (m, 1 H), 7.58 (s, 1 H), 7.63 (m, 1 H), 8.05 (s, 2 H), 13.01 (s, 1 H).

Table 7: Characterisation data for 5-methyl-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid in crystalline form 1

Reference Example 3.3: Crystalline 5-methyl-2-(2H-1,2,3-triazol-2-yl) benzoic acid sodium salt

5-Methyl-2-(2/-/-1 ,2,3-triazol-2-yl)benzoic acid (5 g, 0.0246 mol) and Na₂C0₃ (1 .05 g, 0.4 eq) were suspended in dioxane ( 100 mL) and water (1 mL). The mixture was heated at reflux for 40 min. The mixture was cooled to 20 °C and filtered. Yield: 2.79 g, 50%. MP: 341 °C (DSC Alupan) ¹ H NMR (400 MHz, D20) & 2.32 (s, 3 H), 7.30 (m, 2 H), 7.43 (m, 1 H), 7.83 (s, 2 H).

XRPD corresponds to crystalline form 1 (see Fig. 6, Reference Example 3.1 ).

Reference Example 3.4: 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid potassium salt

2-Bromo-5-methylbenzoic acid (20 g, 0.093 mol, 1 eq. ) copper (I) iodide (0.886 g, 0.05 eq.), and K2CO3 powder (32.1 g, 2.5 eq.) were suspended in dioxane (600 mL). To the mixture was added 1 /-/-1 ,2,3-triazole ( 10.8 mL, 2 eq.) and 8-hydroxy quinoline ( 1 .35 g, 0.1 eq.). The mixture was heated at reflux for 4 h. IPC showed a conversion of >94%. The ratio of the desired N(2) to the regioisomeric Λ/( 1 ) isomer was 78:22. The mixture was cooled to 35 °C and filtered. The cake was washed with dioxane (100 mL). The products were dissolved in water and a LC-MS was recorded. The ratio of N(2) to Λ/(1 ) isomer of was 83: 17.

Reference Example 4.1: Methyl (S)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl) benzoyl)-2-methylpyrrolidine-2-carboxylate

5-Methoxy-2-(2/-/-1 ,2,3-triazol-2-yl) benzoic acid (100 g, 0.46 mol) was suspended in DCM (650 mL) and DMF (10 mL) at 20 °C. To this suspension was added oxalyl chloride (51 mL, 0.59 mol) over a period of 30 min. LC-MS showed 60% conversion to acid chloride intermediate. Oxalyl chloride (17.6 mL, 0.45 eq.) was added dropwise. LC-MS showed full conversion to acid chloride intermediate.

Methyl (S)-2-methylpyrrolidine-2-carboxylate hydrochloride (84 g, 0.47 mol) was suspended in DCM (800 mL) in a second flask. The suspension was cooled to 10 °C. Triethylamine (200 mL, 1.41 mol) was added over 15 min. The acid chloride solution was added to the reaction mixture at 10-20 °C over at least 15 min. The reaction mixture was washed with 1 M HCI (500 mL), 1 N NaOH (500 mL) and water (500 mL). The organic layer was concentrated to dryness to give a light-yellow solid as product. Yield: 157 g, 100%, 99% a/a (LC-MS), M+1 =345. ¹H NMR (400 MHz, DMSO) δ: 8.06 (s, 2 H), 7.79 (d, J = 8.9 Hz, 1 H), 7.21 (dd, J1 = 2.9 Hz, J2 = 8.9 Hz, 1 H), 6.85 (d, J = 1.9 Hz, 1 H), 3.89 (s, 3 H), 3.66 (s, 3 H), 3.29 (m, 1 H), 3.03 (m, 1 H), 2.08 (m, 1 H), 1.82 (m, 3 H), 1.50 (s, 3 H).

Reference Example 4.2: (S)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl) benzoyl)-2-methylpyrrolidine-2-carboxylic acid

Methyl (S)-1-(5-methoxy-2-(2/-/-1 ,2,3-triazol-2-yl) benzoyl)-2-methylpyrrolidine-2-carboxylate (157 g, 0.46 mol) was dissolved in MeOH (750 mL) at 20 °C. To this solution was added 16% NaOH (300 mL). The resulting solution was heated up to 80 °C and stirred for 60 min. Solvent was distilled off under reduced pressure (850 mL). The residue was taken up in DCM (1500 mL) and water (450 ml) at 20 °C. 32% HCI (200 mL) was added. Layers were separated and the organic layer was washed with water (450 mL). The organic layer was concentrated to the minimum stirring volume under reduced pressure. Toluene (750 mL) was added and solvent was further distilled under vacuum (150 mL distilled). The mixture was cooled to 20 °C and stirred for 15 min. The suspension was filtered at 20 °C. The cake was rinsed with toluene (150 mL) and then dried under reduced pressure at 50 °C to give a white solid as product. Yield: 128 g, 85%, 94% a/a (LC-MS), M+1 =331. Melting point: 178 °C (DSC). ¹H NMR (400 MHz, DMSO) δ: 12.3 (s, 1 H), 8.04 (s, 2 H), 7.79 (d, 1 H), 7.20 (dd, J1 = 2.8 Hz, J2 = 8.9 Hz, 1 H), 6.84 (m, 1 H), 3.88 (s, 3 H), 3.29 (m, 1 H), 2.99 (m, 1 H), 2.1 1 (m, 1 H), 1.81 (m, 3 H), 1.47 (s, 3 H).

Reference Example 4.3: (S)-N-(2-amino-4-chloro-3-methylphenyl)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl) benzoyl)-2 methylpyrrolidine-2-carboxamide

(S)-1-(5-Methoxy-2-(2/-/-1 ,2,3-triazol-2-yl) benzoyl)-2-methylpyrrolidine-2-carboxylic acid (128 g, 0.39 mol) was suspended in DCM (850 mL) and DMF (6 mL) at 20 °C. To this suspension was added oxalyl chloride (39 mL, 0.45 mol) over a period of 30 min. 4-Chloro-3-methylbenzene-1 ,2-diamine hydrochloride (75 g, 0.39 mol) was suspended in DCM (1300 mL) in a second flask. The suspension was cooled down to 10 °C. Triethylamine (180 mL, 1.27 mol) was added. The acid chloride solution was added to the reaction mixture at 10-20 °C over at least 15 min. Water (650 mL) was added to the reaction mixture. Layers were separated and the organic phase was concentrated under reduced pressure (1900 mL distilled out). TBME (1000 mL) was added and solvent was further distilled under vacuum (400 mL distilled). The mixture was finally cooled down to 20 °C and stirred for 15 min. The resulting suspension was filtered off at 20 °C. The cake was rinsed with TBME (250 mL) and then dried under reduced pressure at 50 °C to give a white solid as product. Yield: 145 g, 80%, 97% a/a (LC-MS), M+1=469. Melting point: 185 °C (DSC). ¹H NMR (400 MHz, DMSO) δ: 9.10-9.14 (m, 1 H), 7.88-8.12 (m, 2 H), 7.81-7.82 (m, 1 H), 7.38-7.44 (m, 1 H), 7.21 (dd, J1 = 2.7 Hz, J2 = 8.9 Hz, 1 H), 6.84 (d, J = 7.8 Hz, 1 H), 6.64 (d, J = 8.3 Hz, 1 H), 5.01 (brs, 2 H), 3.88 (s, 3 H), 3.61-3.73 (m, 1 H), 3.14-3.26 (m, 1 H), 2.25-2.30 (m, 1 H), 2.13 (s, 3 H), 1.97 (m, 3 H), 1.47-1.61 (m, 3 H).

Reference Example 4.4: (S)-(2-(5-chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl) (5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone hydrochloride

(S)-/V-(2-amino-4-chloro-3-methylphenyl)-1-(5-methoxy-2-(2H-1 ,2,3-triazol-2-yl) benzoyl)-2 methylpyrrolidine-2-carboxamide (145 g, 0.31 mol) was dissolved in isopropanol (870 mL) at 20 °C. To this solution was added carefully 5-6 N HCI in isopropanol (260 mL) over 10 min. the reaction mixture was then heated up to 90 °C and stirred for 4 hours. Water (28 mL) was added and the reaction mixture was stirred for an additional one hour. The reaction mixture was cooled to 20 °C. A light brown suspension was obtained which was filtered. The cake was rinsed with isopropanol (220 mL). The solid was finally dried under reduced pressure at 60 °C to give a beige solid. Yield: 133 g, 88%, 100% a/a (LC-MS), M+1 =451. Melting point: 277 °C (DSC). Ή NMR (400 MHz, DMSO) δ: 8.06 (s, 2 H), 7.76 (d, J = 8.9 Hz, 1 H), 7.63 (d, J = 8.8 Hz, 2 H), 7.55 (m, 1 H), 7.16 (dd, J1 = 2.7 Hz, J2 = 8.9 Hz, 1 H), 3.98 (m, 1 H), 3.90 (s, 3 H), 3.33 (m, 2H), 3.32 (m, 1 H), 2.74 (s, 3 H), 2.55 (m, 1 H), 2.23 (m, 1 H), 2.10 (m, 2 H), 1.95 (s, 3 H).

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REF

References

1. ^ Jump up to:^a b c https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214985s000lbl.pdf
2. ^ Jump up to:^a b Muehlan C, Vaillant C, Zenklusen I, Kraehenbuehl S, Dingemanse J (November 2020). “Clinical pharmacology, efficacy, and safety of orexin receptor antagonists for the treatment of insomnia disorders”. Expert Opin Drug Metab Toxicol. 16 (11): 1063–1078. doi:10.1080/17425255.2020.1817380. PMID 32901578.
3. ^ Jump up to:^a b c “Daridorexant – Idorsia Pharmaceuticals – AdisInsight”.
4. ^ Jump up to:^a b Equihua-Benítez AC, Guzmán-Vásquez K, Drucker-Colín R (July 2017). “Understanding sleep-wake mechanisms and drug discovery”. Expert Opin Drug Discov. 12 (7): 643–657. doi:10.1080/17460441.2017.1329818. PMID 28511597.
5. ^ “Daridorexant: FDA-Approved Drugs”. U.S. Food and Drug Administration (FDA). Retrieved 11 January 2022.
6. ^ “Idorsia receives US FDA approval of Quviviq (daridorexant)” (Press release). Idorsia Pharmaceuticals. 10 January 2022. Retrieved 11 January 2022 – via GlobeNewswire.

External links

• “Daridorexant”. Drug Information Portal. U.S. National Library of Medicine.
• Clinical trial number NCT03545191 for “Study to Assess the Efficacy and Safety of ACT-541468 in Adult and Elderly Subjects With Insomnia Disorder” at ClinicalTrials.gov
• Clinical trial number NCT03575104 for “Study to Assess the Efficacy and Safety of ACT-541468 in Adult and Elderly Subjects Suffering From Difficulties to Sleep” at ClinicalTrials.gov
• Clinical trial number NCT03679884 for “Study to Assess the Long Term Safety and Tolerability of ACT-541468 in Adult and Elderly Subjects Suffering From Difficulties to Sleep” at ClinicalTrials.gov

///////////////Daridorexant, Quviviq, FDA 2022, APPROVALS 2022, INSOMNIA,  ACT541468A, ACT 541468A. ACT-541468A, ACT541468, FDA 2022, APPROVALS 2022

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Tixagevimab

FDA 2021, 2021/12/8

ANTI VIRAL, CORONA VIRUS, PEPTIDE

Monoclonal antibody
Treatment and prevention of SARS-CoV-2 infection

• 2196
• AZD-8895
• AZD8895
• COV2-2196
• Tixagevimab
• Tixagevimab [INN]
• UNII-F0LZ415Z3B
• WHO 11776

• OriginatorVanderbilt University
• DeveloperAstraZeneca; INSERM; National Institute of Allergy and Infectious Diseases
• ClassAntivirals; Monoclonal antibodies
• Mechanism of ActionVirus internalisation inhibitors
• RegisteredCOVID 2019 infections

• 24 Dec 2021Pharmacodynamics data from a preclinical trial in COVID-2019 infections released by AstraZeneca
• 16 Dec 2021Pharmacodynamics data from a preclinical trial in COVID-2019 infections released by AstraZeneca
• 10 Dec 2021Registered for COVID-2019 infections (In the elderly, Prevention, In adults) in USA (IM) – Emergency Use Authorization

Tixagevimab/cilgavimab is a combination of two human monoclonal antibodies, tixagevimab (AZD8895) and cilgavimab (AZD1061) targeted against the surface spike protein of SARS-CoV-2^[4][5] used to prevent COVID-19. It is being developed by British-Swedish multinational pharmaceutical and biotechnology company AstraZeneca.^[6][7] It is co-packaged and given as two separate consecutive intramuscular injections (one injection per monoclonal antibody, given in immediate succession).^[2]

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Development

In 2020, researchers at Vanderbilt University Medical Center discovered particularly potent monoclonal antibodies, isolated from COVID-19 patients infected with a SARS-CoV-2 circulating at that time. Initially designated COV2-2196 and COV2-2130, antibody engineering was used to transfer their SARS-CoV-2 binding specificity to IgG scaffolds that would last longer in the body, and these engineered antibodies were named AZD8895 and AZD1061, respectively (and the combination was called AZD7442).^[8]

To evaluate the antibodies’ potential as monoclonal antibody based prophylaxis (prevention), the ‘Provent’ clinical trial enrolled 5,000 high risk but not yet infected individuals and monitored them for 15 months.^[9][10] The trial reported that those receiving the cocktail showed a 77% reduction in symptomatic COVID-19 and that there were no severe cases or deaths. AstraZeneca also found that the antibody cocktail “neutralizes recent emergent SARS-CoV-2 viral variants, including the Delta variant“.^[7]

In contrast to pre-exposure prophylaxis, the Storm Chaser study of already-exposed people (post-exposure prophylaxis) did not meet its primary endpoint, which was prevention of symptomatic COVID-19 in people already exposed. AZD7442 was administered to 1,000 volunteers who had recently been exposed to COVID.^[9]

Regulatory review

In October 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) started a rolling review of tixagevimab/cilgavimab, which is being developed by AstraZeneca AB, for the prevention of COVID-19 in adults.^[11]

Also in October 2021, AstraZeneca requested Emergency Use Authorization for tixagevimab/cilgavimab to prevent COVID-19 from the U.S. Food and Drug Administration (FDA).^[12][13]

Emergency use authorization

On 14 November 2021, Bahrain granted emergency use authorization.^[14]

On 8 December 2021, the U.S. Food and Drug Administration (FDA) granted emergency use authorization of this combination to prevent COVID-19 (before exposure) in people with weakened immunity or who cannot be fully vaccinated due to a history of severe reaction to coronavirus vaccines.^[15] The FDA issued an emergency use authorization (EUA) for AstraZeneca’s Evusheld (tixagevimab co-packaged with cilgavimab and administered together) for the pre-exposure prophylaxis (prevention) of COVID-19 in certain people aged 12 years of age and older weighing at least 40 kilograms (88 lb).^[2] The product is only authorized for those individuals who are not currently infected with the SARS-CoV-2 virus and who have not recently been exposed to an individual infected with SARS-CoV-2.^[2]

