PATENT

http://www.google.co.in/patents/WO2009149188A1?cl=zh-CN

PATENT

CN 102241625

http://www.google.com/patents/CN102241625A?cl=zh

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2009111947

PAPER

.

 

 

Tecovirimat

4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop(f)isoindol-2(1H)-yl)-benzamide

N- [(3aR,4R,4aR,5aS,6S, 6aS)- 3,3a,4,4a,5,5a,6,6a- octahydro-1,3-dioxo- 4,6- ethenocycloprop[f]iso- indol-2(1H)-yl]-4- (trifluoromethyl)- benzamide

4 -trifluoromethyl -N- (3, 3a, 4, 4a, 5, 5a, 6, 6a- octahydro-1, 3 -dioxo-4, 6 -ethenocycloprop [f] isoindol -2 ( 1H) -yl ) – benzamide

Details

NDA FILED IN  US

2006 ORPHAN DRUG DESIGNATION IN US FOR SMALL POX

2010 ORPHAN DRUG DESIGNATION IN US FOR ORTHOPOX VIRUS

• N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-Dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-ethenocyclopropa(f)isoindol-2(1H)-yl)-4-(trifluoromethyl)benzamide
• N-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-ethenocyclopropa[f]isoindol-2(1H)-yl)-4-(trifluoromethyl)benzamide

 

The smallpox (variola) virus is of particular importance. Recent concerns over the use of smallpox virus as a biological weapon has underscored the necessity of developing small molecule therapeutics that target orthopoxviruses. Variola virus is highly transmissible and causes severe disease in humans resulting in high mortality rates (Henderson et al. (1999) JAMA. 281:2127-2137). Moreover, there is precedent for use of variola virus as a biological weapon. During the French and Indian wars (1754-1765), British soldiers distributed blankets used by smallpox patients to American Indians in order to establish epidemics (Stern, E. W. and Stern A. E. 1945. The effect of smallpox on the destiny of the Amerindian. Boston). The resulting outbreaks caused 50% mortality in some Indian tribes (Stern, E. W. and Stern A. E.). More recently, the soviet government launched a program to produce highly virulent weaponized forms of variola in aerosolized suspensions (Henderson, supra). Of more concern is the observation that recombinant forms of poxvirus have been developed that have the potential of causing disease in vaccinated animals (Jackson et al. (2001) J. Virol., 75:1205-1210).

The smallpox vaccine program was terminated in 1972; thus, many individuals are no longer immune to smallpox infection. Even vaccinated individuals may no longer be fully protected, especially against highly virulent or recombinant strains of virus (Downie and McCarthy. (1958) J. Hyg. 56:479-487; Jackson, supra). Therefore, mortality rates would be high if variola virus were reintroduced into the human population either deliberately or accidentally.

Variola virus is naturally transmitted via aerosolized droplets to the respiratory mucosa where replication in lymph tissue produces asymptomatic infection that lasts 1-3 days. Virus is disseminated through the lymph to the skin where replication in the small dermal blood vessels and subsequent infection and lysis of adjacent epidermal cells produces skin lesions (Moss, B. (1990) Poxyiridae and Their Replication, 2079-2111. In B. N. Fields and D. M. Knipe (eds.), Fields Virology. Raven Press, Ltd., New York). Two forms of disease are associated with variola virus infection; variola major, the most common form of disease, which produces a 30% mortality rate and variola minor, which is less prevalent and rarely leads to death (<1%). Mortality is the result of disseminated intravascular coagulation, hypotension, and cardiovascular collapse, that can be exacerbated by clotting defects in the rare hemorrhagic type of smallpox (Moss, supra).

A recent outbreak of monkeypox virus underscores the need for developing small molecule therapeutics that target viruses in the orthpox genus. Appearance of monkeypox in the US represents an emerging infection. Monkeypox and smallpox cause similar diseases in humans, however mortality for monkeypox is lower (1%).

Vaccination is the current means for preventing orthopox virus disease, particularly smallpox disease. The smallpox vaccine was developed using attenuated strains of vaccinia virus that replicate locally and provide protective immunity against variola virus in greater than 95% of vaccinated individuals (Modlin (2001) MMWR (Morb Mort Wkly Rep) 50:1-25). Adverse advents associated with vaccination occur frequently (1:5000) and include generalized vaccinia and inadvertent transfer of vaccinia from the vaccination site. More serious complications such as encephalitis occur at a rate of 1:300,000, which is often fatal (Modlin, supra). The risk of adverse events is even more pronounced in immunocompromised individuals (Engler et al. (2002) J Allergy Clin Immunol. 110:357-365). Thus, vaccination is contraindicated for people with AIDS or allergic skin diseases (Engler et al.). While protective immunity lasts for many years, the antibody response to smallpox vaccination is significantly reduced 10 to 15 years post inoculation (Downie, supra). In addition, vaccination may not be protective against recombinant forms of ortho poxvirus. A recent study showed that recombinant forms of mousepox virus that express IL-4 cause death in vaccinated mice (Jackson, supra). Given the side effects associated with vaccination, contraindication of immunocompromised individuals, and inability to protect against recombinant strains of virus, better preventatives and/or new therapeutics for treatment of smallpox virus infection are needed.

Vaccinia virus immunoglobulin (VIG) has been used for the treatment of post-vaccination complications. VIG is an isotonic sterile solution of immunoglobulin fraction of plasma derived from individuals who received the vaccinia virus vaccine. It is used to treat eczema vaccinatum and some forms of progressive vaccinia. Since this product is available in limited quantities and difficult to obtain, it has not been indicated for use in the event of a generalized smallpox outbreak (Modlin, supra).

Cidofovir ([(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine][HPMPC]) is a nucleoside analog approved for treatment of CMV retinitis in AIDS patients. Cidofovir has been shown to have activity in vitro against a number of DNA containing viruses including adenovirus, herpesviruses, hepadnaviruses, polyomaviruses, papillomaviruses, and ortho poxviruses (Bronson et al. (1990) Adv. Exp. Med. Biol. 278:277-83; De Clercq et al. (1987) Antiviral Res. 8:261-272; de Oliveira et al. (1996) Antiviral Res. 31:165-172; Snoeck et al. (2001) Clin Infect. Dis. 33:597-602). Cidofovir has also been found to inhibit authentic variola virus replication (Smee et al. (2002) Antimicrob. Agents Chemother. 46:1329-1335).

However, cidofovir administration is associated with a number of issues. Cidofovir is poorly bioavailable and must be administered intravenously (Lalezari et al. (1997) Ann. Intern. Med. 126:257-263). Moreover, cidofovir produces dose-limiting nephrotoxicity upon intravenous administration (Lalezari et al.). In addition, cidofovir-resistance has been noted for multiple viruses. Cidofovir-resistant cowpox, monkeypox, vaccinia, and camelpox virus variants have been isolated in the laboratory by repeated passage in the presence of drug (Smee, supra). Cidofovir-resistance represents a significant limitation for use of this compound to treat orthopoxvirus replication. Thus, the poor bioavailability, need for intravenous administration, and prevalence of resistant virus underscores the need for development of additional and alternative therapies to treat orthopoxvirus infection

In addition to viral polymerase inhibitors such as cidofovir, a number of other compounds have been reported to inhibit orthopoxvirus replication (De Clercq. (2001) Clin Microbiol. Rev. 14:382-397). Historically, methisazone, the prototypical thiosemicarbazone, has been used in the prophylactic treatment of smallpox infections (Bauer et al. (1969) Am. J. Epidemiol. 90:130-145). However, this compound class has not garnered much attention since the eradication of smallpox due to generally unacceptable side effects such as severe nausea and vomiting. Mechanism of action studies suggest that methisazone interferes with translation of L genes (De Clercq (2001), supra). Like cidofovir, methisazone is a relatively non-specific antiviral compound and can inhibit a number of other viruses including adenoviruses, picornaviruses, reoviruses, arboviruses, and myxoviruses (Id.).

Another class of compounds potentially useful for the treatment of poxviruses is represented by inhibitors of S-adenosylhomocysteine hydrolase (SAH). This enzyme is responsible for the conversion of S-adenosylhomocysteine to adenosine and homocysteine, a necessary step in the methylation and maturation of viral mRNA. Inhibitors of this enzyme have shown efficacy at inhibiting vaccinia virus in vitro and in vivo (De Clercq et al. (1998) Nucleosides Nucleotides. 17:625-634.). Structurally, all active inhibitors reported to date are analogues of the nucleoside adenosine. Many are carbocyclic derivatives, exemplified by Neplanacin A and 3-Deazaneplanacin A. While these compounds have shown some efficacy in animal models, like many nucleoside analogues, they suffer from general toxicity and/or poor pharmacokinetic properties (Coulombe et al. (1995) Eur. J. Drug Metab Pharmacokinet. 20:197-202; Obara et al. (1996) J. Med. Chem. 39:3847-3852). It is unlikely that these compounds can be administered orally, and it is currently unclear whether they can act prophylactically against smallpox infections. Identification of non-nucleoside inhibitors of SAH hydrolase, and other chemically tractable variola virus genome targets that are orally bioavailable and possess desirable pharmicokinetic (PK) and absorption, distribution, metabolism, elimination (ADME) properties would be a significant improvement over the reported nucleoside analogues. In summary, currently available compounds that inhibit smallpox virus replication are generally non-specific and suffer from use limiting toxicities and/or questionable efficacies.