References

1. ^ “Evusheld- azd7442 kit”. DailyMed. Retrieved 4 January 2022.
2. ^ Jump up to:^a b c d “Coronavirus (COVID-19) Update: FDA Authorizes New Long-Acting Monoclonal Antibodies for Pre-exposure Prevention of COVID-19 in Certain Individuals”. U.S. Food and Drug Administration (FDA) (Press release). 8 December 2021. Retrieved 9 December 2021.  This article incorporates text from this source, which is in the public domain.
3. ^ O’Shaughnessy, Jacqueline A. (20 December 2021). “Re: Emergency Use Authorization 104” (PDF). Food and Drug Administration. Letter to AstraZeneca Pharmaceuticals LP | Attention: Stacey Cromer Berman, PhD. Archived from the original on 29 December 2021. Retrieved 18 January 2022.
4. ^ “IUPHAR/BPS Guide to PHARMACOLOGY”. IUPHAR. 27 December 2021. Retrieved 27 December 2021.
5. ^ “IUPHAR/BPS Guide to PHARMACOLOGY”. IUPHAR. 27 December 2021. Retrieved 27 December 2021.
6. ^ Ray, Siladitya (21 August 2021). “AstraZeneca’s Covid-19 Antibody Therapy Effective In Preventing Symptoms Among High-Risk Groups, Trial Finds”. Forbes. ISSN 0015-6914. Archived from the original on 21 August 2021. Retrieved 18 January 2022.
7. ^ Jump up to:^a b Goriainoff, Anthony O. (20 August 2021). “AstraZeneca Says AZD7442 Antibody Phase 3 Trial Met Primary Endpoint in Preventing Covid-19”. MarketWatch. Archived from the original on 21 August 2021. Retrieved 18 January 2022.
8. ^ Dong J, Zost SJ, Greaney AJ, Starr TN, Dingens AS, Chen EC, et al. (October 2021). “Genetic and structural basis for SARS-CoV-2 variant neutralization by a two-antibody cocktail”. Nature Microbiology. 6 (10): 1233–1244. doi:10.1038/s41564-021-00972-2. ISSN 2058-5276. PMC 8543371. PMID 34548634.
9. ^ Jump up to:^a b Haridy, Rich (23 August 2021). “”Game-changing” antibody cocktail prevents COVID-19 in the chronically ill”. New Atlas. Retrieved 23 August 2021.
10. ^ “AZD7442 PROVENT Phase III prophylaxis trial met primary endpoint in preventing COVID-19”. AstraZeneca (Press release). 20 August 2021. Retrieved 15 October 2021.
11. ^ “EMA starts rolling review of Evusheld (tixagevimab and cilgavimab)”. European Medicines Agency. 14 October 2021. Retrieved 15 October 2021.
12. ^ “AZD7442 request for Emergency Use Authorization for COVID-19 prophylaxis filed in US”. AstraZeneca US (Press release). 5 October 2021. Retrieved 15 October 2021.
13. ^ “AZD7442 request for Emergency Use Authorization for COVID-19 prophylaxis filed in US”. AstraZeneca (Press release). 5 October 2021. Retrieved 15 October 2021.
14. ^ Abd-Alaziz, Moaz; Elhamy, Ahmad (14 November 2021). Macfie, Nick (ed.). “Bahrain authorizes AstraZeneca’s anti-COVID drug for emergency use”. Reuters. Archived from the original on 23 November 2021. Retrieved 18 January 2022.
15. ^ Mishra, Manas; Satija, Bhanvi (8 December 2021). Dasgupta, Shounak (ed.). “U.S. FDA authorizes use of AstraZeneca COVID-19 antibody cocktail”. Reuters. Archived from the original on 13 January 2022. Retrieved 18 January 2022.

External links

“Tixagevimab”. Drug Information Portal. U.S. National Library of Medicine.

• “Cilgavimab”. Drug Information Portal. U.S. National Library of Medicine.
• Clinical trial number NCT04625972 for “Phase III Double-blind, Placebo-controlled Study of AZD7442 for Post-exposure Prophylaxis of COVID-19 in Adults (STORM CHASER)” at ClinicalTrials.gov
• Clinical trial number NCT04625725 for “Phase III Double-blind, Placebo-controlled Study of AZD7442 for Pre-exposure Prophylaxis of COVID-19 in Adult. (PROVENT)” at ClinicalTrials.gov

/////////////////Tixagevimab, ANTI VIRAL, CORONA VIRUS, PEPTIDE, Monoclonal antibody,  SARS-CoV-2 , WHO 11776, 2196, AZD-8895, AZD 8895, COV2-2196, COVID 19

Fam-trastuzumab deruxtecan-nxki

DS-8201a

Trastuzumab deruxtecan, sold under the brand name Enhertu, is an antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab (Herceptin) covalently linked to the topoisomerase I inhibitor deruxtecan (a derivative of exatecan).^[5][6] It is licensed for the treatment of breast cancer or gastric or gastroesophageal adenocarcinoma.^[6][7] Trastuzumab binds to and blocks signaling through epidermal growth factor receptor 2 (HER2/neu) on cancers that rely on it for growth. Additionally, once bound to HER2 receptors, the antibody is internalized by the cell, carrying the bound deruxtecan along with it, where it interferes with the cell’s ability to make DNA structural changes and replicate its DNA during cell division, leading to DNA damage when the cell attempts to replicate itself, destroying the cell.^[7]

It was approved for medical use in the United States in December 2019,^[6] in Japan in March 2020,^[8] in the European Union in January 2021,^[3][4] and in Australia in October 2021.^[1]

Trastuzumab deruxtecan (DS-8201a) is a HER2-targeting antibody-drug conjugate or ADC), structurally composed of a humanized anti-human HER2 (anti-hHER2) antibody, an enzymatically cleavable peptide-linker, and a proprietary topoisomerase I inhibitor payload (exatecan derivative or DX-8951 / DXd).

CLIP

Trastuzumab deruxtecan active substance, also referred to as DS-8201a, results from the conjugation of the following intermediates: – Trastuzumab monoclonal antibody (MAAL-9001); – A drug-linker (MAAA-1162a) comprised of a Topoisomerase I inhibitor derivative of exatecan (MAAA1181a) and a tetrapeptide based cleavable linker (MFAH). MAAL-9001 is covalently conjugated to approximately 8 molecules of MAAA-1162a. The linker is designed to be stable in plasma to reduce systemic exposure to the released MAAA-1181a drug. After cell internalisation, the released MAAA-1181a drug leads to apoptosis of the target tumour cells via the inhibition of topoisomerase I. The released MAAA-1181a drug is cell-membrane permeable, giving the ability to penetrate and act in surrounding cells. The effect of the ADC derives primarily from the released MAAA-1181a drug and to a lesser extent to the antibody-dependent cellular cytotoxic (ADCC) effector function of the conjugated antibody. The quality of MAAL-9001 antibody, MAAA-1162a drug-linker and the conjugated antibody is described in separate sections. The structures of DS-8201a, MAAA-1162a, MAAA-1181a, and MAAL-9001 are provided in Figure 1.

Full information for the active substance intermediate MAAA-1162a (C52H56FN9O13, MW 1034.05) was provided in the dossier. MAAA-1162a is composed of DX-8951·MsOH (drug intermediate) and MFAH (linker intermediate with maleimide functionality). The maleimide moiety reacts with the antibody (MAAL-9001) in the conjugation reaction to yield trastuzumab deruxtecan (DS-8201a). MAAA-1162a contains 3 stereogenic centres. General information was provided for solid state form, melting point, moisture sorption, UV-Vis absorption, optical rotation and solubility.

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CLIP

Fam-trastuzumab deruxtecan-nxki is an ADC that is comprised of an anti-HER2 antibody and the potent topoisomerase inhibitor exatecan [206]. These two entities are connected via a liner consisting of a maleimide conjugation handle that includes a protease-cleavable Gly-Gly-Phe-Gly (GGFG) tetrapeptide linker. This conjugation handle could release deruxtecan after internalization of the conjugate by the cancer cells that recognize the antibody. Fam-trastuzumabderuxtecan-nxki was developed by Daiichi Sankyo and AstraZeneca, and granted approval by the FDA in December 2019 [207]. There are approximately eight payload molecules/antibodies. Fam-trastuzumab deruxtecan-nxki has been approved for the treatment of adult patients with HER2 positive breast cancer that is unresectable or metastatic [208]. The synthesis of GGFG linker is described in Scheme 38 [209,210]. First, commercial tert-butyl 2-aminoacetate 274 was treated with Fmoc-L-Phe-OH 275 in the presence of HOBt and DIC, giving the corresponding product 276. Further deprotection of Fmoc group and amide formation gave the intermediate 278, which then underwent removal of Fmoc group to give GGFG linker 279. Lastly, treatment of 279 with the activated ester 280 provided 281.

Preparation of the payload exatecan derivative is described in Scheme 39 [211]. Aluminum-catalyzed Friedel-Crafts acylation of o-fluorotoluene 282 with succinic andydride 283 gave intermediate 284 in 90% yield. Next, hydrogenation reduction ofthe carbonyl group of 284, followed by reaction with SOCl2 in MeOH, furnished 285, which then underwent nitration with H2SO4 and KNO3 to give compound 286 in 48% overall yield. Hydrolysis of 286 followed by treatment with polyphosphoric acid (PPA) gave the cyclization product 287 in only 27% yield. The transformation of 287 into 288 was realized following the four-step sequence: carbonyl reduction with NaBH4, acid-mediated elimination reaction, PtO2-catalyzed hydrogenation reduction, and acetylation with Ac2O. Regioselective benzylic oxidation of 288 in acetone with KMnO4 gave 289 in 65% yield, further functionalization with butyl nitrile and Zn-mediated acylation gave compound 290 in 66% yield over 2 steps. Treatment of 290 with aqueous HCl provided hydrolysis product 291 in 50% yield, which then coupled with ethyl trifluoroacetate to provide intermediate 292. Polycyclic compound 294 was prepared from 292 and 293 through a [4+2] cycloaddition reaction in refluxing toluene. The key intermediate 294 next underwent acidic hydrolysis and chiral resolution to provide the chiral product 295. Further condensation reaction with 296 in the presence of T3P and Et3N in DCM and TFA-promoted removal of the Boc group formed 297. The synthesis of fam-trastuzumab deruxtecan-nxki is described in Scheme 40 [212]. The linker 281 was coupled to 297 in the presence of T3P and Et3N to give the linker-payload 298. Through transformation of the disulfide bonds into free sulfhydryl groups for linkage (DTT in pH 8.0 buffer), followed by re-oxidation of the remaining disulfide bonds with cysteine, the linker-payload 298 was conjugated to the anti-HER2 mAb to give fam-trastuzumab deruxtecan-nxki (XXIX) based on the amount of protein with approximately eight linker/payloads per antibody.

[206] T.N. Iwata, K. Sugihara, T. Wada, T. Agatsuma, [Fam-] trastuzumab deruxtecan (DS-8201a)-induced antitumor immunity is facilitated by the anti-CTLA-4 antibody in a mouse model, PLoS One 14 (2019) 0222280.

[207] R. Voelker, Another targeted therapy for ERBB2-positive breast cancer, JAMA 323 (2020) 408.

[208] S. Modi, C. Saura, T. Yamashita, Y.H. Park, S.B. Kim, K. Tamura, F. Andre, H. Iwata, Y. Ito, J. Tsurutani, J. Sohn, N. Denduluri, C. Perrin, K. Aogi, E. Tokunaga, S.A. Im, K.S. Lee, S.A. Hurvitz, J. Cortes, C. Lee, S. Chen, L. Zhang, J. Shahidi, A. Yver, I. Krop, Trastuzumab deruxtecan in previously treated HER2-positive breast cancer, N. Engl. J. Med. 382 (2020) 610-621.

[209] C.L. Law, K. Klussman, A.F. Wahl, P. Senter, S. Doronina, B. Toki, Treatment of immunological disorders using anti-CD30 antibodies, 2003.WO2003043583.

[210] S. Doronina, P.D. Senter, B.E. Toki, Pentapeptide compounds and uses related thereto, 2002. WO2002088172. [211] H. Terasawa, A. Ejima, S. Ohsuki, K. Uoto, Hexa-cyclic compound, 1998. US5834476.

[212] G.M. Dubowchik, R.A. Firestone, L. Padilla, D. Willner, S.J. Hofstead, K. Mosure, J.O. Knipe, S.J. Lasch, P.A. Trail, Cathepsin B-labile dipeptide linkers for lysosomal release of doxorubicin from internalizing immunoconjugates: model studies of enzymatic drug release and antigen-specific in vitro anticancer activity, Bioconjugate. Chem 13 (2002) 855-869.

Medical uses

Trastuzumab deruxtecan-nxki is indicated for the treatment of adults with unresectable (unable to be removed with surgery) or metastatic (when cancer cells spread to other parts of the body) HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting and for adults with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.^[6][7]

Side effects and label warnings

The most common side effects are nausea, fatigue, vomiting, alopecia (hair loss), constipation, decreased appetite, anemia (hemoglobin in blood is below the reference range), decreased neutrophil count (white blood cells that help lead your body’s immune system response to fight infection), diarrhea, leukopenia (other white blood cells that help the immune system), cough and decreased platelet count (component of blood whose function is to react to bleeding from blood vessel injury by clumping, thereby initiating a blood clot).^[6]

The prescribing information for fam-trastuzumab deruxtecan-nxki includes a boxed warning to advise health care professionals and patients about the risk of interstitial lung disease (a group of lung conditions that causes scarring of lung tissues) and embryo-fetal toxicity.^[6] Interstitial lung disease and pneumonitis, including cases resulting in death, have been reported with fam-trastuzumab deruxtecan-nxki.^[6]

History

The U.S. Food and Drug Administration (FDA) approved fam-trastuzumab deruxtecan-nxki in December 2019.^[6][9] The application for fam-trastuzumab deruxtecan-nxki was granted accelerated approval, fast track designation, and breakthrough therapy designation.^[6]

The FDA approved fam-trastuzumab deruxtecan-nxki based on the results of one clinical trial enrolling 184 female patients with HER2-positive, unresectable and/or metastatic breast cancer who had received two or more prior anti-HER2 therapies in the metastatic setting.^[6] These patients were heavily pretreated in the metastatic setting, receiving between two and 17 therapies prior to receiving fam-trastuzumab deruxtecan-nxki.^[6] Patients in the clinical trial received fam-trastuzumab deruxtecan-nxki every three weeks and tumor imaging was obtained every six weeks.^[6] The overall response rate was 60.3%, which reflects the percentage of patients who had a certain amount of tumor shrinkage with a median duration of response of 14.8 months.^[6]

The FDA granted the approval of Enhertu to Daiichi Sankyo.^[6]

On 10 December 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Enhertu, intended for the treatment of metastatic HER2-positive breast cancer.^[10][11] Enhertu was reviewed under EMA’s accelerated assessment program. The applicant for this medicinal product is Daiichi Sankyo Europe GmbH. Trastuzumab deruxtecan was approved for medical use in the European Union in January 2021.^[3][4]