In U.S. Pat. No. 6,433,016 (Aug. 13, 2002) and U.S. Application Publication 2002/0193443 A1 (published Dec. 19, 2002) a series of imidodisulfamide derivatives are described as being useful for orthopox virus infections.

note……………

1a is  desired

1b not desired

A mixture of cycloheptatriene (5 g, 54.26 mmol) and maleic anhydride (6.13 g, 62.40 mmol) in xylenes (35 mL) was heated at reflux under argon overnight. The reaction was cooled to room temperature and a tan precipitate was collected by filtration and dried to give 2.94 grams (28%) of the desired product, which is a mixture of compounds 1(a) and 1(b). Compound 1(a) is normally predominant in this mixture and is at least 80% by weight. The purity of Compound 1(a) may be further enhanced by recrystallization if necessary. Compound 1(b), an isomer of compound 1(a) is normally less than 20% by weight and varies depending on the conditions of the reaction. Pure Compound 1(b) was obtained by concentrating the mother liquid to dryness and then subjecting the residue to column chromatography. Further purification can be carried out by recrystallization if necessary. ¹H NMR (500 MHz) in CDCl₃: δ 5.95 (m, 2H), 3.42 (m, 2H), 3.09 (m, 2H), 1.12 (m, 2H), 0.22 (m, 1H), 0.14 (m, 1H).

b. Preparation of N-[(3aR,4R,4aR,5aS,6S,6aS)-3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl]-4-(trifluoromethyl)-benzamide. desired

A mixture of compound 1(a) (150 mg, 0.788 mmol) and 4-trifluoromethylbenzhydrazide (169 mg, 0.827 mmol) in ethanol (10 mL) was heated under argon overnight. The solvent was removed by rotary evaporation. Purification by column chromatography on silica gel using 1/1 hexane/ethyl acetate provided 152 mg (51%) of the product as a white solid.

c. Preparation of N-[(3aR,4S,4aS,5aR,6R,6aS)-3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl]-4-(trifluoromethyl)-benzamide. UNWANTED

N-[(3aR,4S,4aS,5aR,6R,6aS)-3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl]4-(trifluoromethyl)-benzamide was prepared and purified in the same fashion as for N-[(3aR,4R,4aR,5aS,6S,6aS)-3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl]-4-(trifluoromethyl)-benzamide by replacing 1(a) with 1(b) and was obtained as a white solid. ¹H NMR (300 MHz) in CDCl₃: δ 8.62 (s, 1H), 7.92 (d, 2H), 7.68 (d, 2H), 5.96 (m, 2H), 3.43 (s, 2H), 2.88 (s, 2H), 1.17 (s, 2H), 0.24 (q, 1H), 0.13 (m, 1H); Mass Spec: 377.1 (M+H)⁺.

FINAL COMPD SYNTHESIS

TABLE 1
Example			**Mass
Number	R6	*NMR	Spec	Name
1		1H NMR in DMSO-d6: δ 11.35 (d, 1H); 11.09 (d, 1H); 8.08 (d, 2H); 7.92 (d, 2H); 5.799 (s, 2H); 3.29 (brs, 4H); 1.17 (m, 2H); 0.26 (m, 1H); 0.078 (s, 1H)	375 (M − H)−	N-[(3aR,4R,4aR,5aS,6S, 6aS)-3,3a,4,4a,5,5a,6,6a- octahydro-1,3-dioxo- 4,6-ethenocycloprop[f] isoindol-2(1H)-yl]-4- (trifluoromethyl)- benzamide

TABLE 1 EXAMPLE 1

N- [(3aR,4R,4aR,5aS,6S, 6aS)- 3,3a,4,4a,5,5a,6,6a- octahydro-1,3-dioxo- 4,6- ethenocycloprop[f]iso- indol-2(1H)-yl]-4- (trifluoromethyl)- benzamide

¹H NMR in DMSO-d₆: δ 11.35 (d, 1H); 11.09 (d, 1H); 8.08 (d, 2H); 7.92 (d, 2H); 5.799 (s, 2H); 3.29 (brs, 4H); 1.17 (m, 2H); 0.26 (m, 1H); 0.078 (s, 1H), 375 (M − H)⁻

EXAMPLE 42 Characterization of 4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl)-benzamide (“ ”)

In the present application, ST-246 refers to: N-[(3aR,4R,4aR,5aS,65,6aS)-3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl]-4-(trifluoromethyl)-benzamide.

Physico-Chemical Properties

Appearance: ST-246 is a white to off-white powder.

Melting Point: Approximately 196° C. by DSC.

Permeability: The calculated log P is 2.94. Based on the partition coefficient, ST-246 is expected to have good permeability.

Particle Size: The drug substance is micronized to improve its dissolution in the gastrointestinal fluids. The typical particle size of the micronized material is 50% less than 5 microns.

Solubility: The solubility of ST-246 is low in water (0.026 mg/mL) and buffers of the gastric pH range. Surfactant increases its solubility slightly. ST-246 is very soluble in organic solvents. The solubility data are given in Table 5.

CLICK ON IMAGE

PATENT

http://www.google.com/patents/CN101445478A?cl=en

Tecovirimat (ST-246) is an antiviral with activity against orthopoxviruses such as smallpox and is currently undergoing clinical trials. It was previously owned by Viropharma and discovered in collaboration with scientists at USAMRIID. It is currently owned and is synthesized by Siga Technologies, a drug development company in the biodefense arena. It works by blocking cellular transmission of the virus, thus preventing the disease. Tecovirimat has been effective in laboratory testing, with no serious side effects reported to date. Despite not yet having FDA approval for medical use, tecovirimat is stockpiled in the US Strategic National Stockpile as a defense against a smallpox outbreak.^[1]

Clinical study

 

References

1. Damon, Inger K.; Damaso, Clarissa R.; McFadden, Grant (2014). “Are We There Yet? The Smallpox Research Agenda Using Variola Virus”. PLoS Pathogens 10 (5): e1004108.doi:10.1371/journal.ppat.1004108. PMID 24789223.
2. Siga Technologies
3. Jordan, R; Tien, D; Bolken, T. C.; Jones, K. F.; Tyavanagimatt, S. R.; Strasser, J; Frimm, A; Corrado, M. L.; Strome, P. G.; Hruby, D. E. (2008). “Single-Dose Safety and Pharmacokinetics of ST-246, a Novel Orthopoxvirus Egress Inhibitor”. Antimicrobial Agents and Chemotherapy 52 (5): 1721–1727. doi:10.1128/AAC.01303-07. PMC 2346641. PMID 18316519.
4. Yang, G; Pevear, D. C.; Davies, M. H.; Collett, M. S.; Bailey, T; Rippen, S; Barone, L; Burns, C; Rhodes, G; Tohan, S; Huggins, J. W.; Baker, R. O.; Buller, R. L.; Touchette, E; Waller, K; Schriewer, J; Neyts, J; Declercq, E; Jones, K; Hruby, D; Jordan, R (2005). “An Orally Bioavailable Antipoxvirus Compound (ST-246) Inhibits Extracellular Virus Formation and Protects Mice from Lethal Orthopoxvirus Challenge”. Journal of Virology 79 (20): 13139–13149. doi:10.1128/JVI.79.20.13139-13149.2005. PMC 1235851. PMID 16189015.

Referenced by
Citing Patent Filing date Publication date Applicant Title
CN101912389A * Aug 9, 2010 Dec 15, 2010 中国人民解放军军事医学科学院微生物流行病研究所 Pharmaceutical composition containing ST-246 and preparation method and application thereof
CN102406617A * Nov 30, 2011 Apr 11, 2012 中国人民解放军军事医学科学院生物工程研究所 Tecovirimat dry suspension and preparation method thereof
CN102406617B Nov 30, 2011 Aug 28, 2013 中国人民解放军军事医学科学院生物工程研究所 Tecovirimat dry suspension and preparation method thereof
CN103068232B * Mar 23, 2011 Aug 26, 2015 西佳科技股份有限公司 多晶型物形式st-246和制备方法
US8530509 Jul 29, 2011 Sep 10, 2013 Siga Technologies, Inc. Compounds, compositions and methods for treatment and prevention of orthopoxvirus infections and associated diseases
US8802714 Aug 14, 2013 Aug 12, 2014 Siga Technologies, Inc. Compounds, compositions and methods for treatment and prevention of orthopoxvirus infections and associated diseases
US9045418 Jul 3, 2014 Jun 2, 2015 Siga Technologies, Inc. Compounds, compositions and methods for treatment and prevention of Orthopoxvirus infections and associated diseases

Tecovirimat

Systematic (IUPAC) name
N-{3,5-Dioxo-4- azatetracyclo[5.3.2.0{2,6}.0{8,10}]dodec-11-en-4- yl}-4-(trifluoromethyl)benzamide
Identifiers
UNII	F925RR824R
ChEMBL	CHEMBL1242629
Synonyms	ST-246
Chemical data
Formula	C19H15F3N2O3
Molecular mass	base: 376.3 g/mol

//////////////////

FC(F)(F)c1ccc(cc1)C(=O)NN1C(=O)C2C(C3C=CC2C2CC32)C1=O

Recently, application of the flow technologies for the preparation of fine chemicals, such as natural products or Active Pharmaceutical Ingredients (APIs), has become very popular, especially in academia. Although pharma industry still relies on multipurpose batch or semibatch reactors, it is evident that interest is arising toward continuous flow manufacturing of organic molecules, including highly functionalized and chiral compounds. Continuous flow synthetic methodologies can also be easily combined to other enabling technologies, such as microwave irradiation, supported reagents or catalysts, photochemistry, inductive heating, electrochemistry, new solvent systems, 3D printing, or microreactor technology. This combination could allow the development of fully automated process with an increased efficiency and, in many cases, improved sustainability. It has been also demonstrated that a safer manufacturing of organic intermediates and APIs could be obtained under continuous flow conditions, where some synthetic steps that were not permitted for safety reasons can be performed with minimum risk. In this review we focused our attention only on very recent advances in the continuous flow multistep synthesis of organic molecules which found application as APIs, especially highlighting the contributions described in the literature from 2013 to 2015, including very recent examples not reported in any published review. Without claiming to be complete, we will give a general overview of different approaches, technologies, and synthetic strategies used so far, thus hoping to contribute to minimize the gap between academic research and pharmaceutical manufacturing. A general outlook about a quite young and relatively unexplored field of research, like stereoselective organocatalysis under flow conditions, will be also presented, and most significant examples will be described; our purpose is to illustrate all of the potentialities of continuous flow organocatalysis and offer a starting point to develop new methodologies for the synthesis of chiral drugs. Finally, some considerations on the perspectives and the possible, expected developments in the field are briefly discussed.