In January 2021, the U.S. Food and Drug Administration (FDA) granted accelerated approval to fam-trastuzumab deruxtecan-nxki for the treatment of adults with locally advanced or metastatic HER2-positive gastric or gastroesophageal (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen.^[7][12]

Efficacy was evaluated in a multicenter, open-label, randomized trial (DESTINY-Gastric01, NCT03329690) in participants with HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma who had progressed on at least two prior regimens, including trastuzumab, a fluoropyrimidine- and a platinum-containing chemotherapy.^[7] A total of 188 participants were randomized (2:1) to receive fam-trastuzumab deruxtecan-nxki 6.4 mg/kg intravenously every three weeks or physician’s choice of either irinotecan or paclitaxel monotherapy.^[7]

References

1. ^ Jump up to:^a b c “Enhertu”. Therapeutic Goods Administration (TGA). 18 October 2021. Retrieved 22 October 2021.
2. ^ “Enhertu- fam-trastuzumab deruxtecan-nxki injection, powder, lyophilized, for solution”. DailyMed. Retrieved 15 January 2021.
3. ^ Jump up to:^a b c “Enhertu EPAR”. European Medicines Agency (EMA). 9 December 2020. Retrieved 31 March 2021.
4. ^ Jump up to:^a b c “Enhertu approved in the EU for the treatment of HER2-positive metastatic breast cancer” (Press release). AstraZeneca. 20 January 2021. Retrieved 21 January 2021.
5. ^ A HER2-Targeting Antibody–Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model
6. ^ Jump up to:^{a b c d e f g h i j k l m n} “FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies”. U.S.Food and Drug Administration (FDA) (Press release). 20 December 2019. Archived from the original on 20 December 2019. Retrieved 20 December 2019.  This article incorporates text from this source, which is in the public domain.
7. ^ Jump up to:^{a b c d e f} “FDA approves fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinomas”. U.S. Food and Drug Administration (FDA). 15 January 2021. Retrieved 15 January 2021.  This article incorporates text from this source, which is in the public domain.
8. ^ “Enhertu Approved in Japan for Treatment of Patients with HER2 Positive Unresectable or Metastatic Breast Cancer” (Press release). Daiichi Sankyo. 25 March 2020. Retrieved 21 January 2021 – via Business Wire.
9. ^ “Drug Trials Snapshot: Enhertu”. U.S. Food and Drug Administration (FDA). 20 December 2019. Retrieved 24 January 2020.  This article incorporates text from this source, which is in the public domain.
10. ^ “Enhertu: Pending EC decision”. European Medicines Agency (EMA). 10 December 2020. Retrieved 11 December 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
11. ^ “Trastuzumab deruxtecan recommended for approval in the EU by CHMP for HER2-positive metastatic breast cancer” (Press release). AstraZeneca. 14 December 2020. Retrieved 21 January 2021.
12. ^ “Enhertu approved in the US for the treatment of patients with previously treated HER2-positive advanced gastric cancer” (Press release). AstraZeneca. 18 January 2021. Retrieved 22 January 2021.

Further reading

• Iwata TN, Sugihara K, Wada T, et al. (October 2019). “[Fam-] trastuzumab deruxtecan (DS-8201a)-induced antitumor immunity is facilitated by the anti-CTLA-4 antibody in a mouse model”. PLOS ONE. 14 (10): e0222280. Bibcode:2019PLoSO..1422280I. doi:10.1371/journal.pone.0222280. PMC 6772042. PMID 31574081.
• Modi S, Saura C, Yamashita T, et al. (February 2020). “Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer”. N. Engl. J. Med. 382 (7): 610–621. doi:10.1056/NEJMoa1914510. PMC 7458671. PMID 31825192.

External links

• “Trastuzumab_deruxtecan”. Drug Information Portal. U.S. National Library of Medicine.
• Deruxtecan shows structure
• Clinical trial number NCT03329690 for “DS-8201a in Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing Gastric Cancer [DESTINY-Gastric01]” at ClinicalTrials.gov

////////////Fam-trastuzumab deruxtecan-nxki ,, FDA 2019, APROVALS 2019, DS-8201a

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ADAPALENE

• Molecular FormulaC₂₈H₂₈O₃
• Average mass412.520 Da
• CD 271
• CD-271

 CD-271, Differin, Differine106685-40-9[RN]
2-Naphthalenecarboxylic acid, 6-(4-methoxy-3-tricyclo[3.3.1.1^3,7]dec-1-ylphenyl)-
6-[3-(Adamantan-1-yl)-4-methoxyphenyl]-2-naphthoic acid
6-[4-methoxy-3-(tricyclo[3.3.1.1^3,7]dec-1-yl)phenyl]naphthalene-2-carboxylic acid AdapaleneCAS Registry Number: 106685-40-9 
CAS Name: 6-(4-Methoxy-3-tricyclo[3.3.1.13,7]dec-1-ylphenyl)-2-naphthalenecarboxylic acid 
Additional Names: 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid 
Manufacturers’ Codes: CD-271 
Trademarks: Differin (Galderma) 
Molecular Formula: C28H28O3 
Molecular Weight: 412.52 
Percent Composition: C 81.52%, H 6.84%, O 11.64% 
Literature References: Retinoid selective for retinoic acid receptor (RAR) subtypes b and g. Prepn: B. Shroot et al.,EP199636; eidem,US4717720 (1986, 1988 both to Cent. Int. Recher. Dermatol.); and structure-activity study: B. Charpentier et al.,J. Med. Chem.38, 4993 (1995). Pilot-scale synthesis: Z. Liu, J. Xiang, Org. Process Res. Dev.10, 285 (2006). HPLC determn in plasma and tissue: R. Ruhl, H. Nau, Chromatographia45, 269 (1997). Clinical pharmacology: C. E. M. Griffiths et al.,J. Invest. Dermatol.101, 325 (1993). Clinical trial in acne: A. Shalita et al.,J. Am. Acad. Dermatol.34, 482 (1996). Reviews of pharmacology and clinical potential: B. A. Bernard, Skin Pharmacol.6, Suppl. 1, 61-69 (1993); R. N. Brogden, K. L. Goa, Drugs53, 511-519 (1997); of clinical use in acne vulgaris: J. Waugh et al.,Drugs64, 1465-1478 (2004). 
Properties: White crystals from THF and ethyl acetate, mp 319-322°. pK 4.2. Stable to light. 
Melting point: mp 319-322° 
pKa: pK 4.2 
Therap-Cat: Antiacne. 
Keywords: Antiacne.

Adapalene is a third-generation topical retinoid primarily used in the treatment of mild-moderate acne, and is also used off-label to treat keratosis pilaris as well as other skin conditions.^[1] Studies have found adapalene is as effective as other retinoids, while causing less irritation.^[2] It also has several advantages over other retinoids. The adapalene molecule is more stable compared to tretinoin and tazarotene, which leads to less concern for photodegradation.^[2] It is also chemically more stable compared to the other two retinoids, allowing it to be used in combination with benzoyl peroxide.^[2] Due to its effects on keratinocyte proliferation and differentiation, adapalene is superior to tretinoin for the treatment of comedonal acne and is often used as a first-line agent. ^[3]

Adapalene is a third-generation topical retinoid with anti-comedogenic, comedolytic, and anti-inflammatory properties used to treat acne vulgaris in adolescents and adults.

SYN

AU 9047961; EP 0199636; US 4717720; US 5098895; US 5183889

J Med Chem 1995,38(26),4993

Friedel-Crafts condensation of 4-bromophenol (I) with 1-adamantanol (II) in the presence of H2SO4 yielded the adamantyl phenol (III). Subsequent alkylation of the sodium phenoxide of (III) with iodomethane produced the methyl ether (IV). The Grignard reagent (V), prepared from aryl bromide (IV), was converted to the organozincate derivative, and then subjected to a nickel-catalyzed cross-coupling with methyl 6-bromo-2-naphthoate (VI) to furnish adduct (VII). The target carboxylic acid was finally obtained by saponification of the methyl ester (VII).

SYN

CA 2021550; EP 0409740; FR 2649976; JP 1991063246; US 5073361; US 5149631

The bromination of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid methyl ester (I) with Br2 in dichloromethane gives the dibromo derivative (II), which is hydrogenated with tritium gas over Pd/C in THF containing TEA to yield the bis tritiated ester (III). Finally, ester (III) is hydrolyzed with NaOH in refluxing methanol to afford the target tritiated naphthoic acid.

SYN

doi:10.1071/CH9732303c US4717720

SYN

Adapalene (CAS NO.: 106685-40-9), with its systematic name of 2-Naphthalenecarboxylic acid, 6-(4-methoxy-3-tricyclo(3.3.1.1(sup 3,7))dec-1-ylphenyl)-, could be produced through many synthetic methods.

Following is one of the synthesis routes:
Firstly, Friedel-Crafts condensation of 4-bromophenol (I) with 1-adamantanol (II) in the presence of H₂SO₄ yields the adamantyl phenol (III). Next, subsequent alkylation of the sodium phenoxide of (III) with iodomethane produces the methyl ether (IV). The Grignard reagent (V), prepared from aryl bromide (IV), is converted to the organozincate derivative, and then subjects to a nickel-catalyzed cross-coupling with methyl 6-bromo-2-naphthoate (VI) to furnish adduct (VII). Finally, the target carboxylic acid is obtained by saponification of the methyl ester (VII).

Synthesis Reference

Graziano Castaldi, Pietro Allegrini, Gabriele Razzetti, Mauro Ercoli, “Process for the preparation of adapalene.” U.S. Patent US20060229465, issued October 12, 2006.

US20060229465

PATENT

https://patents.google.com/patent/US8119834B2/enThe chemical name for adapalene is 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid, which is represented by Compound I (below):

Adapalene has been approved by the FDA as a cream, a gel, a solution and pledgets for the topical treatment of acne vulgaris and is marketed under the tradename of DIFFERIN®.U.S. Pat. No. 4,717,720 (“the ‘720 patent”) discloses benzonaphthalene derivatives, including adapalene. The ‘720 patent describes a process for preparing adapalene (i.e., according to example 9c followed by example 10) that involves two reaction steps.The first step for preparing adapalene according to the ‘720 patent involves the preparation of the methyl ester of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid. According to example 9c of the ‘720 patent, 2-(1-adamantyl)-4-bromoanisole (also known as 1-(5-bromo-2-methoxyphenyl)adamantane) is converted to its organomagnesium derivative and then into its organozinc derivative. The organozinc derivative is next coupled to methyl 6-bromo-2-naphthoate by adding a catalytic amount of NiCl₂/DPPE complex (also known as [bis(diphenylphosphino) ethane]dichloronickel(II)). Upon completion of the reaction, the mixture is poured into water, extracted with dichloromethane, and then dried. The product is next isolated by column chromatography by eluting with a mixture of heptane (70%) and dichloromethane (30%). The resulting product is then recrystallized in ethyl acetate (yield: 78%).The second step for preparing adapalene according to the ‘720 patent involves hydrolyzing the product of step 1 (above). According to example 10 of the ‘720 patent, the ester obtained in Example 9c can be treated with a solution of soda in methanol followed by heating at reflux for 48 hours. The solvents are then evaporated and the resulting residue is taken up in water and acidified with concentrated HCl to neutralize the resulting adapalene sodium salt. The resulting solid is next filtered and dried under vacuum over phosphoric anhydride and then recrystallized in a mixture of tetrahydrofuran and ethyl acetate to yield adapalene (yield: 81%).The process of preparing adapalene according to the ‘720 patent is both difficult and uneconomical to conduct on an industrial scale. Regarding step 1, the use of dichloromethane is both toxic and hazardous for the environment. Additionally, purification of the intermediate product by column chromatography, followed by recrystallization, in order to obtain a crystalline product of acceptable purity is both expensive and laborious. Moreover, the step 1 process produces as a biaryllic C—C bond, and the catalytic coupling is noticeably exothermic. Regarding step 2, the synthesis of adapalene and/or its sodium salt requires a long reaction time (i.e., 48 hours) at methanol reflux and further requires a high ratio of solvent (volume) to product (mass).Additionally, according to the prior art, the manufacture of adapalene is not satisfactory for industrial implementation because the presence of high amounts of undesired by-products makes it necessary to use uneconomical purification procedures to isolate the product according to quality specifications. One significant undesired by-product produced during the Grignard reaction of step 1 in the synthesis of adapalene is 3,3′-diadamantyl-4,4′-dimethoxybiphenyl, which has not been previously described in the literature and which is represented by Compound VI (below):

The level of the by-product in a sample of adapalene, adapalene methyl ester and/or an adapalene salt can be determined using standard analytical techniques known to those of ordinary skill in the art. For example, the level can be determined by HPLC. A specific method for determining the level of this impurity is provided herein.Since the solubility of the dimeric by-product is very low in most solvents, the design of an economical industrial process that yields pure adapalene without the use of expensive chromatographic methods requires the selection of the proper solvents and conditions to inhibit formation of the by-product during the manufacturing process.Additionally, adapalene has been described as being white (see, e.g., Merck Index, 13^th ed., p. 29). It has been observed that adapalene has a tendency to yellow under certain synthetic conditions or due to the quality of the starting materials used in its preparation. In this regard, color must be attributed to the presence of some specific impurities that may or may not be detectable by conventional methods such as HPLC.

ExampleStep 2: Preparation of 6-[3-(1-adamantyl)-4-methoxy phenyl]-2-naphthoic acid-potassium Salt (i.e., Adapalene Potassium Salt)In a 2 L, five necked cylindrical reaction vessel equipped with reflux condenser, distillation kit, heat-transfer jacket, anchor impeller and purged with nitrogen, were added 48.38 g (dry equivalent amount) of methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate (1.134×10⁻¹ mol), wet with methanol, 2.73 g of tetrabutylammonium bromide (8.47×10⁻³ mol), 18.39 g of potassium hydroxide (85% alkali content, freshly titrated. 2.79×10⁻¹ mol) and 581 mL of toluene. The mixture was heated to reflux temperature, and the methanol/water was removed by distillation. The distilled mixture was replaced by pure toluene and the mixture was stirred at reflux for approximately three hours (including the time required for the distillation). The solution was then cooled to approximately 20-25° C., filtered and the resulting solid was washed with toluene.The solid was next suspended in 187 mL of tetrahydrofuran and stirred for approximately 30 minutes. Then, 375 mL of toluene was added, and the mixture was heated to reflux and maintained at that temperature for approximately 1 hour. The solution was then cooled to approximately 20-25° C., filtered, and the resulting solid washed with toluene. The toluene-wet product was then suspended in 256 mL of methanol, heated to reflux for approximately 30 minutes and cooled to 50-60° C. After cooling, 409 mL of water was added dropwise. The mixture was then again heated to reflux for approximately 15 additional minutes, cooled to room temperature and filtered. The resulting solid was washed with water to yield 50.69 g (wet) of adapalene potassium salt (1.12×10⁻¹ mol, dry equivalent amount calculated from loss on drying; yield: 99.18%). Analytical data: HPLC Purity (HPLC at 272 nm): 99.86%; Impurity (i.e., 3,3′-diadamantyl-4,4′-dimethoxybiphenyl) area percent (HPLC at 272 nm): not detected; ¹H-NMR (300 MHz, CD₃OD): δ 1.83 (broad s, 6H), 2.08 (broad s, 3H), 2.21 (broad s, 6H), 3.88 (s, 3H), 7.04 (d, 1H, J=8.4 Hz), 7.56 (overlapped, 1H, J=2.4, 9.6 Hz), 7.57 (overlapped s, 1H), 7.74 (dd, 1H, J=8.7, 1.8 Hz), 7.87 (d, 1H, J=9.0 Hz), 7.97 (d, 1H, J=8.7 Hz), 8.00 (broad d, 1H, J=0.9 Hz), 8.06 (dd, 1H, 8.4, J=1.8 Hz), 8.47 (broad d, 1H, J=0.9 Hz); ¹³C-NMR (75.4 MHz, CD₃OD): δ 30.6, 38.3, 41.8, 55.5, 113.3, 125.3, 126.4, 126.6, 127.8, 128.3, 130.0, 130.4, 133.0, 134.2, 136.1, 136.3, 139.7, 141.1, 159.9, 175.4.