Two examples out of several in the publication discussed below……………

1  Diphenhydramine Hydrochloride

2 Olanzapine

SEE MORE IN THE PUBLICATION…………..

Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products

Riccardo Porta

 PhD Student

University of Milan, Milano · Department of Chemistry

Alessandra Puglisi

University of Milan, Milano · Department of Chemistry

Dipartimento di Chimica, Università degli Studi di Milano Via Golgi 19, I-20133 Milano, Italy

//////////

Indoline 7  as in ACS MEDCHEM LETTERS, DOI: 10.1021/acsmedchemlett.5b00404

and

eg 10 as in WO2015054088

(2R)- 1,1,1 -trifluoro-3-(3-(3-(trifluoromethoxy)benzyl)-3-(3- (trifluoromethoxy)-phenyl)indolin-l-yl)propan-2-ol.

1H-​Indole-​1-​ethanol, 2,​3-​dihydro-​3-​[3-​(trifluoromethoxy)​phenyl]​-​3-​[[3-​(trifluoromethoxy)​phenyl]​methyl]​-​α-​(trifluoromethyl)​-​, (αR)​-

cas 1699732-96-1 R ISOMER

Merck Sharp & Dohme Corp. INNOVATOR

Using the collective body of known (CETP) inhibitors as inspiration for design, a structurally novel series of tetrahydroquinoxaline CETP inhibitors were discovered. An exemplar from this series, compound 5, displayed potent in vitro CETP inhibition and was efficacious in a transgenic cynomologus-CETP mouse HDL PD (pharmacodynamic) assay. However, an undesirable metabolic profile and chemical instability hampered further development of the series. A three-dimensional structure of tetrahydroquinoxaline inhibitor 6 was proposed from ¹H NMR structural studies, and this model was then used in silico for the design of a new class of compounds based upon an indoline scaffold. This work resulted in the discovery of compound 7, which displayed potent in vitro CETP inhibition, a favorable PK–PD profile relative to tetrahydroquinoxaline 5, and dose-dependent efficacy in the transgenic cynomologus-CETP mouse HDL PD assay.

chemical compounds that inhibit cholesterol ester transfer protein (CETP) and are expected to have utility in raising HDL-C, lowering LDL-C, and in the treatment and prevention of atherosclerosis.

see………….http://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.5b00404

http://pubs.acs.org/doi/suppl/10.1021/acsmedchemlett.5b00404/suppl_file/ml5b00404_si_001.pdf

Discovery of Novel Indoline Cholesterol Ester Transfer Protein Inhibitors (CETP) through a Structure-Guided Approach

Example 18 as in patent

(R)- 1,1, 1 -trifluoro-3-((R)-4-(3-trifluoromethoxy)benzyl)-2-(3-(l, 1 ,2,2,-tetrafluoroethoxy)phenyl)-3,4- dihydroquinoxalin- 1 (2H)-yl)propan-2-ol

SPA: 15 nM

Example 18 was prepared from 2-bromo-l-(3-(l , 1 ,2,2,-tetrafluoroethoxy)phenyl)ethanone in three steps, using the reactions detailed in Schemes A6, A2 and Al . Spectral data are as follows: 1H NMR (400 MHz, CDC1₃) £2.70 (bd, J=4.1 Hz, IH), 3.24 (dd, J=l 1.3, 3.4 Hz, IH), 3.34 (dd, J=15.5, 9.7 Hz, IH), 3.58 (dd, J=l 1.3, 3.3 Hz, IH), 3.86 (d, J=15.4 Hz, IH), 4.20 (d, J=15.7 Hz, IH), 4.40 (d, J=15.8 Hz, IH), 4.46 (m, IH), 4.927 (t, J=3.3 Hz, IH), 5.90 (tt, J=53.1 , 2.7 Hz, IH), 6.59 (d, J= 7.9 Hz, IH), 6.72 (m, 2H), 6.84 (m, 2H), 6.92 (d, J=7.6 Hz, IH), 7.20 (m, 2H), 7.35 (t, J=7.9 Hz, IH), MS m/z = 613.03.

Scheme A12

Methyl 3 – { 1 – [(R)-3 ,3 ,3 -trifluoro-2-hy droxypropyl] -4- [3 -(trifluoromethoxy) benzyl]-l,2,3,4-tetrahydroquinoxalin-2-yl}benzoate (700 mg, 1.262 mmol) is made as described in Example 16 but with one stereochemical center unresolved. The compound was dissolved in MeOH (12.6mL), lithium hydroxide monohydrate (530 mg, 12.62 mmol) was added, and the reaction mixture was heated to 60°C for 4 hours. The crude mixture was dissolved in saturated ammonium chloride solution and extracted into EtOAc, the organic phase was dried with anhydrous magnesium sulfate, filtered, concentrated, and purified on a silica gel column with a 0-100% Hex/EtOAc gradient. The major peak was concentrated to afford 3-{l-[(R)-3,3,3-trifluoro-2-hydroxypropyl]-4-[3-(trifluoromethoxy)benzyl]-l,2,3,4-tetra-hydroquinoxalin-2-yl} benzoic acid. MS m/z = 541.09.

Patent

WO2015054088

http://google.com/patents/WO2015054088A1?cl=en

Scheme Al

Scheme A2

Scheme A3

R = Ar, NR_2l C0₂R, CN, S0₂Me

es

es

SEE EXAMPLE ………SIMILAR BUT NOT SAME

Example 1. (2R)- 1,1,1 -trifluoro-3-(3-(3-(trifluoromethoxy)benzyl)-3-(3- (trifluoromethyl)-phenyl)indolin-l-yl)propan-2-ol. This material was prepared according to Scheme Al, as described below.

3-(3-(trifluoromethyl)phenyl)indolin-2-one. Oxindole (1.598 g, 12 mmol), 3-bromo-a,a,a-trifluoromethyltoluene (2.009 ml, 14.40 mmol), potassium carbonate (3.32 g, 24.00 mmol), Pd₂dba₃ (0.220 g, 0.240 mmol), and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (0.458 g, 0.960 mmol) were combined in THF (12 ml) and the mixture was degassed with nitrogen. The solution was then heated to 80 °C for 18h. The mixture was cooled to room temperature, filtered through silica eluting with ethyl acetate, and concentrated. The material was then purified by silica gel chromatography (Biotage lOOg SNAP cartridge, 0-50% ethyl acetate in hexanes) to provide 3-(3-(trifluoromethyl)phenyl)indolin-2-one as a white solid.

1H NMR (500 MHz) δ 8.58 (s, 1H), 7.61 (d, J=7 Hz, 1H), 7.53-7.45 (m, 3H), 7.33-7.29 (m, 1H), 7.16 (d, J=7 Hz, 1H), 7.10 (m, 1H), 7.01-6.90 (m, 1H), 4.73 (s, 1H).

3 -(3 -(trifluoromethoxy)benzyl)-3 -(3 -(trifluoromethyl)phenyl)indolin-2-one . 3 -Trifluoromethoxy-benzylbromide (0.204 ml, 1.255 mmol) was added to a mixture of 3-(3-(trifluoromethyl)-phenyl)indolin-2-one (290 mg, 1.046 mmol) and potassium carbonate (289 mg, 2.092 mmol) (sodium carbonate may be used in place of potassium carbonate) in DMA (2.5 ml). The mixture was stirred at r.t. for 16h. The reaction was diluted with ethyl acetate and washed with water (3×5 mL). The organic layer was dried with Na₂S0₄, filtered, and concentrated. The products were then purified by silica gel chromatography (Biotage 50g SNAP cartridge; 0-40%> ethyl acetate in hexanes) to provide 3-(3-(trifluoromethoxy)benzyl)-3-(3-(trifluoromethyl)-phenyl)indolin-2-one .

1H NMR (500 MHz) δ 7.79 (s, 1H), 7.73 (d, J=7 Hz, 1H), 7.62-7.60 (m, 2H), 7.51 (t, J=7 Hz, 1H), 7.26- 7.22 (m, 2H), 7.14 (t, J=7.0 Hz, 1H), 7.11 (m, 1H), 6.97 (m, 1H), 6.92 (m, 1H), 6.78 (m, 1H), 6.73 (s, 1H), 3.77 (d, J=13 Hz, 1H), 3.49 (d, J=13 Hz, 1H).

LCMS m/z = 451.8 (M+H)

3-(3-(trifluoromethoxy)benzyl)-3-(3-(trifluoromethyl)phenyl)indoline. Borane tetrahydrofuran complex (1.673 ml, 1.673 mmol) was added to a solution of 3-(3-(trifluoromethoxy)benzyl)-3-(3-(trifluoromethyl)phenyl)indolin-2-one (302 mg, 0.669 mmol) in THF (1.5 ml). The mixture was heated to 70 °C for 20h. The reaction was cooled to room temperature and quenched with saturated NH₄C1 solution, and this mixture was stirred vigorously for 20 minutes. The product was extracted with ethyl acetate. The extracts were dried over Na₂S0₄, filtered, and concentrated. The product was purified by silica gel chromatography (Biotage 25g SNAP cartridge, 0-50% ethyl acetate in hexanes) to provide 3-(3-(trifluoromethoxy)benzyl)-3-(3-(trifluoromethyl)phenyl)indoline. This material may also be used without purification in the final step of the sequence, epoxide opening.

1H NMR (500 MHz) δ 7.66 (s, IH), 7.59 (d, J=7 Hz, IH), 7.53 (d, J=7 Hz, IH), 7.45 (t, J=8 Hz, IH), 7.18-7.13 (m, 2H), 7.04 (d, J=8 Hz, IH), 6.98 (d, J=7 Hz, IH), 6.81 (t, J=7.5 Hz, IH), 6.71 (m, 2H), 6.60 (s, IH), 3.83 (m, IH), 3.75-3.73 (m, 2H), 3.46 (d, J=13 Hz, IH), 3.41 (d, J=13 Hz, IH).