ExampleStep 3: Preparation of 6-[3-(1-adamantyl)-4-methoxy phenyl]-2-naphthoic Acid (i.e., Adapalene)In 500 mL of methanol was added 49.59 g (1.10×10⁻¹ mol, dry equivalent amount) of the wet solid obtained in Example/Step 2, and the mixture was heated to reflux for 30 minutes and cooled to approximately 40° C. Next, 33.17 g of concentrated HCl was slowly added over approximately 1 hour with gentle stirring in order to ensure homogeneity, followed by the slow addition of 248 mL of water. The resulting mixture was stirred for approximately 30 additional minutes at approximately 40° C. and then cooled to room temperature, filtered and washed with methanol. The wet solid was then suspended with 1020 mL of tetrahydrofuran and heated to reflux for approximately 10 minutes or until complete dissolution. The solution was then cooled to approximately 35° C., the solid particles were removed by filtration, and the filter was washed with tetrahydrofuran.The collected mother liquors were heated to reflux, and 654 g of tetrahydrofuran was removed by distillation. The mixture was then cooled to approximately 55-60° C. Thereafter, 650 mL of methanol was added over approximately 10 minutes, and the mixture heated to reflux for approximately 30 minutes, cooled, and filtered. The resulting solid was filtered with methanol and dried at 80° C. in a vacuum oven to yield 40.54 g of adapalene (9.83×10⁻² mol; yield: 89.29% (from adapalene potassium salt); 88.56% (from adapalene methyl ester); and 78.67% (from methyl 6-bromo-2-naphthoate)). Analytical data: HPLC Purity (HPLC at 272 nm): 100.00%; Assay: 99.99%; Residue on Ignition: 0.02%; IR: matches reference.Table 1 (below) lists the peak assignments of the X-ray powder diffractogram of the adapalene obtained and are illustrated in FIG. 1.

ExampleStep 4: Preparation of 3,3′-diadamantyl-4,4′-dimethoxybiphenylTo a 100 mL rounded bottom reaction vessel equipped with a magnetic stirrer, thermometer, reflux condenser, pressure compensated addition funnel, were added 0.15 g of 1-(5-bromo-2-methoxyphenyl)adamantane, 0.47 g of magnesium turnings and 7 mL of tetrahydrofuran. The mixture was heated to approximately 35° C., and 0.13 mL of 1,2-dibromoethane were added to the mixture. Reaction exothermy self-heated the mixture. Next, a solution of 4.85 g of 1-(5-bromo-2-methoxyphenyl)adamantane and 28 mL of tetrahydrofuran was added to the mixture dropwise. During this addition, the temperature of the mixture dropped from reflux temperature to approximately 45° C. The reaction was then stirred for approximately 45 additional minutes at approximately 45° C. and was permitted to cool to approximately 22° C. Next, 2.3 g of ZnCl₂ was added to the mixture, resulting in an exothermic reaction that raised the temperature of the mixture to approximately 38° C. The mixture was then permitted to cool to approximately 22° C. and was stirred for approximately 1 hour at this temperature.Next, 0.03 g of Pd(OAc)₂ and 3.5 g of 1-(5-bromo-2-methoxyphenyl) adamantane were added to the mixture, followed by 25 mL of tetrahydrofuran in order to improve agitation, and the mixture was heated at reflux for approximately 24 hours. The resulting mixture was then evaporated to dryness and poured into 103 mL of 0.015 N HCl. Next, 150 mL of dichloromethane and 100 mL of water were added to yield a mixture consisting of a solid, an aqueous layer and an organic layer. The mixture was then filtered to separate the solid, the aqueous layer was discarded, and the organic layer was washed with 200 mL of water and decanted again. This process was repeated twice on the filtered solid. The three collected organic layers were evaporated to dryness, washed in methanol, and dried to yield 2.1 g of 3,3′-diadamantyl-4,4′-dimethoxybiphenyl (yield: 39.9%). Analytical data: Melting point: 288.1-289.1° C.; Elemental analysis: C 83.63%, H 8.73%; ¹H-NMR (300 MHz, CDCl₃): δ 1.78 (broad s, 12H), 2.08 (broad s, 6H), 2.15 (broad s, 12H), 3.86 (s, 6H), 6.92 (dm, 2H, J=8.1 Hz), 7.34 (dd, 2H, J=2.4, 8.1 Hz), 7.39 (d, 2H, J=2.4 Hz); ¹³C-NMR (75.4 MHz, CDCl₃): δ 29.2, 37.1, 37.2, 40.6, 55.1, 111.9, 125.0, 125.5, 134.0, 138.5, 157.8; MS (EI, 70 eV): m/z=484 (6), 483 (36), 412 (1,100), 410 (5), 347 (8), 135 (22), 107 (7), 93 (14), 79 (17), 67 (9), 55 (6); IR (Selected absorption bands): 2992, 2964, 2898, 2850, 1603 cm⁻¹. 

PATENT

https://patents.google.com/patent/WO2008126104A2/en

The compound 6-[3-(l – Adamantyl) – 4 – methoxy phenyl] – 2 – naphthoic acid of Formula – I known as Adapalene is used in dermatology, particularly in the treatment of acne vulgaris and psoriasis.

Formula – 1Adapalene was first time disclosed in the US patent No. 4,717,720 (herein after referred as ‘720) describe the preparation of compound of Formula – I using Negishi cross Coupling. In this reaction, 2-(l-adamantyl)-4-bromoanisole is converted to its organomagnesium compound followed by conversion to organozinc compound using zinc chloride and reacted with 6-bromo-2-methylnaphthoate employing transition metal as reaction catalyst such as palladium or nickel or one of its complexes with various phosphines. The reaction sequence is as shown in scheme – 1 below:

Scheme – 1 Another US patent No. 5,015,758 describe the process for preparation of 6[3-(l- Adamantyl) – 4 – methoxyphenyl] – 2 – naphthoate a penultimate step for preparation of Adapalene using Friedel – Crafts alkylation by reacting 1 – acetoxy adamantane with methyl – 6 – (4 – hydroxyphenyl) – 2 – naphthoate in presence of cone. Sulfuric acid in solvent n – heptane.Another improved process was published in the journal, Organic Process Research & Development, 2006, 10, 285 – 288 for the preparation of Adapalene. The process involves the preparation of intermediates followed by Negishi cross Coupling, where in 2-(l-adamantyl)-4-bromophenol was prepared using 1 – adamentol and 4- bromo phenol in presence of 98% sulphuric acid and acetic acid, which on methylation with dimethyl sulfate and potassium carbonate in dry acetone yields 2-(l -adamantyl)-4-bromoanisole. The compound is reacted with magnesium to form Grignard reagent and then coupled with 6-bromo-2-methylnaphthoate in presence of novel Pd – Zn double metal catalyst to yield ester, which on saponification followed by treatment with acid yields Adapalene.The recent published application WO 2006/108717 describes the use of Suzuki coupling for the synthesis of adapalene the compound of formula – 1. The application describes the preparation of 3-adamantyl-4-methoxyphenyl boronic acid from 2-(l-adamantyl)-4- bromoanisole using n-Butyl Lithium and triisopropyl borate in solvent tetrahydrofuran. Finally 3-adamantyl-4-methoxyphenyl boronic acid is reacted with 6-bromo-2-naphthoic acid involving Suzuki coupling in presence of Palladium acetate catalyst, a ligand 2 – (dicyclohexyl – phosphino) biphenyl, an inorganic base in solvent to get the compound adapalene.Some of the drawbacks of the prior art processes include:- The reported process in US patent 4717720, using Negishi cross coupling involves Grignard reaction. This requires anhydrous condition and a possibility of runaway reaction during Grignard reagent formation. Also the reaction involves the addition of fused ZnC12 and the preparation of the catalyst NiC12 (DPPE) complex, which needs to be freshly prepared increases the reaction step and has to be thoroughly dried before its use for coupling. Further the coupling reaction, results in the formation of dimer impurities during the organozinc compound reaction, with 2-(I -adamantyl)-4-bromoanisole and 6-bromo-2-methylnaphthoate respectively, which are difficult to remove. All these operations make the entire synthesis extremely sensitive and difficult to handle.Some of the above drawbacks were addressed by the authors in the article published in Organic Process Research & Development, 2006, 10, 285 – 288 for the preparation of Adapalene. But the use of Pd catalyst with the ligand like PdCl₂ (PPh₃)₂ for the direct conversion of Grignard reagent employing ZnCYl in catalytic amount has its own limitations. The use of Grignard reagent, palladium catalyst with ligand and hygroscopic ZnCl₂ demerits this process for industrial application.The recent published application WO 2006/108717; describes the use of Suzuki coupling for the synthesis of adapalene the compound of formula – I. The use of organo boronic acids for the Suzuki reaction has some limitations because of the indeterminate stoichiometry associated with the use of boronic acid, and its difficulty in purification and the byproducts formed during the reaction.Therefore there remains a need for an improved process for preparing adapalene that eliminates or substantially reduces the impurities, decreases the number of steps, and employs a more robust process which is convenient and cost efficient.

Examples:Example 1: Preparation of 3 – Adamantyl – 4 – methoxy phenyl potassium trifluoroborate:In a 2.0 L round bottom flask equipped with stirring and under nitrogen atmosphere 100.0 gm of 2-(l- adamantyl) 4-bromo anisole was charged in 600 ml tetrahydrofuran. The reaction mixture was cooled to -55 ± 5⁰C and 302 ml of 1.6 M n – butyl Lithium was slowly added and stirred. 87 ml of tri isopropyl borate was then charged and stirring was continued for 30 minutes at -55 ± 5°C. Cooling was removed and the temperature raised slowly to 25 – 30⁰C. 1.0 L of 1.2N hydrochloric acid was then charged and reaction mass was stirred for 30 minutes and separated the organic layer. The organic layer was charged in 1.0 L round bottom flask and freshly prepared aqueous solution of potassium hydrogen difluoride (230 gm, in 700 ml water) was added at 25 – 30⁰C and stirring was maintained till white precipitate is obtained. The mixture was continued under stirring and cooled to 0 – 5⁰C. The product, 3 – adamantyl – 4 – methoxyphenyl potassium trifluoroborate obtained was filtered, washed with 100 ml of ethyl acetate. The product was dried at 60 – 65°C till constant weight. Yield: 90.5 gm (83%), Purity: 99.0 % by HPLC.Example 2: Preparation of 6 – [3-(l- Adamantyl) – 4 – methoxyphenyl] – 2 – naphthoic acid:In a 1.0 L round bottom flask equipped with stirring and under nitrogen atmosphere 50.0 gm of 3 – Adamantyl – 4 – methoxyphenyl potassium trifluoroborate, 23 gm of 6- bromo -2-methyl napthoate in 300 ml tetrahydrofuran (THF) was charged. Stirred for 15 min and charged 3.0 gm of 5% Pd / C was and aqueous potassium hydroxide solution (50.0 gm in 300 ml water). Stirring was continued and the temperature was raised to reflux. The reaction mass was maintained for 10 hours at reflux and after the completion of the reaction, 200 ml of tetrahydrofuran: water (1 : 1) mixture was added and then filtered through hyflow bed at 45-50⁰C. The hyflow bed was washed with tetrahydrofuran: water (1 : 1) mixture at 45-50⁰C. 500 ml water was charged and the reaction mass was stirred. The aqueous layer was acidified with 1.2N hydrochloric acid. The precipitated mass was filtered, washed with water till neutral pH. The solid product obtained was dried at 70 – 75°C till constant weight to get 6 – [3-(l- adamantyl) – 4 – methoxyphenyl] – 2 – naphthoic acid.The dried product was taken in 300 ml of tetrahydrofuran and stirred. The temperature was raised to reflux and was maintained for 30 minutes. The heating was stopped and cooled the reaction mass to 25 – 30⁰C. 500 ml of n – heptane was charged to the reaction mass and stirred for 30 minutes. The reaction mass was then chilled to 0 – 5°C and maintained stirring at 0 – 5°C temperature for 2.0 hours. The precipitated solid was filtered and washed with n – heptane. The pure crystalline 6 – [3-(l- adamantyl) – 4 methoxyphenyl] – 2 – naphthoic acid thus obtained was then dried till constant weight. Yield = 40 – 42 gms (68 – 72 %)

PATENT

https://pubs.acs.org/doi/10.1021/op050223f

Strategies that were adopted during the process development of adapalene to achieve a cost-effective commercial-scale synthesis are described herein. These included (1) the use of AcOH/H₂SO₄ to afford 2-(1-adamantyl)-4-bromophenol in quantitative yield; (2) the dimethyl sulfate methylation to enhance the yield of methylation to 95%; (3) direct conversion of the Grignard reagent into methyl 6-(3-(1-adamantyl)-4-methoxyphenyl)-2-naphthoate by the catalysis of both PdCl₂(PPh₃)₂ and ZnCl₂ in high yield; (4) the use of EDTA-disodium salt dihydrate to ensure the heavy metal’s content within acceptable limits; (5) the use of toluene to simplify the original chromatographic purification to recrystallization. The pilot-scale synthesis of adapalene is described in detail in the Experimental Section.

6-(3-(1-Adamantyl)-4-methoxyphenyl)-2-naphthoic Acid (Adapalene, 1). Compound 7 (213 g, 0.5 mol) was treated with 2 N NaOH solution (8 L) in methanol under reflux for 8 h. After evaporation of methanol (7 L) and addition of water (1.5 L), the mixture was acidified until pH 1 with 6 N HCl and filtrated through Celite. The residue was washed with water (3 × 5 L), and recrystallized twice in THF (194 g/2 L/time) to give pure (99% HPLC) 1 (177 g, 85%), mp 320-322 °C.1 H NMR (400 MHz, DMSO-d6) δ 1.77 (6 H,s, H on 1-adamantyl), 2.07 (3 H, s, H on 1-adamantyl), 2.14 (6 H, s, H on 1-adamantyl), 3.87 (3 H, s, H on ArOCH3), 7.12 (1 H, d, J ) 8.4 Hz, 5-phenyl H), 7.58 (1 H, d, J ) 2.0 Hz, 2-phenyl H), 7.65 (1 H, dd, J ) 8.4 Hz, J ) 2.0 Hz, 6-phenyl H), 7.89 (1 H, d, J ) 8.8 Hz, 7-naphthyl H), 7.98 (1 H, d, J ) 8.8 Hz, 4-naphthyl H), 8.08 (1 H, d, J ) 8.8 Hz, 8-naphthyl H), 8.15 (1 H, d, J ) 8.8 Hz, 3-naphthyl H), 8.22 (1 H, s, 5-naphthyl H), 8.60 (1 H, s, 1-naphthyl H), 13.05 (1 H, s, -COOH); 13C NMR (100 MHz, DMSO-d6) δ 28.32, 36.47, 40.09, 55.28, 112.68, 123.99, 124.99, 125.38, 125.68, 125.85, 127.55, 128.25, 129.72, 130.13, 130.83, 131.46, 135.38, 138.00, 140.13, 158.53, 167.34.

PATENT

https://patents.google.com/patent/US7345189B2/en

Adapalene, namely 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid, having the following chemical formula:

is disclosed in U.S. Pat. No. 4,717,720 and used in dermatology, in particular for the treatment of acne vulgaris and psoriasis.According to U.S. Pat. No. 4,717,720 the synthesis is carried out by a coupling reaction between a magnesium, lithium or zinc derivative of a compound of formula (A) and a compound of formula (B), wherein X and Y are Cl, Br, F or I; R is hydrogen or alkyl; and Ad is 1-adamantyl

in an anhydrous solvent, in the presence of a metal transition or a complex thereof as a catalyst.A number of alternative synthetic approaches have been suggested in order to reduce the preparation costs. Surprisingly, particularly advantageous proved the alternative synthesis of the invention, which makes use of easily-available, low-cost 6-hydroxy-2-naphthoic acid alkyl esters as intermediates, and provides good yields.EXAMPLE 1Synthesis of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid methyl ester [adapalene methyl ester]A round-bottom flask is loaded with nickel (II) chloride (0.158 g; 1.2 mmol) and THF (20 ml), and tris(hydroxypropyl)phosphine (1.53 g; 7.3 mmol) is added to the mixture, which is refluxed for an hour, then cooled to a temperature of 50° C. and added in succession with methyl 6-tosyl-naphthalene-2-carboxylate (8.7 g; 24.4 mmol), potassium phosphate (10.38 g; 48.8 mmol), 4-methoxy-3-adamantyl-phenylboronic acid (7-g; 24.4 mmol), water (0.88 g; 48.8 mmol) and THF (50 ml). The mixture is heated under reflux for 24 hours, then cooled to a temperature ranging from 50 to 55° C. and added with water, adjusting pH to a value below 7 with acetic acid. After cooling to a temperature of 15° C., the resulting product is filtered, thereby obtaining crystalline adapalene methyl ester (8.5 g; 20.08 mmol) in 82% yield.¹H NMR: (300 MHz, DMSO), δ 8.6 (s, 1H), δ 8.3-7.8 (m, 6H), δ 7.7-7.5 (m, 2H), δ 7.1 (d, 1H), δ 3.9 (s, 3H), δ 3.85 (s, 3H), δ 2 (m, 9H), δ 1.7 (m, 6H).EXAMPLE 2Synthesis of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid sodium salt [adapalene sodium salt]A round-bottom flask is loaded with adapalene methyl ester (7 g; 16.41 mmol), THF (42 ml), water (7 ml) and a 50% w/w sodium hydroxide aqueous solution (1.44 g; 18.05 mmol). The mixture is refluxed for 6 hours, then added with water (133 ml) and THF is distilled off to a residual content of approx. 5% w/w, heated to a temperature of about 80° C. until complete dissolution of the solid, then cooled to 15° C. The crystallized product is filtered and dried under vacuum in a static dryer at a temperature of 50° C., thereby obtaining adapalene sodium salt (6.7 g; 15.42 mmol) in 94% yield.EXAMPLE 3Synthesis of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid [adapalene]A round-bottom flask is loaded with adapalene sodium salt (6.7 g; 15.42 mmol), THF (40 ml) and water (7 ml) and the mixture is refluxed until complete dissolution of the solid. The resulting solution is dropped into a 3% w/w acetic acid aqueous solution, keeping the temperature above 60-70° C., to precipitate adapalene acid (6.3 g; 15.27 mmol), which is filtered and dried under vacuum at a temperature of 50-60° C. The yield is 95%.EXAMPLE 4Synthesis of adapalene methyl esterA round-bottom flask is loaded with nickel (II) chloride (0.158 g; 1.2 mmol) and THF (20 ml), and tris(hydroxypropyl)phosphine (1.53 g; 7.3 mmol) is added. The mixture is refluxed for an hour, then cooled to a temperature of 50° C. and added in succession with methyl 6-tosyl-naphthalene-2-carboxylate (8.7 g; 24.4 mmol), potassium phosphate (10.38 g; 48.8 mmol), 4-methoxy-3-adamantyl-phenylboronic acid (9.1 g; 31.8 mmol), water (10.53 g; 585.3 mmol) and THF (50 ml). The mixture is refluxed for 24 hours, then cooled to a temperature ranging from 50 to 55° C., added with water, and adjusted to pH lower than 7 with acetic acid. After cooling to 15° C., the resulting product is filtered, thereby obtaining adapalene methyl ester (9 g; 21.2 mmol) in 86% yield.EXAMPLE 5Synthesis of adapalene methyl esterA round-bottom flask is loaded with nickel (II) chloride (0.158 g; 1.2 mmol) and THF (15 ml), and tris(hydroxypropyl)phosphine (1.53 g; 7.3 mmol) is added. The mixture is refluxed for an hour, then cooled to a temperature of 50° C. and added in succession with methyl 6-tosyl-naphthalene-2-carboxylate (8.7 g; 24.4 mmol), potassium carbonate (6.75 g; 48.8 mmol), 4-methoxy-3-adamantyl-phenylboronic acid (9.1 g; 31.8 mmol), water (8.11 g; 450.5 mmol) and THF (30 ml). The mixture is refluxed for 24 hours, then cooled to a temperature ranging from 50 to 55° C., added with water, and adjusted to pH lower than 7 with acetic acid. After cooling to 15° C., the resulting product is filtered, thereby obtaining adapalene methyl ester (9.37 g; 21.96 mmol) in 90% yield.EXAMPLE 6Synthesis of adapalene methyl esterA round-bottom flask is loaded with methyl 6-tosyl-naphthalene-2-carboxylate (8.7 g; 24.4 mmol), THF (70 ml), potassium phosphate (10.38 g; 48.8 mmol), 4-methoxy-3-adamantyl-phenylboronic acid (7 g; 24.4 mmol), nickel chloride complexed with tri(cyclohexyl)phosphine (0.83 g; 1.2 mmol) and tri(cyclohexyl)phosphine (1.37 g; 4.88 mmol). The mixture is refluxed for 24 hours, then cooled to a temperature ranging from 50 to 55° C. and added with water, then cooled to 15° C. The resulting product is filtered, thereby obtaining adapalene methyl ester (8.1 g; 19.0 mmol) in 78% yield.

PATENThttps://patents.google.com/patent/WO2008126104A2/en

The compound 6-[3-(l – Adamantyl) – 4 – methoxy phenyl] – 2 – naphthoic acid of Formula – I known as Adapalene is used in dermatology, particularly in the treatment of acne vulgaris and psoriasis.

Formula – 1Adapalene was first time disclosed in the US patent No. 4,717,720 (herein after referred as ‘720) describe the preparation of compound of Formula – I using Negishi cross Coupling. In this reaction, 2-(l-adamantyl)-4-bromoanisole is converted to its organomagnesium compound followed by conversion to organozinc compound using zinc chloride and reacted with 6-bromo-2-methylnaphthoate employing transition metal as reaction catalyst such as palladium or nickel or one of its complexes with various phosphines. The reaction sequence is as shown in scheme – 1 below:

Scheme – 1 Another US patent No. 5,015,758 describe the process for preparation of 6[3-(l- Adamantyl) – 4 – methoxyphenyl] – 2 – naphthoate a penultimate step for preparation of Adapalene using Friedel – Crafts alkylation by reacting 1 – acetoxy adamantane with methyl – 6 – (4 – hydroxyphenyl) – 2 – naphthoate in presence of cone. Sulfuric acid in solvent n – heptane.Another improved process was published in the journal, Organic Process Research & Development, 2006, 10, 285 – 288 for the preparation of Adapalene. The process involves the preparation of intermediates followed by Negishi cross Coupling, where in 2-(l-adamantyl)-4-bromophenol was prepared using 1 – adamentol and 4- bromo phenol in presence of 98% sulphuric acid and acetic acid, which on methylation with dimethyl sulfate and potassium carbonate in dry acetone yields 2-(l -adamantyl)-4-bromoanisole. The compound is reacted with magnesium to form Grignard reagent and then coupled with 6-bromo-2-methylnaphthoate in presence of novel Pd – Zn double metal catalyst to yield ester, which on saponification followed by treatment with acid yields Adapalene.The recent published application WO 2006/108717 describes the use of Suzuki coupling for the synthesis of adapalene the compound of formula – 1. The application describes the preparation of 3-adamantyl-4-methoxyphenyl boronic acid from 2-(l-adamantyl)-4- bromoanisole using n-Butyl Lithium and triisopropyl borate in solvent tetrahydrofuran. Finally 3-adamantyl-4-methoxyphenyl boronic acid is reacted with 6-bromo-2-naphthoic acid involving Suzuki coupling in presence of Palladium acetate catalyst, a ligand 2 – (dicyclohexyl – phosphino) biphenyl, an inorganic base in solvent to get the compound adapalene.Some of the drawbacks of the prior art processes include:- The reported process in US patent 4717720, using Negishi cross coupling involves Grignard reaction. This requires anhydrous condition and a possibility of runaway reaction during Grignard reagent formation. Also the reaction involves the addition of fused ZnC12 and the preparation of the catalyst NiC12 (DPPE) complex, which needs to be freshly prepared increases the reaction step and has to be thoroughly dried before its use for coupling. Further the coupling reaction, results in the formation of dimer impurities during the organozinc compound reaction, with 2-(I -adamantyl)-4-bromoanisole and 6-bromo-2-methylnaphthoate respectively, which are difficult to remove. All these operations make the entire synthesis extremely sensitive and difficult to handle.Some of the above drawbacks were addressed by the authors in the article published in Organic Process Research & Development, 2006, 10, 285 – 288 for the preparation of Adapalene. But the use of Pd catalyst with the ligand like PdCl₂ (PPh₃)₂ for the direct conversion of Grignard reagent employing ZnCYl in catalytic amount has its own limitations. The use of Grignard reagent, palladium catalyst with ligand and hygroscopic ZnCl₂ demerits this process for industrial application.The recent published application WO 2006/108717; describes the use of Suzuki coupling for the synthesis of adapalene the compound of formula – I. The use of organo boronic acids for the Suzuki reaction has some limitations because of the indeterminate stoichiometry associated with the use of boronic acid, and its difficulty in purification and the byproducts formed during the reaction.Therefore there remains a need for an improved process for preparing adapalene that eliminates or substantially reduces the impurities, decreases the number of steps, and employs a more robust process which is convenient and cost efficient.The present inventors have come out with a novel process which ameliorates the problems in the prior art with a one – pot process for the preparation of adapalene by employing Suzuki – Miyaura coupling involving the use of novel reactant 3-adamantyl-4- methoxyphenyl potassium trifiuoroborate.The novel compound 3 – Adamantyl – 4 – methoxy phenyl potassium trifiuoroborate, exhibit superb behavior in the Suzuki-Miyaura reaction and provides a powerful method for the preparation of 6 – [3-(I – Adamantyl) – 4 – methoxy phenyl] – 2 – naphthoic acid, the compound of Formula – I.

Formula – 1Potassium organotrifluoroborates are air and moisture-stable crystalline solids which can be stored for extended periods of time making it more industrial friendly to use on large scale production.The other advantage of the present invention is in the use of methyl ester of 6 – Bromo – 2 -naphthoic acid and isolating adapalane directly from the reaction instead of its methyl ester, the above process becomes more robust and eliminates the saponification step as reported in prior art. Also the use of readily and cheaply available Pd catalyst on carbon over the conventional and costlier Pd-catalyst with ligands offers further advantage to the current process.Examples:Example 1: Preparation of 3 – Adamantyl – 4 – methoxy phenyl potassium trifluoroborate:In a 2.0 L round bottom flask equipped with stirring and under nitrogen atmosphere 100.0 gm of 2-(l- adamantyl) 4-bromo anisole was charged in 600 ml tetrahydrofuran. The reaction mixture was cooled to -55 ± 5⁰C and 302 ml of 1.6 M n – butyl Lithium was slowly added and stirred. 87 ml of tri isopropyl borate was then charged and stirring was continued for 30 minutes at -55 ± 5°C. Cooling was removed and the temperature raised slowly to 25 – 30⁰C. 1.0 L of 1.2N hydrochloric acid was then charged and reaction mass was stirred for 30 minutes and separated the organic layer. The organic layer was charged in 1.0 L round bottom flask and freshly prepared aqueous solution of potassium hydrogen difluoride (230 gm, in 700 ml water) was added at 25 – 30⁰C and stirring was maintained till white precipitate is obtained. The mixture was continued under stirring and cooled to 0 – 5⁰C. The product, 3 – adamantyl – 4 – methoxyphenyl potassium trifluoroborate obtained was filtered, washed with 100 ml of ethyl acetate. The product was dried at 60 – 65°C till constant weight. Yield: 90.5 gm (83%), Purity: 99.0 % by HPLC.Example 2: Preparation of 6 – [3-(l- Adamantyl) – 4 – methoxyphenyl] – 2 – naphthoic acid:In a 1.0 L round bottom flask equipped with stirring and under nitrogen atmosphere 50.0 gm of 3 – Adamantyl – 4 – methoxyphenyl potassium trifluoroborate, 23 gm of 6- bromo -2-methyl napthoate in 300 ml tetrahydrofuran (THF) was charged. Stirred for 15 min and charged 3.0 gm of 5% Pd / C was and aqueous potassium hydroxide solution (50.0 gm in 300 ml water). Stirring was continued and the temperature was raised to reflux. The reaction mass was maintained for 10 hours at reflux and after the completion of the reaction, 200 ml of tetrahydrofuran: water (1 : 1) mixture was added and then filtered through hyflow bed at 45-50⁰C. The hyflow bed was washed with tetrahydrofuran: water (1 : 1) mixture at 45-50⁰C. 500 ml water was charged and the reaction mass was stirred. The aqueous layer was acidified with 1.2N hydrochloric acid. The precipitated mass was filtered, washed with water till neutral pH. The solid product obtained was dried at 70 – 75°C till constant weight to get 6 – [3-(l- adamantyl) – 4 – methoxyphenyl] – 2 – naphthoic acid.The dried product was taken in 300 ml of tetrahydrofuran and stirred. The temperature was raised to reflux and was maintained for 30 minutes. The heating was stopped and cooled the reaction mass to 25 – 30⁰C. 500 ml of n – heptane was charged to the reaction mass and stirred for 30 minutes. The reaction mass was then chilled to 0 – 5°C and maintained stirring at 0 – 5°C temperature for 2.0 hours. The precipitated solid was filtered and washed with n – heptane. The pure crystalline 6 – [3-(l- adamantyl) – 4 methoxyphenyl] – 2 – naphthoic acid thus obtained was then dried till constant weight. Yield = 40 – 42 gms (68 – 72 %)