= 437.9 (M+H)

(2R)- 1,1,1 -trifluoro-3-(3-(3-(trifluoromethoxy)benzyl)-3-(3-(trifluoromethyl)-phenyl)indolin-l-yl)propan-2-ol. (S)-2-(trifluoromethyl)oxirane (81 μΐ, 0.933 mmol) was added to a solution of 3-(3-(trifluoromethoxy)benzyl)-3-(3-(trifluoromethyl)phenyl)indoline (136 mg, 0.311 mmol) in l,l,l,3,3,3-hexafluoro-2-propanol (412 μΐ, 3.91 mmol). The reaction was stirred at room temperature overnight. The solvent was removed and the product was purified by silica gel chromatography (Biotage 25 g SNAP cartridge; 0-25% ethyl acetate in hexanes) to provide (2R)- 1 ,1,1 -trifluoro-3 -(3 -(3 -(trifluoromethoxy)benzyl)-3 -(3 -(trifluoromethyl)phenyl)indolin- 1 -yl)propan-2-ol.

1H NMR (500 MHz) (mixture of diastereomers) δ 7.72 (s, 0.5 H), 7.69 (s, 0.5 H), 7.65 (d, J=6.5 Hz, 0.5 H), 7.61 (d, J=7.5 Hz, 0.5 H), 7.56 (s, 1H), 7.50 (m, 1H), 7.25-7.17 (m, 2H), 7.07 (broad s, 2H), 6.91-6.89 (m, 1H), 6.79-6.75 (m, 1H), 6.53 (m, 2H), 4.00 (broad s, 1H), 3.83 (d, J= 9 Hz, 0.5H), 3.77 (d, J=9 Hz, 0.5H), 3.59-3.55 (m, 1H), 3.45-3.43 (m, 1H), 3.39-3.29 (m, 2H), 3.21-3.15 (m, 1H), 2.32 (m, 0.5H), 2.15 (m, 0.5H).

LCMS m/z = 549.8 (M+H)

Examples 1-25, in the table below, were prepared according to Scheme Al in a

SEE EG 10…….(2R)- 1,1,1 -trifluoro-3-(3-(3-(trifluoromethoxy)benzyl)-3-(3- (trifluoromethoxy)-phenyl)indolin-l-yl)propan-2-ol.

ABOUT AUTHOR

https://www.linkedin.com/in/jonathan-wilson-23206523

Experience

Education

///////CETP inhibition, cholesterol ester transfer protein, HDL,  indoline,  tetrahydroquinoxaline, merck, discovery

c21ccccc1N(C[C@@]2(c3cccc(c3)OC(F)(F)F)Cc4cc(ccc4)OC(F)(F)F)C(C(F)(F)F)O

FC(F)(F)Oc1cccc(c1)C3(CN(C[C@@H](O)C(F)(F)F)c2ccccc23)Cc4cccc(OC(F)(F)F)c4

see…………http://worlddrugtracker.blogspot.in/2016/01/mercks-novel-indoline-cholesterol-ester.html

A prostaglandin receptor antagonist potentially for the treatment of rheumatoid arthritis.

cas 116686-15-8

This compound has been obtained by two different ways: 1) The oxidation of 4′-amino-3′-chloroacetophenone (I) with NaNO2 and HCl in water gives 3′-chloro-4-nitroacetophenone (II), which is condensed with 2,4-difluorophenol (III) by means of K2CO3 in xylene yielding 3′-(2,4-difluorophenyl)-4′-nitroacetophenone (IV). The reduction of (IV) with Fe and NH4Cl in ethanol affords the corresponding 4′-amino compound (V), which is finally treated with methanesulfonyl chloride and pyridine. 2) The reaction of 4′-aminoacetophenone (VI) with methanesulfonyl chloride as before gives the corresponding sulfonamide (VII), which is brominated with Br2 in acetic acid yielding N-(4-acetyl-3-bromophenyl)methanesulfonamide (VIII). Finally, this compound is condensed with 2,4-difluorophenol (III) by means of K2CO3 and CuCl as before.

Chem Pharm Bull 1992,40(9),2399

\\\\\\\\\\\\\CC(=O)C1=CC(=C(C=C1)NS(=O)(=O)C)OC2=C(C=C(C=C2)F)F

SEE………..http://apisynthesisint.blogspot.in/2016/01/fk-3311.html

MW 422.79,  MF C₁₈ H₁₄ Cl F₃ N₆ O

cas 1627748-32-6

1,​2,​4-​Triazolo[4,​3-​a]​pyrazin-​8(5H)​-​one, 7-​[[2-​chloro-​3-​(trifluoromethyl)​phenyl]​methyl]​-​6,​7-​dihydro-​6-​methyl-​3-​(2-​pyrazinyl)​-​, (6S)​-

(6S)-7-[[2-chloro-3-(trifluoromethyl)phenyl]methyl]-6-methyl-3-pyrazin-2-yl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8-one

(6S)-7-[2-Chloro-3-(trifluoromethyl)benzyl]-6-methyl-3-pyrazin-2-yl-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one

Janssen Pharmaceutica Nv INNOVATOR

Michael K. Ameriks, Jason C. Rech, Brad M. Savall

(6S)-7-[[2-chloro-3-(trifluoromethyl)phenyl]methyl]-6-methyl-3-pyrazin-2-yl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8-one

PAPER

The synthesis, SAR, and preclinical characterization of a series of substituted 6,7-dihydro[1,2,4]triazolo[4,3]pyrazin-8(5H)-one P2X7 receptor antagonists are described. Optimized leads from this series comprise some of the most potent human P2X7R antagonists reported to date (IC₅₀s < 1 nM). They also exhibit sufficient potency and oral bioavailability in rat to enable extensive in vivo profiling. Although many of the disclosed compounds are peripherally restricted, compound 11d is brain penetrant and upon oral administration demonstrated dose-dependent target engagement in rat hippocampus as determined by ex vivo receptor occupancy with radiotracer 5 (ED₅₀ = 0.8 mg/kg).

Volume 26, Issue 2, 15 January 2016, Pages 257–261

Preclinical characterization of substituted 6,7-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one P2X7 receptor antagonists

• Michael K. Ameriks, et al

• Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States

doi:10.1016/j.bmcl.2015.12.052

http://www.sciencedirect.com/science/article/pii/S0960894X15303656

PATENT

US 20140275096

http://www.google.com/patents/US20140275096

Intermediate 1. 3-(pyrazin-2-yl)-6,7-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one

Step A. tert-butyl 3-ethoxy-5,6-dihydropyrazine-1(2H)-carboxylate

• To a solution of tert-butyl 3-oxopiperazine-1-carboxylate (1 g, 5 mmol) in DCM (15 mL) was added triethyloxonium tetrafluoroborate (2.9 g, 15 mmol). Stirred for 2 h and neutralized with sat. aq NaHCO₃. Layers separated and aqueous layer extracted with DCM. Combined organic layers dried over Na₂SO₄, filtered, and concentrated to give the title compound, which was used directly without further purification.

Step B. tert-butyl 3-(pyrazin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate

• To a solution of tert-butyl 3-ethoxy-5,6-dihydropyrazine-1(2H)-carboxylate (1.14 g, 5 mmol) in 1-butanol (30 mL) was added pyrazine-2-carbohydrazide (685 mg, 5 mmol). The reaction mixture was heated at reflux for 16 h. After cooling to rt, the reaction mixture was concentrated and purified by chromatography (SiO2; 2.5% MeOH in DCM) to afford the desired product as a white solid (700 mg, 50% over 2 steps). MS (ESI): mass calcd. for C₁₄H₁₈N₆O₂, 302.2; m/z found, 303.2 [M+H]⁺.
• 1H NMR (500 MHz, CDCl3) d 9.57 (d, J=1.4 Hz, 1H), 8.62 (d, J=2.5 Hz, 1H), 8.59-8.54 (m, 1H), 4.94 (s, 2H), 4.63-4.50 (m, 2H), 3.89 (t, J=5.4 Hz, 2H), 1.51 (s, 9H).

Step C. 3-(pyrazin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine

• To a solution of tert-butyl 3-(pyrazin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (9.3 g, 30 mmol) in DCM (100 mL) was added 1.25M HCl in EtOH (30 mL, 37.5 mmol). After 3 h, the reaction mixture was concentrated, and the resulting solid was purified by chromatography (SiO₂; 10% MeOH in DCM) to provide the desired product as a white solid (3.7 g, 61%). MS (ESI): mass calcd. for C₉H₁₀N₆, 202.1; m/z found, 203.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 9.35 (d, J=1.4 Hz, 1H), 8.72 (dd, J=2.5, 1.6 Hz, 1H), 8.66 (d, J=2.6 Hz, 1H), 4.50 (t, J=5.6 Hz, 2H), 4.22 (s, 2H), 3.24 (t, J=5.6 Hz, 2H).

Step D. 2-(trimethylsilyl)ethyl 3-(pyrazin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate

• To a solution of 3-(pyrazin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (1.0 g, 5.0 mmol) and N,N-diisopropylethylamine (1.7 mL, 9.9 mmol) in DMF (15 mL) was added 1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidin-2,5-dione (1.5 g, 5.9 mmol). Stirred for 18 h and poured into ice cold brine (150 mL). Precipitate filtered and washed successively with water and ether to afford the desired product as a white solid (1.5 g, 89%). MS (ESI): mass calcd. for C₁₅H₂₂N₆O₂Si, 346.2; m/z found, 347.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 9.50 (d, J=1.4 Hz, 1H), 8.56 (d, J=2.5 Hz, 1H), 8.52-8.48 (m, 1H), 4.91 (s, 2H), 4.60-4.45 (m, 2H), 4.25-4.14 (m, 2H), 3.87 (t, J=5.3 Hz, 2H), 1.07-0.92 (m, 2H), 0.01-0.04 (m, 9H).

Step E. 2-(trimethylsilyl)ethyl 8-oxo-3-(pyrazin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate

• To a vigorously stirred solution of 2-(trimethylsilyl)ethyl 3-(pyrazin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (172 mg, 0.5 mmol) in 1:1 CHCl₃:MeCN (3.8 mL) was added a solution of ruthenium (IV) oxide hydrate (9.8 mg, 0.07 mmol) and sodium metaperiodate (504 mg, 2.3 mmol) in water (4.7 mL). After 4 h, the reaction mixture was diluted with water and extracted with CHCl₃ (×3). The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated to afford a green oil. Purification by chromatography (SiO₂; EtOAc—10% IPA/EtOAc) provided the desired product as a white solid (663 mg, 63%).
• [0140]
  MS (ESI): mass calcd. for C₁₅H₂₀H₆O₃Si, 360.1; m/z found, 361.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 9.59 (d, J=1.5 Hz, 1H), 8.63 (d, J=2.5 Hz, 1H), 8.55 (dd, J=2.5, 1.6 Hz, 1H), 4.88-4.75 (m, 2H), 4.47-4.33 (m, 2H), 4.33-4.24 (m, 2H), 1.18-1.04 (m, 2H), 0.04-(−0.02) (m, 9H).

Step F. 3-(pyrazin-2-yl)-6,7-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one

• To a solution of 2-(trimethylsilyl)ethyl 8-oxo-3-(pyrazin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (1.0 g, 2.9 mmol) in DCM (29 mL) was added TFA (5.7 mL, 75 mmol). After 1 h, the reaction mixture was concentrated. The crude residue was diluted with EtOAc, sonicated, and filtered to provide the desired product as a white solid (1.2 g, 95%). MS (ESI): mass calcd. for C₉H₈N₆O, 216.1; m/z found, 217.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.39 (d, J=1.1 Hz, 1H), 8.77 (q, J=2.6 Hz, 2H), 8.56 (s, 1H), 4.73-4.60 (m, 2H), 3.67-3.55 (m, 2H).

Intermediate 3. (±)-6-methyl-3-(pyrazin-2-yl)-6,7-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one
• Intermediate 3 was made in a manner analogous to Intermediate 1 substituting (±)-tert-butyl 2-methyl-5-oxopiperazine-1-carboxylate for tert-butyl 3-oxopiperazine-1-carboxylate in Step A. MS (ESI): mass calcd. for C₁₀H₁₀N₆O, 230.1; m/z found, 231.1 [M+H]⁺.

Intermediate 4. (6S)-1-(2-chloro-3-(trifluoromethyl)benzyl)-6-methylpiperazine-2,3-dione

• [0146]

Step A. (S)-tert-butyl(2-aminopropyl)carbamate

• To a solution of (S)-1,2-diaminopropane dihydrochloride (16 g, 109 mmol) in MeOH (64 mL) and water (16 mL) was added di-tert-butyl dicarbonate (28.5 g, 131 mmol) in MeOH (16 mL). The resulting solution was cooled in an ice bath, and 4N NaOH (35 mL, 140 mL) was added dropwise over 2 h. The mixture was allowed to warm to rt and stirred for a total of 20 h. The reaction was filtered, and the filtrate concentrated to remove MeOH. 200 mL EtOAc, 200 mL water, and 16 mL 1M HCl were added sequentially. The layers were separated and the aqueous layer washed with EtOAc (200 mL). The combined organic extracts were washed with 0.04M HCl (208 mL). The organic phase was separated and discarded. The aqueous phases were combined, adjusted to pH=14 with 10N NaOH (20 mL), and extracted with DCM (400 mL×2). The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated to afford the desired product as a clear oil (8.0 g, 42%). MS (ESI): mass calcd. for C₈H₁₈N₂O₂, 174.1; m/z found, 175.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 5.01 (br s, 1H), 3.24-3.09 (m, 1H), 3.09-2.95 (m, 1H), 2.92-2.84 (m, 1H), 1.45 (s, 9H), 1.35-1.19 (m, 2H), 1.07 (d, J=6.4 Hz, 3H).

Step B. (6S)-tert-butyl(2-((2-chloro-3-(trifluoromethyl)benzyl)amino)propyl) carbamate

• A solution of (S)-tert-butyl(2-aminopropyl)carbamate (4.0 g, 23 mmol) and 2-chloro-3-trifluoromethylbenzaldehyde (4.8 g, 23 mmol) in DCE (100 mL) was stirred at rt for 2 h. Sodium triacetoxyborohydride (7.3 g, 34 mmol) was added at once and stirring continued overnight. Saturated aqueous NaHCO₃ was added, and the resulting mixture was extracted with DCM (×2). The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated to afford a clear oil. Purification by chromatography (SiO₂; hex—60% EtOAc/hex) provided the desired product as a clear oil (7.2 g, 85%). MS (ESI): mass calcd. for C₁₆H₂₂ClF₃N₂O₂, 366.1; m/z found, 367.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.72-7.56 (m, 2H), 7.35 (t, J=7.7 Hz, 1H), 4.94 (s, 1H), 3.99 (d, J=14.1 Hz, 1H), 3.90 (d, J=14.1 Hz, 1H), 3.29-3.14 (m, 1H), 3.11-2.99 (m, 1H), 2.84 (dd, J=11.1, 6.2 Hz, 1H), 1.44 (s, 9H), 1.11 (d, J=6.4 Hz, 3H).

Step C. (6S)-methyl 2-((1-((tert-butoxycarbonyl)amino)propan-2-yl)(2-chloro-3-(trifluoromethyl)benzyl)amino)-2-oxoacetate

• To an ice cold solution of (6S)-tert-butyl(2-((2-chloro-3-(trifluoromethyl)benzyl)amino)propyl) carbamate (7.2 g, 20 mmol) and triethylamine (2.8 mL, 21 mmol) in DCM (121 mL) was added methyl chlorooxoacetate (1.9 mL, 21 mmol) dropwise. The resulting mixture was warmed to rt and stirred overnight. After diluting with brine, the layers were separated, and the aqueous layer washed with DCM. The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated to afford the desired product as a white solid (8.5 g, 97%). ¹H NMR (400 MHz, CDCl₃) δ 7.72-7.56 (m, 1H), 7.49-7.32 (m, 2H), 4.83 (d, J=17.1 Hz, 1H), 4.79-4.62 (m, 1H), 4.51 (d, J=17.1 Hz, 1H), 4.11-3.97 (m, 1H), 3.93 (s, 3H), 3.24-3.13 (m, 2H), 1.44 (s, 9H), 1.16-1.12 (m, 3H).

Step D. (6S)-methyl 2-((1-aminopropan-2-yl)(2-chloro-3-(trifluoromethyl)benzyl)amino)-2-oxoacetate hydrochloride

• To a solution of 4M HCl in dioxane (75 mL) was added (6S)-methyl 2-((1-((tert-butoxycarbonyl)amino)propan-2-yl)(2-chloro-3-(trifluoromethyl)benzyl)amino)-2-oxoacetate (7.5 g, 16.7 mmol). After 30 minutes, the reaction mixture was concentrated and the product was used in the next step without further purification (6.5 g, 100%). MS (ESI): mass calcd. for C₁₄H₁₆ClF₃N₂O₃, 352.1; m/z found, 353.1 [M+H]⁺.

Step E. (6S)-1-(2-chloro-3-(trifluoromethyl)benzyl)-6-methylpiperazine-2,3-dione

• To a solution of (6S)-methyl 2-((1-aminopropan-2-yl)(2-chloro-3-(trifluoromethyl)benzyl)amino)-2-oxoacetate hydrochloride (7.3 g, 18.9 mmol) in DCM (90 mL) was added triethylamine (7.9 mL, 57 mmol) at once. After 2 h, 1N HCl was added and the layers were separated. The aqueous layer was extracted with DCM (×2). The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated to afford the desired product as a white solid (5.9 g, 98%). MS (ESI): mass calcd. for C₁₃H₁₁ClF₃N₂O₂, 320.1; m/z found, 321.1 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.24 (d, J=3.6 Hz, 1H), 7.68 (dd, J=7.8, 1.1 Hz, 1H), 7.59 (d, J=7.7 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 5.22 (d, J=15.7 Hz, 1H), 4.52 (d, J=15.7 Hz, 1H), 3.82-3.73 (m, 1H), 3.69-3.61 (m, 1H), 3.31 (ddd, J=13.2, 5.2, 2.3 Hz, 1H), 1.46-1.38 (m, 3H).
• Example 14

(±)-7-[2-Chloro-3-(trifluoromethyl)benzyl]-6-methyl-3-pyrazin-2-yl-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one………..
……………………(±) FORM

• Example 14 was made in a manner analogous to Example 2 substituting Intermediate 3 for Intermediate 1 and 1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene for 1-(bromomethyl)-2,3-dichlorobenzene to provide the desired compound as a white solid (102 mg, 63%). MS (ESI): mass calcd. for C₁₈H₁₄ClF₃N₆O, 422.1; m/z found, 423.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) 89.48 (d, J=1.2 Hz, 1H), 8.84-8.82 (m, 2H), 7.85-7.82 (m, 2H), 7.56 (t, J=7.8 Hz, 1H), 5.20 (d, J=16.5 Hz, 1H), 4.98 (dd, J=13.8, 2.2 Hz, 1H), 4.80 (dd, J=13.8, 4.6 Hz, 1H), 4.56 (d, J=16.6 Hz, 1H), 4.23-4.10 (m, 1H), 1.23 (d, J=6.7 Hz, 3H).

Example 15

(6R)-7-[2-Chloro-3-(trifluoromethyl)benzyl]-6-methyl-3-pyrazin-2-yl-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one

……………………UNDESIRED R CONFIGURATION
• Chiral SFC separation of (±)-7-[2-Chloro-3-(trifluoromethyl)benzyl]-6-methyl-3-pyrazin-2-yl-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one on a CHIRALCEL OD-H column (5 μM, 250×20 mm) using 70% CO₂/30% MeOH provided 39 mg of the title compound as the first eluting enantiomer. [α]=+40° (c 2.2, CHCl₃).
• MS (ESI): mass calcd. for C₁₈H₁₄ClF₃N₆O, 422.1; m/z found, 423.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 9.66 (d, J=1.5 Hz, 1H), 8.68 (d, J=2.5 Hz, 1H), 8.59 (dd, J=2.5, 1.5 Hz, 1H), 7.76-7.72 (m, 1H), 7.69 (dd, J=7.9, 1.6 Hz, 1H), 7.41 (t, J=7.8 Hz, 1H), 5.44 (d, J=15.5 Hz, 1H), 5.17 (dd, J=13.9, 2.1 Hz, 1H), 4.62-4.54 (m, 2H), 4.08-4.02 (m, 1H), 1.36 (d, J=6.8 Hz, 3H).