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Medical uses

Per the recommendations of the Global Alliance on Improving Outcomes of Acne, retinoids such as adapalene are considered first-line therapy in acne treatment and are to be used either independently or in conjunction with benzoyl peroxide and/or an antimicrobial agent, like clindamycin, for maximum efficacy.^[4][5] Furthermore, adapalene, like other retinoids, increases the efficacy and penetration of other topical acne medications that are used in conjunction with topical retinoids as well as hastens the improvement of the post-inflammatory hyperpigmentation caused by acne.^[4] In the long term, it can be used as maintenance therapy.^[4]

Off-label uses

Adapalene has the unique ability to inhibit keratinocyte differentiation and decrease keratin deposition. This property makes adapalene an effective treatment for keratosis pilaris and callus. It may be used by men undergoing foreskin restoration to reduce excess keratin that forms a layer on the exterior of the human penis after circumcision. Other non-FDA approved indications that have been reported in the literature include treatment of warts, molluscum contagiosum, Darier disease, photoaging, pigmentary disorders, actinic keratoses and alopecia areata.^[6]

Side effects

Adapalene is known to cause mild adverse effects such as photosensitivity, irritation, redness, dryness, itching, and burning.^[2] It is common (between 1% and 10% of users)^[7] to experience a brief sensation of warmth or stinging, as well as dry skin, peeling and redness during the first 2–4 weeks of using the medication.^[4][8] These effects are considered mild and generally decrease over time.^[4][8] Any serious allergic reaction is rare.^[8] Furthermore, of the three topical retinoids, adapalene is often regarded as the most tolerable.^[6]

In pregnancy

Use of topical adapalene in pregnancy has not been well studied, but has a theoretical risk of retinoid embryopathy.^[9] Thus far, there is no evidence that the cream causes problems in the baby if used during pregnancy. Use is at the consumer’s own risk.^[10]

According to the Drugs and Lactation Database, topical adapalene has poor systemic absorption and results in low blood levels (less than 0.025 mcg/L) despite long term use, suggesting that there is low risk of harm for a nursing infant.^[11] However, it is recommended that the topical medication should not be applied to the nipple or any other area that may come into direct contact with the infant’s skin.^[11]

Interactions

Adapalene has been shown to enhance the efficacy of topical clindamycin, although adverse effects are also increased.^[12][13] Application of adapalene gel to the skin 3–5 minutes before application of clindamycin enhances penetration of clindamycin into the skin, which may enhance the overall efficacy of the treatment as compared to clindamycin alone.^[14]

Pharmacology

Unlike the retinoid tretinoin (Retin-A), adapalene has also been shown to retain its efficacy when applied at the same time as benzoyl peroxide due to its more stable chemical structure.^[15] Furthermore, photodegradation of the molecule is less of a concern in comparison to tretinoin and tazarotene.^[6]

Pharmacokinetics

Absorption of adapalene through the skin is low. A study with six acne patients treated once daily for five days with two grams of adapalene cream applied to 1,000 cm² (160 sq in) of skin found no quantifiable amounts, or less than 0.35 ng/mL of the drug, in the patients’ blood plasma.^[16] Controlled trials of chronic users of adapalene have found drug levels in the patients’ plasma to be 0.25 ng/mL.^[9]

Pharmacodynamics

Adapalene is highly lipophilic. When applied topically, it readily penetrates hair follicles and absorption occurs 5 minutes after topical application.^[2] After penetration into the follicle, adapalene binds to nuclear retinoic acid receptors (namely retinoic acid receptor beta and gamma).^[5][9] These complexes then bind to the retinoid X receptor which induces gene transcription by binding to specific DNA sites, thus modulating downstream keratinocyte proliferation and differentiation.^[2][9] This results in normalization of keratinocyte differentiation, allowing for decreased microcomedone formation, decreased clogging of pores, and increased exfoliation by increasing cell turnover.^[6][9][17] Adapalene is also regarded as an anti-inflammatory agent, as it suppresses the inflammatory response stimulated by the presence of Cutibacterium acnes,^[6] and inhibits both lipoxygenase activity and the oxidative metabolism of arachidonic acid into prostaglandins.^[9]

Adapalene selectively targets retinoic acid receptor beta and retinoic acid receptor gamma when applied to epithelial cells such as those found in the skin.^[18] Its agonism of the gamma subtype is largely responsible for adapalene’s observed effects. In fact, when adapalene is applied in conjunction with a retinoic acid receptor gamma antagonist, adapalene loses clinical efficacy.^[19]

Retinization is a common temporary phenomenon reported by patients when initiating use of retinols.^[20] Within the initial period of treatment, skin can become red, irritated, dry and may burn or itch from retinol application; however, this tends to resolve within four weeks with once a day use.^[20]

History

Adapalene is a research product of Galderma Laboratories, France.^[21] Adapalene was approved in 1996 by the U.S. Food and Drug Administration (FDA) for use in the treatment of acne.^[22]

Research

A study has concluded that adapalene can be used to treat plantar warts and may help clear lesions faster than cryotherapy.^[23]

References

1. ^ Rolewski SL (October 2003). “Clinical review: topical retinoids”. Dermatology Nursing. 15 (5): 447–50, 459–65. PMID 14619325.
2. ^ Jump up to:^{a b c d e f} Tolaymat, L; Zito, PM (January 2021). “Adapalene”. PMID 29494115.
3. ^ Asai, Yuka; Baibergenova, Akerke; Dutil, Maha; Humphrey, Shannon; Hull, Peter; Lynde, Charles; Poulin, Yves; Shear, Neil H.; Tan, Jerry; Toole, John; Zip, Catherine (2 February 2016). “Management of acne: Canadian clinical practice guideline”. Canadian Medical Association Journal. 188 (2): 118–126. doi:10.1503/cmaj.140665. PMC 4732962. PMID 26573753.
4. ^ Jump up to:^{a b c d e} Kolli, Sree S.; Pecone, Danielle; Pona, Adrian; Cline, Abigail; Feldman, Steven R. (2019-01-23). “Topical Retinoids in Acne Vulgaris: A Systematic Review”. American Journal of Clinical Dermatology. 20 (3): 345–365. doi:10.1007/s40257-019-00423-z. ISSN 1179-1888. PMID 30674002. S2CID 59225325.
5. ^ Jump up to:^a b Xiang, Leihong Flora; Troielli, Patricia; Lozada, Vicente Torres; Tan, Jerry; Suh, Dae Hun; See, Jo-Ann; Piquero-Martin, Jaime; Perez, Montserrat; Orozco, Beatriz (2018-02-01). “Practical management of acne for clinicians: An international consensus from the Global Alliance to Improve Outcomes in Acne”. Journal of the American Academy of Dermatology. 78 (2): S1–S23.e1. doi:10.1016/j.jaad.2017.09.078. hdl:10067/1492720151162165141. ISSN 0190-9622. PMID 29127053. S2CID 31654121.
6. ^ Jump up to:^{a b c d e} Tolaymat, Leila; Zito, Patrick M. (2018), “Adapalene”, StatPearls, StatPearls Publishing, PMID 29494115, retrieved 2019-03-13
7. ^ “Differin”. Swedish Drug Formulary. Retrieved 2017-12-11.
8. ^ Jump up to:^a b c “Adapalene Gel”. WebMD. Retrieved 2017-12-11.
9. ^ Jump up to:^{a b c d e f} Piskin, Suleyman; Uzunali, Erol (August 2007). “A review of the use of adapalene for the treatment of acne vulgaris”. Therapeutics and Clinical Risk Management. 3 (4): 621–624. ISSN 1176-6336. PMC 2374937. PMID 18472984.
10. ^ “FDA approves Differin Gel 0.1% for over-the-counter use to treat acne”. July 8, 2016. Retrieved 14 July 2016.
11. ^ Jump up to:^a b “Adapalene”, Drugs and Lactation Database (LactMed), National Library of Medicine (US), 2006, PMID 30000483, retrieved 2019-03-13
12. ^ Wolf JE, Kaplan D, Kraus SJ, Loven KH, Rist T, Swinyer LJ, Baker MD, Liu YS, Czernielewski J (September 2003). “Efficacy and tolerability of combined topical treatment of acne vulgaris with adapalene and clindamycin: a multicenter, randomized, investigator-blinded study”. Journal of the American Academy of Dermatology. 49 (3 Suppl): S211-7. doi:10.1067/S0190-9622(03)01152-6. PMID 12963897.
13. ^ Jain, GauravK; Ahmed, FarhanJ (2007). “Adapalene pretreatment increases follicular penetration of clindamycin: In vitro and in vivo studies”. Indian Journal of Dermatology, Venereology and Leprology. 73 (5): 326–9. doi:10.4103/0378-6323.34010. ISSN 0378-6323. PMID 17921613.
14. ^ Jain GK, Ahmed FJ (2007). “Adapalene pretreatment increases follicular penetration of clindamycin: in vitro and in vivo studies” (PDF). Indian Journal of Dermatology, Venereology and Leprology. 73 (5): 326–9. doi:10.4103/0378-6323.34010. PMID 17921613.
15. ^ Martin B, Meunier C, Montels D, Watts O (October 1998). “Chemical stability of adapalene and tretinoin when combined with benzoyl peroxide in presence and in absence of visible light and ultraviolet radiation”. The British Journal of Dermatology. 139 Suppl 52: 8–11. doi:10.1046/j.1365-2133.1998.1390s2008.x. PMID 9990414. S2CID 43287596.
16. ^ “DIFFERIN® (adapalene) Cream, 0.1% Label” (PDF). FDA. May 25, 2000. Retrieved 4 Oct 2011.
17. ^ “DIFFERIN® (adapalene) Gel, 0.3%” (PDF). Retrieved March 12, 2019.
18. ^ Mukherjee S, Date A, Patravale V, Korting HC, Roeder A, Weindl G (2006). “Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety”. Clinical Interventions in Aging. 1 (4): 327–48. doi:10.2147/ciia.2006.1.4.327. PMC 2699641. PMID 18046911.
19. ^ Michel S, Jomard A, Démarchez M (October 1998). “Pharmacology of adapalene”. The British Journal of Dermatology. 139 Suppl 52: 3–7. doi:10.1046/j.1365-2133.1998.1390s2003.x. PMID 9990413. S2CID 23084886.
20. ^ Jump up to:^a b “Differin Gel: An Over-the-Counter Retinoid for Acne”. http://www.differin.com. Retrieved 2019-03-25.
21. ^ US Patent 4717720A, Shroot B, Eustache J, Bernardon J-M, “Benzonaphthalene derivatives and compositions”, published 1988-01-05, issued 1988-01-05, assigned to Galderma Research and Development SNC
22. ^ “FDA approval of DIFFERIN® (adapalene) Solution, 0.1%”. FDA. May 31, 1996. Retrieved 29 May 2017.
23. ^ Gupta, Ramji; Gupta, Sarthak (2015). “Topical Adapalene in the Treatment of Plantar Warts; Randomized Comparative Open Trial in Comparison with Cryo-Therapy”. Indian Journal of Dermatology. 60 (1): 102. doi:10.4103/0019-5154.147835. ISSN 0019-5154. PMC 4318023. PMID 25657417.

External links

• “Adapalene”. Drug Information Portal. U.S. National Library of Medicine.

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Fluphenazine

• Molecular FormulaC₂₂H₂₆F₃N₃OS
• Average mass437.522 Da
• SQ 10733
• Squibb 16144

UNIIS79426A41Z

CAS number69-23-8

Product Ingredients

2-(Trifluoromethyl)-10-[3-[1-(b-hydroxyethyl)-4-piperazinyl]propyl]phenothiazine
200-702-9[EINECS]
4-(3-(2-(trifluoromethyl)phenothiazin-10-yl)propyl)-1-Piperazineethanol
4-[3-[2-(Trifluoromethyl)-10H-phenothiazin-10-yl]propyl]-1-piperazineethanol
69-23-8[RN]
فلوفينازين[Arabic][INN]
氟奋乃静[Chinese][INN]
1-(2-Hydroxyethyl)-4-[3-(trifluoromethyl-10-phenothiazinyl)propyl]piperazine
10-[3′-[4”-(b-Hydroxyethyl)-1”-piperazinyl]propyl]-3-trifluoromethylphenothiazine
1-Piperazineethanol, 4-(3-(2-(trifluoromethyl)-10H-phenothiazin-10-yl)propyl)-
1-Piperazineethanol, 4-[3-[2-(trifluoromethyl)-10H-phenothiazin-10-yl]propyl]-

read https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/071413s019lbl.pdfFluphenazineCAS Registry Number: 69-23-8 
CAS Name: 4-[3-[2-(Trifluoromethyl)-10H-phenothiazin-10-yl]propyl]-1-piperazineethanol 
Additional Names: 1-(2-hydroxyethyl)-4-[3-(trifluoromethyl-10-phenothiazinyl)propyl]piperazine; 10-[3¢-[4¢¢-(b-hydroxyethyl)-1¢¢-piperazinyl]propyl]-3-trifluoromethylphenothiazine; 2-(trifluoromethyl)-10-[3-[1-(b-hydroxyethyl)-4-piperazinyl]propyl]phenothiazine 
Manufacturers’ Codes: S-94; SQ-4918 
Molecular Formula: C22H26F3N3OS, Molecular Weight: 437.52 
Percent Composition: C 60.39%, H 5.99%, F 13.03%, N 9.60%, O 3.66%, S 7.33% 
Literature References: Prepn: H. L. Yale, F. Sowinski, J. Am. Chem. Soc.82, 2039 (1960); GB829246; G. E. Ullyot, US3058979 (1960, 1962 both to SKF); GB833474 (1960 to Scherico), C.A.54, 21143e (1960); E. L. Anderson et al.,Arzneim.-Forsch.12, 937 (1962); H. L. Yale, R. C. Merrill, US3194733 (1965 to Olin Mathieson). Metabolism: J. Dreyfuss, A. J. Cohen, J. Pharm. Sci.60, 826 (1971). Comprehensive description of the enanthate ester: K. Florey, Anal. Profiles Drug Subs.2, 245-262 (1973); of the dihydrochloride: idem,ibid. 263-294; of the decanoate ester: G. Clarke, ibid.9, 275-294 (1980). 
Properties: Dark brown viscous oil, bp0.5 268-274°; bp0.3 250-252°. 
Boiling point: bp0.5 268-274°; bp0.3 250-252° 
Derivative Type: Dihydrochloride 
CAS Registry Number: 146-56-5 
Trademarks: Anatensol (BMS); Dapotum (BMS); Lyogen (Promonta Lundbeck); Moditen (Sanofi Winthrop); Omca (BMS); Pacinol (Schering); Permitil (Schering); Prolixin (Apothecon); Siqualone (BMS); Tensofin (BMS); Valamina (Schering) 
Molecular Formula: C22H26F3N3OS.2HCl, Molecular Weight: 510.44 
Percent Composition: C 51.77%, H 5.53%, F 11.17%, N 8.23%, O 3.13%, S 6.28%, Cl 13.89% 
Properties: Crystals from abs ethanol, mp 235-237°. Also reported as mp 224.5-226°. 
Melting point: mp 235-237°; Also reported as mp 224.5-226° 

Derivative Type: Decanoate 
CAS Registry Number: 5002-47-1 
Manufacturers’ Codes: SQ-10733; QD-10733 
Trademarks: Modecate (Sanofi Winthrop) 
Molecular Formula: C32H44F3N3O2S, Molecular Weight: 591.77 
Percent Composition: C 64.95%, H 7.49%, F 9.63%, N 7.10%, O 5.41%, S 5.42% 
Properties: Pale yellow-orange, viscous liquid. Slowly crystallizes at room temp. mp 30-32°. Very sol in chloroform, ether, cyclohexane, methanol, ethanol. Insol in water. 
Melting point: mp 30-32° 
Derivative Type: Enanthate 
CAS Registry Number: 2746-81-8 
Manufacturers’ Codes: SQ-16144 
Molecular Formula: C29H38F3N3O2S, Molecular Weight: 549.69Percent Composition: C 63.36%, H 6.97%, F 10.37%, N 7.64%, O 5.82%, S 5.83% 
Properties: Pale yellow to yellow-orange viscous liquid or oily solid. 
Therap-Cat: Antipsychotic. 
Keywords: Antipsychotic; Phenothiazines.