Example 16

(6S)-7-[2-Chloro-3-(trifluoromethyl)benzyl]-6-methyl-3-pyrazin-2-yl-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one………………  DESIRED
• Chiral SFC separation of (±)-7-[2-Chloro-3-(trifluoromethyl)benzyl]-6-methyl-3-pyrazin-2-yl-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one on a CHIRALCEL OD-H column (5 μM, 250×20 mm) using 70% CO₂/30% MeOH provided 40 mg of the title compound as the second eluting enantiomer.
• [α]=−44° (c 2.2, CHCl₃).
• MS (ESI): mass calcd. for C₁₈H₁₄ClF₃N₆O, 422.1; m/z found, 423.1 [M+H]⁺.
• ¹H NMR (500 MHz, CDCl₃) δ 9.66 (d, J=1.5 Hz, 1H), 8.68 (d, J=2.5 Hz, 1H), 8.59 (dd, J=2.5, 1.5 Hz, 1H), 7.76-7.72 (m, 1H), 7.69 (dd, J=7.9, 1.6 Hz, 1H), 7.41 (t, J=7.8 Hz, 1H), 5.44 (d, J=15.5 Hz, 1H), 5.17 (dd, J=13.9, 2.1 Hz, 1H), 4.62-4.54 (m, 2H), 4.08-4.02 (m, 1H), 1.36 (d, J=6.8 Hz, 3H).

see,,,,,,,,,http://worlddrugtracker.blogspot.in/2016/01/preclinical-characterization-of.html

//////////////P2X7, 6,7-Dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one, Autoradiography, Depression, CNS, Preclinical characterization, substituted 6,7-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one,  P2X7 receptor antagonists, Janssen Pharmaceutical Research & Development L.L.C, 1627748-32-6

FC(F)(F)c4cccc(CN1C(=O)c2nnc(n2C[C@@H]1C)c3cnccn3)c4Cl

CC1CN2C(=NN=C2C(=O)N1CC3=C(C(=CC=C3)C(F)(F)F)Cl)C4=NC=CN=C4

see………………..http://www.gmp-compliance.org/enews_05135_FDA-gives-Advice-on-the-Use-of-Control-Charts_15093,15290,15250,15405,Z-VM_n.html

In our News entitled “Statistics and Process Validation: current Findings of the FDA“, we pointed out that the FDA has been observing more and more deficiencies in the area of statistics with regard to process validation. One of the “statistical methods” – also stated in FDA’s Process Validation Guidance – is the use of control charts in the context of a statistical process control (SPC). A SPC can be a valuable resource, particularly in stage 3 of the process validation lifecycle (continued/ongoing process verification).

During an event with the Product Quality Research Institute (PQRI), Dr Daniel Peng from CDER’s Office of Processes and Facilities (OPF) presented his views on the use of SPC under the heading “Using Control Charts to Evaluate Process Variability”. He began with the history of control charts and their fields of application. He furthermore considered the most important rules to create and manage control charts, including types of control charts, sampling and evaluation rules according to the Western Electric Rules.

He concluded his presentation with examples of control charts for evaluating intra and inter-batch variabilities and site performance monitoring.

The slides of the presentation “Using Control Charts to Evaluate Process Variability” are very easy to read and available for free.

Are you interested in SPC and control charts? On 18/19 February, the ECA organises the Education Course “Statistical Process Control – A key tool for process understanding in the process validation life cycle” in Heidelberg, Germany.

The “new” FDA’s process validation guideline has been effective since January 2011. One considerable change was made to the original validation guideline from 1987 to put a significantly greater emphasis on statistics in the context of process validation. So far, relatively few inspection deficiencies had been observed by the FDA with regard to statistics. At a conference in September 2015 co-sponsored by the FDA, Grace McNally – Senior FDA official – reported about current “findings” in the 483s deficiency reports and in Establishment Inspection Reports (EIR). Now, deficiencies regarding statistical problematics can also be found here.

For example, it has been criticised that a (statistical) sampling plan had be misinterpreted. Wrong AQL values with regard to the number of samples have been noted based on MIL-STD-105D. Moreover, it has been criticised that the company didn’t know the operation characteristics of its sampling plan.

Another criticised “finding” was that PPQ batches had been considered as “accepted” when all in-process controls and release specifications were met. It has also been criticised that no intra-batch variabilities have been examined. In addition, it has been noticed that there was no information available in the validation plan concerning the assessment of the process itself. There was also no indication about the objective of the determination of inter-batch variabilities.

Although OOS results had been found in 2 out of 4 PPQ batches, reduced IPC tests have been recommended in the PPQ report giving the justification that this was a standard procedure. Regarding this point, the FDA criticises the lack of scientific rationales for reduced sampling and monitoring. Interestingly, Grace McNally mentions possibilities for rationales of IPC sampling plans and the adaptation to a reduced size. In this context, she refers to the ANSI/ASQ Z1.4 norm and ISO 2859 whereby it is expressly pointed out that the ANSI norm recommends the production of at least 10 successful batches before reducing testing. According to the ISO norm even 15 successful batches are necessary.

The FDA notified a tablet process, criticising the fact that no rationales for warning and action limits were available. Furthermore, it has been criticised that no analyses on variabilities were available although they had been required internally and no capacity indices had been determined. There have been no analyses on the distribution of data, neither planned nor performed. The FDA also remarked that the calculation of variabilities is necessary to be able to make statements about process capacities.

Conclusion: Reinforcing the emphasis on statistics in the US FDA Process Validation Guideline from 2011 hasn’t been really often addressed in the official deficiencies reports. This seems to be changing.

see………http://www.gmp-compliance.org/enews_05077_Statistics-and-Process-Validation-current-Findings-of-the-FDA.html

////////////Statistics, Process Validation,  current Findings,  FDA

The Variations Regulation (EC) no. 1234/2008 of the European Commission defines the procedure for variations of existing marketing authorisations. The “detailed guidelines for the various categories of variations“, which were published in the consolidated version in August 2013 in the European Official Journal, explain the interpretation and application of this Variations Regulation.

Although the “detailed guidelines” describe a number of scenarios of possible variations in some detail, there are formulations in the Guideline text which require clarification due to their blur. The EMA adopted such a case in a recent update of itsquestions and answers collection “Quality of Medicines Questions and Answers: Part 1” to concretise the case through a statement.

It is about the term “complex manufacturing processes”, which is used in two scenarios associated with type II variations (found in the “detailed guidelines” p 40ff):

• Replacement or addition of a manufacturing site for part or all of the manufacturing process of the finished product (Guideline change code B.II.b.1)
  …
  c) Site where any manufacturing operation(s) take place, except batch release, batch control, and secondary packaging, for biological/immunological medicinal products, or for pharmaceutical forms manufactured by complex manufacturing processes.
• Change in the batch size (including batch size ranges) of the finished product (Guideline change code B.II.b.4)
  …
  d) The change relates to all other pharmaceutical forms manufactured by complex manufacturing processes .

The EMA now clarified this term as follows:

• Guideline Change Code B.II.b.1: Complex manufacturing processes are given when the understanding of the relation between quality characteristics of the product and its in vivo efficacy is lacking. This is often the case in innovative medicines such as products of nanomedicine.
• Guideline Change Code B.II.b.4: Complex manufacturing processes are those which contain one or more sub-steps, where a scale-up can lead to problems.

In both scenarios, the approving authority will decide on a case by case basis. If the applicant submits the variation as a Type IB, he must provide a valid justification that the production process is not “complex”. However, in doubt the authority may upgrade the variation to a Type II. Therefore, the EMA recommends that the applicant clarifies the situation with the authority before submitting the variation.

What are “complex manufacturing processes”? A recent reply from the EMA………..http://www.gmp-compliance.org/enews_05072_What-are-%22complex-manufacturing-processes%22-A-recent-reply-from-the-EMA.html

4-(Diphenylacetyl)-a-[(5-quinolinyloxy)methyl]-1-Piperazineethanol (E)-2-butenedioate fumarate (1:1.5), C₃₀ H₃₁ N₃ O₃ . ³/₂ C₄ H₄ O₄

Dofequidar fumarate(MS-209 fumarate), an orally active quinoline compound, has been reported to overcome MDR by inhibiting ABCB1/P-gp, ABCC1/MDR-associated protein 1, or both.

Dofequidar fumarate(MS-209 fumarate), an orally active quinoline compound, has been reported to overcome MDR by inhibitingABCB1/P-gp, ABCC1/MDR-associated protein 1, or both.
IC50 value:
Target: P-gp
in vitro: MS-209 at 3 microM effectively overcame docetaxel resistance in MDR cancer cells, and this concentration was achieved in blood plasma for > 7 h without serious toxicity [1]. MS-209 restored chemosensitivity of SBC-3 / ADM cells to VP-16, ADM, and VCR in a dose-dependent manner in vitro [2]. dofequidar inhibits the efflux of chemotherapeutic drugs and increases the sensitivity to anticancer drugs in CSC-like side population (SP) cells isolated from various cancer cell lines. Dofequidar treatment greatly reduced the cell number in the SP fraction [3]. In 4-1St cells, which are extremely resistant to ADM and VCR, MS-209 at a concentration of 3 microM enhanced the cytotoxicity of ADM and VCR, 88- and 350-fold, respectively [4].
in vivo: Treatment with docetaxel alone at the maximal tolerated dose (MTD) showed an apparent antitumor activity to an intrinsically resistant HCT-15 tumor xenograft, and MS-209 additionally potentiated the antitumor activity of docetaxel. Against a MCF-7/ADM tumor xenograft expressing larger amounts of P-gp, docetaxel alone at the MTD showed no antitumor activity, whereas the MTD of docetaxel combined with MS-209 greatly reduced MCF-7/ADM tumor growth [1]. Intravenous injection with SBC-3 or SBC-3 / ADM cells produced metastatic colonies in the liver, kidneys and lymph nodes in natural killer (NK) cell-depleted severe combined immunodeficiency (SCID) mice, though SBC-3 / ADM cells more rapidly produced metastases than did SBC-3 cells. Treatment with VP-16 and ADM reduced metastasis formation by SBC-3 cells, whereas the same treatment did not affect metastasis by SBC-3 / ADM cells. Although MS-209 alone had no effect on metastasis by SBC-3 or SBC-3 / ADM cells, combined use of MS-209 with VP-16 or ADM resulted in marked inhibition of metastasis formation by SBC-3 / ADM cells to multiple organs [2].

Dofequidar fumarate is a multidrug resistance (MDR)-reversing quinoline derivative that interacts directly with P-glycoprotein and inhibits the efflux of antitumor agents. The agent had been in phase III clinical development by Nihon Schering (now Bayer) for the treatment of advanced and recurrent breast cancer and non-small lung cancer (NSCLC) and at the National Cancer Institute in combination with docetaxel for the treatment of solid tumors. In 2000, Schering AG obtained dofequidar fumarate when Nihon Schering acquired Mitsui Pharmaceuticals, originator of the compound.

PAPER

Structure-activity relationship of newly synthesized quinoline derivatives for reversal of multidrug resistance in cancer
J Med Chem 1997, 40(13): 2047

5-[3-{4-(2,2-Diphenylacetyl)piperazin-1-yl}-2-hydroxypropoxy]quinoline 1.5Fumarate (16, MS-209)

free form of 16 (7.37 g, 70%):  mp 161−162 °C; ¹H-NMR (CDCl₃) δ 2.2−2.8 (m, 6 H), 3.5−3.6 (m, 2H), 3.7−3.9 (m, 2H), 4.1−4.3 (m, 3H), 5.20 (s, 1H), 6.86 (d, 1H, J = 7.3 Hz), 7.2−7.4 (m, 11H), 7.59 (t, 1H, J = 8.1 Hz), 7.71 (d, 1H, J = 8.1 Hz), 8.54 (d, 1H, J = 7.3 Hz), 8.91 (dd, 1H, J = 2, 4 Hz); IR (KBr) 2954, 1630, 1587, 1268, 1091, 802, 748, 703 cm^-1.

16 1.5Fumarate(1.0 g, 60%):  mp 210 °C dec; ¹H-NMR (DMSO-d₆) δ 2.2−2.6 (m, 6H), 3.4−3.6 (m, 4H), 4.0−4.2 (m, 3H), 5.53 (s, 1H), 6.63 (s, 3H), 7.03 (d, 1H, J = 8.1 Hz), 7.2−7.4 (m, 10H), 7.5−7.7 (m, 3H), 8.61 (d, 1H, J = 8.1 Hz), 8.89 (dd, 1H, J = 1.5, 4.4 Hz); IR (KBr) 3424, 1644, 1592, 1277, 1180, 1110, 799 cm^-1.

Patent

WO 2004099151

https://www.google.co.in/patents/WO2004099151A1?cl=en

A method for producing the purest rac-1 – {4- [2-hydroxy-3- (5-quinolyloxy) propyI] -piperazin-1-yl} -2,2-diphenylethan-1-one fumarate and the purest rac-1 – {4- [2-hydroxy-3- (5-quinoly loxy) propylene l] piperazin-1-yl} -2,2-diphenylethan-1 -one fumarate

The invention relates to a method for producing the purest rac-1 – {4- [2-hydroxy-3- (5-quinolyloxy) propyl] -piperazin-1-yl} -2,2-diphenylethan-1-one fumarate as well as rac -1- {4- [2- hydroxy-3- (5-quinolyloxy) propyl] piperazin-1-yl} -2,2-diphenylethan-1-one fumarate with a purity of at least 99.55%

The multidrug resistance modulator rac-1 – {4- [2-hydroxy-3- (5-quinolyloxy) propyl] – piperazin-1-yl} -2,2-diphenylethan-1 -one fumarate, its preparation and use as carcinostatic drug is described as well as other derivatives of this compound in EP 575,890.

According to the process described in EP 575 890 A process for the preparation of pure rac-1 – {4- [2-hydroxy-3- (5-quinolyloxy) propyl] -piperazin-1-yl} -2,2-dϊphenylethan-1-one fumarate is first by coupling the two modules epoxiline (B) (5- (2,3-epoxypropoxy) – quinoline) and Diphenpiperazid (C) (N- (2,2-Diphenylacetyl) piperazine), the free base 5- [3- {4- (2,2-diphenylacetyl) piperazin-1-yl} -2-hydroxypropoxy] quinoline isolated as a crude product. This implementation includes two sub-stages. First, the Epoxylat with hydroxyquinoline (A) is reacted. In the second step the epoxiline (B) (5- (2,3-epoxypropoxy) -quinolin) by Diphenpiperazid (C) (N- (2,2-Diphenylacetyl) piperazine) is opened, it gives the secondary alcohol (D). This reaction takes place in ethanol, water catalyzes the conversion. The workup / isolation is then carried out by precipitation from acetone / water and drying under vacuum at 60 ° C.

The overall reaction results from the following scheme:

On the isolation of the free base, the many impurities (purity of the crude product is typically about 80%), joins in the next step a very expensive cleaning procedures. After charcoal treatment of the free base and the formation of the fumarate in methanol, the free base is again prepared by treatment with dilute sodium hydroxide solution for purification. Subsequently, as the last step, repeated fumarate formation. The two fumarate formations are procedurally identical and differ only in the batch size (T. Suzuki et al., J. Med. Chem. (1997) 40, 2047) (JP 2000281653). Starting from the crude free base, the typical yield for this laboratory cleaning sequence 45% of theory.

A disadvantage of this method is not only the low yield (about 50% loss in the final stage), but also the complex technical implementation, which binds many operational capacities and thus caused increased costs. A particular disadvantage is the extremely poor filterability of the free base, the filter must be dried partially over several weeks.

Despite the high procedural expenses according to this known method, the extremely high purity requirements of rac-1 – {4- [2-hydroxy-3- (5- quinolyloxy) propyl] piperazine-1-yl} -2,2-diphenylethane-1 -one fumarate not always be achieved completely satisfactory.

. Furthermore provides the method described in EP 575 890 any reasonable results during scale-up an overview of the individual reactions are the following scheme:

It has now been found that these known disadvantages can be overcome with the process of this invention. In the process of this invention also the epoxiline (B) and Diphenpiperazid (C) is first coupled by opening of the epoxide. But is not the free base (D) but after the addition of solid fumaric acid directly the fumarate salt (E) is then isolated as a crude product.

The present application thus provides a process for the preparation of pure rac-1 – {4- [2-hydroxy-3- (5-quinolyloxy) propyl] -piperazin-1-yl} -2,2-diphenylethan-1 -one fumarate , which is characterized in that firstly

a) a Epoxytosylat of structure I

OTs

(0 with

b) 5-hydroxyquinoline (II)

(II) and cesium carbonate in a suitable solvent and at a suitable temperature to 5- (2,3-epoxypropoxy) -quinolin of formula III

allowed to react, and then the 5- (2,3-epoxypropoxy) -quinolin of formula III

c) with N- (2,2-Diphenylacefyl) piperazine of the formula IV

in a suitable solvent and at a suitable temperature followed by the addition of solid fumaric acid to the crude rac-1 – {4- [2-hydroxy-3- (5-quinolyloxy) propyl] – piperazin-1-yl} -2,2-diphenylethane 1-one fumarate of the formula V

And subsequently reacting (V)

d) the thus formed crude rac-1 – fumarate {4- [2-hydroxy-3- (5-quinolyloxy) propyl] -piperazin-1-yl} -2,2-diphenylethan-1 -one (V) is isolated and is dissolved in a solvent mixture of methanol and methylene chloride, is treated with activated carbon and subsequently filtered through a pressure filter having silica gel as column material, and the thus obtained pure rac-1 – {4- [2-hydroxy-3- (5-quinolyloxy) propyl] -piperazin-1-yl} -2,2-diphenylethan-1-one fumarate (V) is crystallized from a suitable alcohol.

Preparation Example

Preparation of rac-1 – 4- [2-Hy droxy-3- (5-quinolyloxy) propylene l] -piperazin-1 -yl> -2,2-diphenylethan-1-one fumarate

A) Under nitrogen, 44.2 g of 5-hydroxy-quinoline and 151.9 g of cesium carbonate with 560 ml acetone will give at room temperature together and stirred for 30 minutes at 60 ° C bath temperature. At 50 ° C internal temperature 73.0 g of 5- (2,3-epoxypropoxy) -quinolin dissolved in

153.3 g of dichloromethane, admit. The mixture is stirred at 50 ° C for two hours. The mixture is filtered at 50 ° C. The filter residue (inorganic salts) is washed with 560 ml of 50 ° C warmed acetone. 85.4 g are then N- (2,2-diphenyl-acetyl) piperazine admit and concentrated at a bath temperature of 40 ° C under vacuum to 374 g final weight. It will then add 374 g of demineralized water and 2

Stirred at 40 ° C hours. Then 255 g of acetone and 201 g of demineralized water will admit. The mixture is cooled to room temperature and 89.1 g of fumaric acid are in solid form to Gege-ben. It is stirred for 60 minutes at 60 ° C bath temperature and then stirred at 0 ° C for 2 hours. The solid is suction filtered and washed with 150 ml of ice-cold methanol. The filter residue is dried at 60 ° C under vacuum.