Fluphenazine is a phenothiazine used to treat patients requiring long-term neuroleptic therapy.

A phenothiazine used in the treatment of psychoses. Its properties and uses are generally similar to those of chlorpromazine.

Fluphenazine, sold under the brand names Prolixin among others, is a high-potency typical antipsychotic medication.^[1] It is used in the treatment of chronic psychoses such as schizophrenia,^[1][2] and appears to be about equal in effectiveness to low-potency antipsychotics like chlorpromazine.^[3] It is given by mouth, injection into a muscle, or just under the skin.^[1] There is also a long acting injectable version that may last for up to four weeks.^[1] Fluphenazine decanoate, the depot injection form of fluphenazine, should not be used by people with severe depression.^[4]

Common side effects include movement problems, sleepiness, depression and increased weight.^[1] Serious side effects may include neuroleptic malignant syndrome, low white blood cell levels, and the potentially permanent movement disorder tardive dyskinesia.^[1] In older people with psychosis as a result of dementia it may increase the risk of dying.^[1] It may also increase prolactin levels which may result in milk production, enlarged breasts in males, impotence, and the absence of menstrual periods.^[1] It is unclear if it is safe for use in pregnancy.^[1]

Fluphenazine is a typical antipsychotic of the phenothiazine class.^[1] Its mechanism of action is not entirely clear but believed to be related to its ability to block dopamine receptors.^[1] In up to 40% of those on long term phenothiazines, liver function tests become mildly abnormal.^[5]

Fluphenazine came into use in 1959.^[6] The injectable form is on the World Health Organization’s List of Essential Medicines.^[7] It is available as a generic medication.^[1] It was discontinued in Australia around mid 2017.^[8]

Synthesis Reference

Ullyot, G.E.; U.S. Patent 3,058,979; October 16, 1962; assigned to Smith Kline & French Laboratories.

US3058979

syn

syn

Antipsychotics (Neuroleptics)

R.S. Vardanyan, V.J. Hruby, in Synthesis of Essential Drugs, 2006

Fluphenazine

Fluphenazine, 4-[3-[2-(trifluoromethyl)phenothiazin-10-yl]propyl]-1-piperazineethanol (6.1.8), is synthesized by any of the methods described above [21–27]. Alkylation of 2-trifluoromethylphenothiazine using 4-formyl-1-piperazineylpropylchlo-ride in the presence of sodium amide synthesizes 2-trifluoromethyl-10-[3-(4-formyl-1-piperazinyl)propyl]phenothizine (6.1.6). Further alkaline hydrolysis removes the N-formyl group, giving 2-trifluoromethyl-10-[3-(1-piperazinyl)propyl]phenothiazine (6.1.7). This is alkylated by 2-bromethanol-1 acetate, which upon further acidic hydrolysis removes the protecting acetyl group, yielding fluphenazine (6.1.8) [27,28].

Fluphenazine is an extremely strong antipsychotic drug. A stimulatory effect accompanies the neuroleptic effect. It is used in psychiatry for treating various forms of schizophrenia and other mental illnesses. The most common synonyms are fluorphenazine, moditen, dapotum, motival, permitil, and others.SYN

Manufacturing Process

A suspension of 69.0 grams of 2-trifluoromethylphenothiazine in 1 liter of toluene with 10.9 grams of sodium amide is heated at reflux with high speed stirring for 15 minutes. A solution of 54.1 grams of 1-formyl-4-(3’chloropropyl)-piperazine, [prepared by formylating 1-(3′-hydroxypropyl)piperazine by refluxing in an excess of methyl formate, purifying the 1-formyl4-(3′-hydroxypropyl)-piperazine by vacuum distillation, reacting this compound with an excess of thionyl chloride at reflux and isolating the desired 1-formyl-4(3′-chloropropyl)-piperazine by neutralization with sodium carbonate solution followed by distillation] in 200 ml of toluene is added. The reflux period is continued for 4 hours. The cooled reaction mixture is treated with 200 ml of water. The organic layer is extracted twice with dilute hydrochloric acid. The acid extracts are made basic with ammonia and extracted with benzene. The volatiles are taken off in vacuo at the steam bath to leave a dark brown oil which is 10-[3′-(N-formylpiperazinyl)-propyl]-2trifluoromethylphenothiazine. It can be distilled at 260°C at 10 microns, or used directly without distillation if desired.
A solution of 103.5 grams of 10-[3′-(N-formylpiperazinyl)-propyl]-2trifluoromethylphenothiazine in 400 ml of ethanol and 218 ml of water containing 26 ml of 40% sodium hydroxide solution is heated at reflux for 2 hours. The alcohol is taken off in vacuo on the steam bath. The residue is swirled with benzene and water. The dried benzene layer is evaporated in vacuo. The residue is vacuum distilled to give a viscous, yellow oil, 10(3’piperazinylpropyl)-2-trifluoromethylphenothiazine, distilling at 210° to235°C at 0.5 to 0.6 mm.
A suspension of 14.0 grams of 10-(3′-piperazinylpropyl)-2trifluoromethylphenothiazine, 6.4 grams of β-bromoethyl acetate and 2.6 grams of potassium carbonate in 100 ml of toluene is stirred at reflux for 16 hours. Water (50 ml) is added to the cooled mixture. The organic layer is extracted into dilute hydrochloric acid. After neutralizing the extracts and taking the separated base up in benzene, a viscous, yellow residue is obtained by evaporating the organic solvent in vacuo. This oil is chromatographed on alumina. The purified fraction of 7.7 grams of 10-[3′-(Nacetoxyethylpiperazinyl)-propyl] -2-trifluoromethylphenothiazine is taken up in ethyl acetate and mixed with 25 ml of alcoholic hydrogen chloride. Concentration in vacuo separates white crystals of the dihydrochloride salt, MP 225° to 227°C.
A solution of 1.0 gram of 10-[3′-(N-acetoxyethylpiperazinyl)-propyl]-2trifluoromethylphenothiazine in 25 ml of 1 N hydrochloric acid is heated at reflux briefly. Neutralization with dilute sodium carbonate solution and extraction with benzene gives the oily base, 10-[3′-(N-βhydroxyethylpiperazinyl)-propyl]-2-trifluoromethylphenothiazine. The base is reacted with an excess of an alcoholic hydrogen chloride solution. Trituration with ether separates crystals of the dihydrochloride salt, MP 224° to 226°C, (from US Patent 3,058,979).

Chemical Synthesis

Fluphenazine, 4-[3-[2-(trifluoromethyl)phenothiazin-10-yl]propyl]-1- piperazineethanol (6.1.8), is synthesized by any of the methods described above [21–27]. Alkylation of 2-trifluoromethylphenothiazine using 4-formyl-1-piperazineylpropylchloride in the presence of sodium amide synthesizes 2-trifluoromethyl-10-[3-(4-formyl- 1-piperazinyl)propyl]phenothizine (6.1.6). Further alkaline hydrolysis removes the N-formyl group, giving 2-trifluoromethyl-10-[3-(1-piperazinyl)propyl]phenothiazine (6.1.7). This is alkylated by 2-bromethanol-1 acetate, which upon further acidic hydrolysis removes the protecting acetyl group, yielding fluphenazine (6.1.8) [27,28].

SYN

Indian Pat. Appl., 2014MU02033,

PATENT

CN 105153062

https://patents.google.com/patent/CN105153062A/en

Embodiment 1(1) preparation of 2-trifluoromethyl thiodiphenylamine: by 100g(0.356mol) Tecramine adds in reaction flask, be heated to 180-190 DEG C, open and stir, treat that it melts in backward reaction flask completely and add 10g(0.178mol) iron powder, stirring reaction about 2 hours at 180-190 DEG C of temperature, after reaction terminates, reaction solution is cooled to pour in beaker by reaction solution while hot when 100 DEG C, and iron powder stays (used water flushing) bottom reaction flask.Reaction solution is added underpressure distillation in clean reaction flask, collects 134-135 DEG C of (3mmHg) cut, obtain weak yellow liquid 3-trifluoromethyl pentanoic and be about 67.5g, yield about 80%.By 3-trifluoromethyl pentanoic 60g(0.253mol), sublimed sulphur 8g(0.253mol) add in reaction flask, whipped state is warming up to about 130 DEG C, after the complete melting of sulphur, in reaction flask, add 3g elemental iodine, continue to be warming up to 185-190 DEG C, react about 1 hour at this temperature.There is hydrogen sulfide to release in reaction process, note tail gas absorption.After reaction terminates, reaction solution is cooled to about 100 DEG C, adds 200g toluene in reaction flask, about raised temperature to 100 DEG C, in reaction flask, add 100g water, stir layering while hot after 5 minutes, water layer discarded, toluene layer returns reaction flask, and whipped state borehole cooling, to 15-18 DEG C, filters, filtrate retains (to be recycled apply mechanically 3-trifluoromethyl pentanoic), filter cake adopts 60 DEG C, vacuum to dry 10 hours, and obtain 29g intermediate 2-trifluoromethyl thiodiphenylamine, yield is about 85%(and calculates by sulphur)(2) preparation of 1-(3-chloropropyl)-4-(2-hydroxyethyl) piperazine: by 79g(0.5mol) 1,3-bromo-chloropropane, 320g toluene add in reaction flask, 130g(1.0mol is dripped under control 32-35 DEG C condition) 1-(2-hydroxyethyl) piperazine, time for adding about 2 hours.After dropwising, 32-35 DEG C of stirring reaction 10 hours, after reaction terminates, passes into hydrogen chloride gas to reaction system, regulate PH=8, solids removed by filtration, filtrate decompression distillation and concentration removing toluene solvant and unreacted complete 1,3-bromo-chloropropane, obtains viscous liquid product 95g, yield about 92%.(3) fluorine puts forth energy to be the preparation of nearly alkali: by 2-trifluoromethyl thiodiphenylamine 28g(0.105mol), toluene 140g, granular sodium hydroxide 28g(0.7mol) drop in reaction flask, whipped state is warming up to reflux state (110-112 DEG C), drip (the mixing solutions solution of 1-(3-chloropropyl)-4-(2-hydroxyethyl) piperazine and 50g toluene, the dropping process lasts about 1.5 hours of 26g (0.126mol) at reflux.After dropwising, reflux state reaction about 8 hours, whole reflux course notices that system moisture removes by timely water trap.After reaction terminates, be cooled to room temperature, solids removed by filtration insolubles, 150g purifying moisture three washing organic phases.Add the 10% concentration aqueous hydrochloric acid of 100g to organic phase, stir static layering after 10 minutes, discard upper toluene organic phase, retain lower floor’s aqueous phase, wash aqueous phase at twice with 150g toluene.In aqueous phase, add toluene 140g, drip the sodium hydroxide solution of 20% of 62g under whipped state, in process, hierarchy of control temperature is no more than 45 DEG C, after dropwising, stir 20 minutes, static layering, discard lower floor’s aqueous phase, retain upper organic phase, organic phase 15g anhydrous sodium sulfate drying, underpressure distillation removing toluene solvant, residue carries out underpressure distillation, collect 230 DEG C of (0.5mmHg) cuts, obtain 33g fluorine and put forth energy to be nearly alkali, yield 72%.(4) preparation of fluophenazine hydrochloride: 32g alkali is dissolved in 128g dehydrated alcohol, stirring is dissolved backward system completely and is led to hydrogen chloride gas, process temperature is no more than 20 DEG C, logical hydrogen chloride gas is stopped as PH=2, stir after 30 minutes and filter, filter cake 50g absolute ethanol washing, product puts into vacuum drying oven, dry after 10 hours for 45 DEG C and obtain fluophenazine hydrochloride 36g, yield about 95%.embodiment 2.(1) preparation of 2-trifluoromethyl thiodiphenylamine: by 500g(1.78mol) Tecramine adds in reaction flask, be heated to 180-190 DEG C, open and stir, treat that it melts in backward reaction flask completely and add 50g(0.89mol) iron powder, stirring reaction about 2 hours at 180-190 DEG C of temperature, after reaction terminates, reaction solution is cooled to pour in beaker by reaction solution while hot when 100 DEG C, and iron powder stays (used water flushing) bottom reaction flask.Reaction solution is added underpressure distillation in clean reaction flask, collects 134-135 DEG C of (3mmHg) cut, obtain weak yellow liquid 3-trifluoromethyl pentanoic and be about 346g, yield about 82%.By 3-trifluoromethyl pentanoic 300g(1.265mol), sublimed sulphur 40g(1.265mol) add in reaction flask, whipped state is warming up to about 130 DEG C, after the complete melting of sulphur, in reaction flask, add 15g elemental iodine, continue to be warming up to 185-190 DEG C, react about 1 hour at this temperature.There is hydrogen sulfide to release in reaction process, note tail gas absorption.After reaction terminates, reaction solution is cooled to about 100 DEG C, adds 1000g toluene in reaction flask, about raised temperature to 100 DEG C, in reaction flask, add 1000g water, stir layering while hot after 5 minutes, water layer discarded, toluene layer returns reaction flask, and whipped state borehole cooling, to 15-18 DEG C, filters, filtrate retains (to be recycled apply mechanically 3-trifluoromethyl pentanoic), filter cake adopts 60 DEG C, vacuum to dry 10 hours, and obtain 147g intermediate 2-trifluoromethyl thiodiphenylamine, yield is about 86%(and calculates by sulphur)(2) preparation of 1-(3-chloropropyl)-4-(2-hydroxyethyl) piperazine: by 395g(2.5mol) 1,3-bromo-chloropropane, 1600g toluene add in reaction flask, 650g(5.0mol is dripped under control 32-35 DEG C condition) 1-(2-hydroxyethyl) piperazine, time for adding about 2 hours.After dropwising, 32-35 DEG C of stirring reaction 10 hours, after reaction terminates, passes into hydrogen chloride gas to reaction system, regulate PH=8, solids removed by filtration, filtrate decompression distillation and concentration removing toluene solvant and unreacted complete 1,3-bromo-chloropropane, obtains viscous liquid product 470g, yield about 91%.(3) fluorine puts forth energy to be the preparation of nearly alkali: by 2-trifluoromethyl thiodiphenylamine 140g(0.525mol), toluene 700g, granular sodium hydroxide 140g(3.5mol) drop in reaction flask, whipped state is warming up to reflux state (110-112 DEG C), drip (the mixing solutions solution of 1-(3-chloropropyl)-4-(2-hydroxyethyl) piperazine and 300g toluene, the dropping process lasts about 1.5 hours of 130g (0.63mol) at reflux.After dropwising, reflux state reaction about 8 hours, whole reflux course notices that system moisture removes by timely water trap.After reaction terminates, be cooled to room temperature, solids removed by filtration insolubles, 750g purifying moisture three washing organic phases.Add the 10% concentration aqueous hydrochloric acid of 500g to organic phase, stir static layering after 10 minutes, discard upper toluene organic phase, retain lower floor’s aqueous phase, wash aqueous phase at twice with 750g toluene.In aqueous phase, add toluene 720g, drip the sodium hydroxide solution of 20% of 310g under whipped state, in process, hierarchy of control temperature is no more than 45 DEG C, after dropwising, stir 20 minutes, static layering, discard lower floor’s aqueous phase, retain upper organic phase, organic phase 75g anhydrous sodium sulfate drying, underpressure distillation removing toluene solvant, residue carries out underpressure distillation, collect 230 DEG C of (0.5mmHg) cuts, obtain 168g fluorine and put forth energy to be nearly alkali, yield 73%.(4) preparation of fluophenazine hydrochloride: 160g alkali is dissolved in 640g dehydrated alcohol, stirring is dissolved backward system completely and is led to hydrogen chloride gas, process temperature is no more than 20 DEG C, logical hydrogen chloride gas is stopped as PH=2, stir after 30 minutes and filter, filter cake 300g absolute ethanol washing, product puts into vacuum drying oven, dry after 10 hours for 45 DEG C and obtain fluophenazine hydrochloride 182g, yield about 96%.embodiment 3.(1) preparation of 2-trifluoromethyl thiodiphenylamine: by 1000g(3.56mol) Tecramine adds in reaction flask, be heated to 180-190 DEG C, open and stir, treat that it melts in backward reaction flask completely and add 100g(1.78mol) iron powder, stirring reaction about 2 hours at 180-190 DEG C of temperature, after reaction terminates, reaction solution is cooled to pour in beaker by reaction solution while hot when 100 DEG C, and iron powder stays (used water flushing) bottom reaction flask.Reaction solution is added underpressure distillation in clean reaction flask, collects 134-135 DEG C of (3mmHg) cut, obtain weak yellow liquid 3-trifluoromethyl pentanoic and be about 1029g, yield about 82%.By 3-trifluoromethyl pentanoic 600g(2.53mol), sublimed sulphur 80g(2.53mol) add in reaction flask, whipped state is warming up to about 130 DEG C, after the complete melting of sulphur, in reaction flask, add 30g elemental iodine, continue to be warming up to 185-190 DEG C, react about 1 hour at this temperature.There is hydrogen sulfide to release in reaction process, note tail gas absorption.After reaction terminates, reaction solution is cooled to about 100 DEG C, adds 2000g toluene in reaction flask, about raised temperature to 100 DEG C, in reaction flask, add 1000g water, stir layering while hot after 5 minutes, water layer discarded, toluene layer returns reaction flask, and whipped state borehole cooling, to 15-18 DEG C, filters, filtrate retains (to be recycled apply mechanically 3-trifluoromethyl pentanoic), filter cake adopts 60 DEG C, vacuum to dry 10 hours, and obtain 294g intermediate 2-trifluoromethyl thiodiphenylamine, yield is about 86%(and calculates by sulphur)(2) preparation of 1-(3-chloropropyl)-4-(2-hydroxyethyl) piperazine: by 790g(5mol) 1,3-bromo-chloropropane, 3200g toluene add in reaction flask, 1300g(10mol is dripped under control 32-35 DEG C condition) 1-(2-hydroxyethyl) piperazine, time for adding about 2 hours.After dropwising, 32-35 DEG C of stirring reaction 10 hours, after reaction terminates, passes into hydrogen chloride gas to reaction system, regulate PH=8, solids removed by filtration, filtrate decompression distillation and concentration removing toluene solvant and unreacted complete 1,3-bromo-chloropropane, obtains viscous liquid product 940g, yield about 91%.(3) fluorine puts forth energy to be the preparation of nearly alkali: by 2-trifluoromethyl thiodiphenylamine 280g(1.05mol), toluene 1400g, granular sodium hydroxide 280g(7mol) drop in reaction flask, whipped state is warming up to reflux state (110-112 DEG C), drip (the mixing solutions solution of 1-(3-chloropropyl)-4-(2-hydroxyethyl) piperazine and 500g toluene, the dropping process lasts about 1.5 hours of 260g (1.26mol) at reflux.After dropwising, reflux state reaction about 8 hours, whole reflux course notices that system moisture removes by timely water trap.After reaction terminates, be cooled to room temperature, solids removed by filtration insolubles, 1500g purifying moisture three washing organic phases.Add the 10% concentration aqueous hydrochloric acid of 1000g to organic phase, stir static layering after 10 minutes, discard upper toluene organic phase, retain lower floor’s aqueous phase, wash aqueous phase at twice with 1500g toluene.In aqueous phase, add toluene 1400g, drip the sodium hydroxide solution of 20% of 620g under whipped state, in process, hierarchy of control temperature is no more than 45 DEG C, after dropwising, stir 20 minutes, static layering, discard lower floor’s aqueous phase, retain upper organic phase, organic phase 150g anhydrous sodium sulfate drying, underpressure distillation removing toluene solvant, residue carries out underpressure distillation, collect 230 DEG C of (0.5mmHg) cuts, obtain 344g fluorine and put forth energy to be nearly alkali, yield 75%.(4) preparation of fluophenazine hydrochloride: 320g alkali is dissolved in 1280g dehydrated alcohol, stirring is dissolved backward system completely and is led to hydrogen chloride gas, process temperature is no more than 20 DEG C, logical hydrogen chloride gas is stopped as PH=2, stir after 30 minutes and filter, filter cake 500g absolute ethanol washing, product puts into vacuum drying oven, dry after 10 hours for 45 DEG C and obtain fluophenazine hydrochloride 364g, yield about 96%.

PATENT

WO 2015103587

https://patents.google.com/patent/WO2015103587A2/no

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Medical use

A 2018 Cochrane review found that fluphenazine was an imperfect treatment and other inexpensive drugs less associated with side effects may be an equally effective choice for people with schizophrenia.^[9]

Side effects

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.^[10] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.^[11] Other symptoms may include restlessness, increased sweating, and trouble sleeping.^[11] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.^[11] Symptoms generally resolve after a short period of time.^[11]

There is tentative evidence that discontinuation of antipsychotics can result in psychosis.^[12] It may also result in reoccurrence of the condition that is being treated.^[13] Rarely tardive dyskinesia can occur when the medication is stopped.^[11]

Pharmacology

Pharmacodynamics

See also: Antipsychotic § Pharmacodynamics, and Antipsychotic § Comparison of medications

Fluphenazine acts primarily by blocking post-synaptic D2 receptors in the basal ganglia, cortical and limbic system. It also blocks alpha-1 adrenergic receptors, muscarinic-1 receptors, and histamine-1 receptors.^[14][15]

Pharmacokinetics

History

Fluphenazine came into use in 1959.^[6]

Availability

The injectable form is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system.^[7] It is available as a generic medication.^[1] It was discontinued in Australia around mid 2017.^[8]

Other animals

In horses, it is sometimes given by injection as an anxiety-relieving medication, though there are many negative common side effects and it is forbidden by many equestrian competition organizations.^[27]

References

1. ^ Jump up to:^{a b c d e f g h i j k l m n o} “fluphenazine decanoate”. The American Society of Health-System Pharmacists. Archived from the original on 8 December 2015. Retrieved 1 December 2015.
2. ^ “Product Information: Modecate (Fluphenazine Decanoate Oily Injection )” (PDF). TGA eBusiness Services. Bristol-Myers Squibb Australia Pty Ltd. 1 November 2012. Archived from the original on 2 August 2017. Retrieved 9 December 2013.
3. ^ Tardy M, Huhn M, Engel RR, Leucht S (August 2014). “Fluphenazine versus low-potency first-generation antipsychotic drugs for schizophrenia”. The Cochrane Database of Systematic Reviews. 8 (8): CD009230. doi:10.1002/14651858.CD009230.pub2. PMID 25087165.
4. ^ “Modecate Injection 25mg/ml – Patient Information Leaflet (PIL) – (eMC)”. http://www.medicines.org.uk. Retrieved 6 November 2017.
5. ^ “Fluphenazine”. livertox.nih.gov. Retrieved 6 November 2017.
6. ^ Jump up to:^a b McPherson EM (2007). Pharmaceutical Manufacturing Encyclopedia (3rd ed.). Burlington: Elsevier. p. 1680. ISBN 9780815518563.
7. ^ Jump up to:^a b World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
8. ^ Jump up to:^a b Rossi S, ed. (July 2017). “Fluphenazine – Australian Medicines Handbook”. Australian Medicines Handbook. Adelaide, Australia: Australian Medicines Handbook Pty Ltd. Retrieved 8 August 2017.
9. ^ Matar HE, Almerie MQ, Sampson SJ (June 2018). “Fluphenazine (oral) versus placebo for schizophrenia”. The Cochrane Database of Systematic Reviews. 6: CD006352. doi:10.1002/14651858.CD006352.pub3. PMC 6513420. PMID 29893410.
10. ^ Joint Formulary Committee, BMJ, ed. (March 2009). “4.2.1”. British National Formulary (57 ed.). United Kingdom: Royal Pharmaceutical Society of Great Britain. p. 192. ISBN 978-0-85369-845-6. Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse.
11. ^ Jump up to:^{a b c d e} Haddad P, Haddad PM, Dursun S, Deakin B (2004). Adverse Syndromes and Psychiatric Drugs: A Clinical Guide. OUP Oxford. pp. 207–216. ISBN 9780198527480.
12. ^ Moncrieff J (July 2006). “Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse”. Acta Psychiatrica Scandinavica. 114 (1): 3–13. doi:10.1111/j.1600-0447.2006.00787.x. PMID 16774655. S2CID 6267180.
13. ^ Sacchetti E, Vita A, Siracusano A, Fleischhacker W (2013). Adherence to Antipsychotics in Schizophrenia. Springer Science & Business Media. p. 85. ISBN 9788847026797.
14. ^ Siragusa S, Saadabadi A (2020). “Fluphenazine”. StatPearls. PMID 29083807.
15. ^ PubChem. “Fluphenazine”. pubchem.ncbi.nlm.nih.gov. Retrieved 30 September 2019.
16. ^ Jump up to:^{a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al} Roth, BL; Driscol, J. “PDSP K_i Database”. Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
17. ^ Parent M, Toussaint C, Gilson H (1983). “Long-term treatment of chronic psychotics with bromperidol decanoate: clinical and pharmacokinetic evaluation”. Current Therapeutic Research. 34 (1): 1–6.
18. ^ Jump up to:^a b Jørgensen A, Overø KF (1980). “Clopenthixol and flupenthixol depot preparations in outpatient schizophrenics. III. Serum levels”. Acta Psychiatrica Scandinavica. Supplementum. 279: 41–54. doi:10.1111/j.1600-0447.1980.tb07082.x. PMID 6931472.
19. ^ Jump up to:^a b Reynolds JE (1993). “Anxiolytic sedatives, hypnotics and neuroleptics.”. Martindale: The Extra Pharmacopoeia (30th ed.). London: Pharmaceutical Press. pp. 364–623.
20. ^ Ereshefsky L, Saklad SR, Jann MW, Davis CM, Richards A, Seidel DR (May 1984). “Future of depot neuroleptic therapy: pharmacokinetic and pharmacodynamic approaches”. The Journal of Clinical Psychiatry. 45 (5 Pt 2): 50–9. PMID 6143748.
21. ^ Jump up to:^a b Curry SH, Whelpton R, de Schepper PJ, Vranckx S, Schiff AA (April 1979). “Kinetics of fluphenazine after fluphenazine dihydrochloride, enanthate and decanoate administration to man”. British Journal of Clinical Pharmacology. 7 (4): 325–31. doi:10.1111/j.1365-2125.1979.tb00941.x. PMC 1429660. PMID 444352.
22. ^ Young D, Ereshefsky L, Saklad SR, Jann MW, Garcia N (1984). Explaining the pharmacokinetics of fluphenazine through computer simulations. (Abstract.). 19th Annual Midyear Clinical Meeting of the American Society of Hospital Pharmacists. Dallas, Texas.
23. ^ Janssen PA, Niemegeers CJ, Schellekens KH, Lenaerts FM, Verbruggen FJ, van Nueten JM, et al. (November 1970). “The pharmacology of fluspirilene (R 6218), a potent, long-acting and injectable neuroleptic drug”. Arzneimittel-Forschung. 20 (11): 1689–98. PMID 4992598.
24. ^ Beresford R, Ward A (January 1987). “Haloperidol decanoate. A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in psychosis”. Drugs. 33 (1): 31–49. doi:10.2165/00003495-198733010-00002. PMID 3545764.
25. ^ Reyntigens AJ, Heykants JJ, Woestenborghs RJ, Gelders YG, Aerts TJ (1982). “Pharmacokinetics of haloperidol decanoate. A 2-year follow-up”. International Pharmacopsychiatry. 17 (4): 238–46. doi:10.1159/000468580. PMID 7185768.
26. ^ Larsson M, Axelsson R, Forsman A (1984). “On the pharmacokinetics of perphenazine: a clinical study of perphenazine enanthate and decanoate”. Current Therapeutic Research. 36 (6): 1071–88.
27. ^ Loving NS (31 March 2012). “Effects of Behavior-Modifying Drug Investigated (AAEP 2011)”. The Horse Media Group. Archived from the original on 6 January 2017. Retrieved 13 December 2016.

External links

• “Fluphenazine”. Drug Information Portal. U.S. National Library of Medicine.

////////////Fluphenazine, فلوفينازين , 氟奋乃静 , SQ 10733, Squibb 16144

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