Yield: 65 – 85% of theory

B) 56.0 g of the thus prepared rac-1 – {4- [2-hydroxy-3- (5-quinolyIoxy) propyl] -piperazin-1-yl} – 2,2-diphenylethan-1-one fumarate were nitrogen and treated at room temperature with 5.6 g of activated carbon, Norit SX plus, 672 ml of methanol and 1008 ml of dichloromethane. The resulting suspension is stirred at a bath temperature of 75 ° C to warm to reflux temperature and refluxed for 30 min. At an internal temperature of 40 ° C is rac-1 – {4- [2-hydroxy-3- (5-quinolyloxy) propyl] -piperazin-1-yl} -2,2-diphenylethan-1-one fumarate in solution. The mixture is then filtered hot through 300% silica gel and the silica gel with 560 ml of a mixture of 168 ml of methanol and 392 ml of dichloromethane at room temperature RT. The solution is concentrated at a bath temperature of 40 ° C and an initial vacuum of 400 mbar to a final volume of 517 ml. The ultimate vacuum of 350 mbar. The distilled volume is about the difference in volume (about 1, 7 I). There are 404 ml of methanol was added so that a final volume of 921 ml is achieved. The solution is cooled to 0 ° C, whereupon the product precipitates. The resulting suspension is stirred for 2 hours at 0 ° C and then filtered through a paper filter. The filter residue is washed with 56.0 ml of ice-cold methanol. The filter residue is dried at 60 ° C and under vacuum at 100 mbar for 10 hours.

Yield (. Uncorr): 47.29 g (84.45% FS)

Purity: 99.65% (HPLC, 100% method)

References on Dofequidar fumarate

http://jco.ascopubs.org/content/25/4/411.full.pdf

SEE………http://apisynthesisint.blogspot.in/2016/01/ms-209-dofequidar-fumarate.html

///////////MS-209,  Dofequidar fumarate, PHASE 3

AZD2716

Antiplaque candidate drug

AstraZenecaINNOVATOR

DETAILS COMING……………

1H NMR

13C NMR

An Enantioselective Hydrogenation of an Alkenoic Acid as a Key Step in the Synthesis of AZD2716

A classical resolution of a racemic carboxylic acid through salt formation and an asymmetric hydrogenation of an α,β-unsaturated carboxylic acid were investigated in parallel to prepare an enantiomerically pure alkanoic acid used as a key intermediate in the synthesis of an antiplaque candidate drug. After an extensive screening of rhodium- and ruthenium-based catalysts, we developed a rhodium-catalyzed hydrogenation that gave the alkanoic acid with 90% ee, and after a subsequent crystallization with (R)-1-phenylethanamine, the ee was enriched to 97%. The chiral acid was then used in sequential Negishi and Suzuki couplings followed by basic hydrolysis of a nitrile to an amide to give the active pharmaceutical ingredient in 22% overall yield.

/////////

c1c(cc(c(c1)C(=O)N)c2cccc(c2)CC(C(=O)O)C)Cc3ccccc3

(4R,5R)-5-(2,5-difluorophenyl)-4-(5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one

cas 1375751-08-8
Chemical Formula: C22H14F2N2O2
Exact Mass: 376.1023

Bristol-Myers Squibb Company INNOVATOR

BMS-955829 is a Positive allosteric modulators (PAMs). BMS-955829 shows high functional PAM potency, excellent mGluR5 binding affinity, low glutamate fold shift, and high selectivity for the mGluR5 subtype. BMS-955829 is a potent mGluR5 PAM (EC50 = 2.6 ± 1.0 nM; n = 6), devoid of inherent mGluR5 agonist activity (EC50 > 30μM). The measured binding Ki of BMS-955829 was found to be 1.6 nM, which was in good agreement with its functional potency.

SYNTHESIS AND INTERMEDIATES…….https://www.google.co.in/patents/WO2012064603A1?cl=en

Intermediate 73

Diethyl 2,5-difluorobenzylphosphonate. A mixture of 2-(bromomethyl)-l,4- difluorobenzene (3 g, 14.49 mmol) and triethyl phosphite (7.72 ml, 43.5 mmol) was heated to 160 °C with stirring for 4 hours, cooled to ambient temperature and concentrated under high vacuum to remove most triethyl phosphite. The resulting residue was purified by column chromatography (20% to 30 % EtO Ac/Toluene) providing diethyl 2,5-difluorobenzylphosphonate (3.76 g, 13.52 mmol, 93 % yield) as colorless oil. ¾ NMR (500MHz, DMSO-d₆) δ 7.30 – 7.10 (m, 3H), 4.05 – 3.91 (m, 4H), 3.31 – 3.20 (m, 2H), 1.18 (t, J=7.0 Hz, 6H). MS Anal. Calcd. for [M+H]⁺ CiiHieFzOsP: 265.2; found 265.3.

Intermediate 74

(E)-3-Bromo-5-(2,5-difluorostyryl)pyridine. To a stirred solution of diethyl 2,5-difluorobenzylphosphonate (63.5 g, 240 mmol) and 5-bromonicotinaldehyde (50.7 g, 264 mmol) in tetrahydrofuran (1923 ml) was added potassium tert-butoxide in tetrahydrofuran (312 ml, 312 mmol) at -10 °C. After three hours, the reaction mixture was allowed to warm to ambient temperature and stirring was continued for another 16 hours at which time the reaction mixture was diluted with ether (800 mL) and washed with H₂O. The organic layer was dried over anhydrous magnesium sulfate, filered and concentrated to provide a yellow wax to which was added 300 mL of hexane and after sonication filtered to provide (is)-3-bromo-5-(2,5- difluorostyryl)pyridine (54 g, 173 mmol, 72.1%) as a white solid. ^XH NMR

(500MHz, DMSO-d₆) δ 8.78 (d, J=1.8 Hz, IH), 8.63 (d, J=2.1 Hz, IH), 8.44 (t, J=2.0 Hz, IH), 7.67 (ddd, J=9.4, 6.0, 3.2 Hz, IH), 7.56 – 7.48 (m, IH), 7.46 – 7.40 (m, IH), 7.34 (td, J=9.6, 4.6 Hz, IH), 7.24 (tt, J=8.3, 3.6 Hz, IH). MS Anal. Calcd. for [M+H]⁺ Ci₃H₉BrF₂N: 296.0; found 298.1

Intermediate 75

Tert-butyl (lR,2R)-l-(5-bromopyridin-3-yl)-2-(2,5-difluorophenyl)-2- hydroxyethylcarbamate. A solution of tert-butyl carbamate (4.18 g, 35.0 mmol) in propanol (39 ml) was sequentially treated with sodium hydroxide (1.376 g, 34.4 mmol) in water (72 ml) and tert-butyl hypochlorite (3.88 ml, 34.4 mmol). After 5 min of stirring, the reaction mixture was cooled to 0 °C. A solution of

(DHQD)₂PHAL (0.555 g, 0.677 mmol) in propanol (39 ml), a solution of (E)-3- bromo-5-(2,5-difluorostyryl)pyridine (3.34 g, 11.28 mmol) in propanol (68 ml) , and potassium osmate dihydrate (0.166 g, 0.451 mmol) were sequentially added. The reaction mixture was stirred for three additional hours at 0 °C, warmed to ambient temperature and after an additional 16 hours the light yellow homogenous solution was quenched with saturated aqueous sodium sulfite (100 mL). The aqueous phase was extracted with ethyl acetate( 2 X 50 mL), the combined organic phases were washed with brine (100 mL), dried over anhydrous magnesium sulfate and concentrated to afford a residue which was purified via column chromatography (25% to 40 % EtO Ac/Hex) to provide tert-butyl (7R,2R)-l-(5-bromopyridin-3-yl)-2- (2,5-difluorophenyl)-2-hydroxyethylcarbamate (2.2991 g, 5.09 mmol, 45.1 % yield) as an optically enriched mixture of enantiomers. ^XH NMR (500MHz, DIVISOR) δ 8.56 (d, J=1.8 Hz, IH), 8.40 (s, IH), 8.03 (s, IH), 7.52 (d, J=9.5 Hz, IH), 7.25 (br. s., IH), 7.10 (t, J=5.6 Hz, 2H), 5.89 (d, J=4.9 Hz, IH), 5.03 (t, J=5.0 Hz, IH), 4.83 (dd, J=8.9, 5.2 Hz, IH), 1.40 – 1.34 (m, 9H), MS Anal. Calcd. for [M+H]⁺

Ci₈H₂oBrF₂ 20₃: 429.1; found 431.3.

Intermediate 77

(lR,2R)-2-Amino-2-(5-bromopyridin-3-yl)-l-(2,5-difluorophenyl)ethanol To a stirred solution of tert-butyl tert-butyl (7R,2R,)-l-(5-bromopyridin-3-yl)-2-(2,5- difluorophenyl)-2-hydroxyethylcarbamate (2.30 g, 5.09 mmol) in methylene chloride (30 mL) was added HC1 in dioxane (30 ml, 120 mmol). The reaction mixture was placed in an oil bath set to 50 °C. After three hours, the reaction mixture was concentrated providing (7R,2R^-2-amino-2-(5-bromopyridin-3-yl)-l-(2,5- difluorophenyl)ethanol 2HC1 salt (2.10 g, 4.97 mmol, 98 % yield) as an optically enriched yellow wax. ^XH NMR (500MHz, DMSO-d₆) δ 8.95 (d, J=3.7 Hz, 2H), 8.64 (d, J=2.4 Hz, 1H), 8.45 (d, J=1.5 Hz, 1H), 8.31 (t, J=2.0 Hz, 1H), 7.47 – 7.09 (m, 3H), 7.04 (td, J=9.2, 4.4 Hz, 1H), 5.29 (d, J=9.2 Hz, 1H), 4.57 (dd, J=9.0, 5.3 Hz, 1H). Anal. Calcd. for [M+H]⁺ Ci₃H₁₂BrF₂N₂0: 329.0; found 331.2.

Intermediate 78

(4R,5R)-4-(5-Bromopyridin-3-yl)-5-(2,5-difluorophenyl)oxazotidin-2-one. To optically enriched (7R,2R)-2-amino-2-(5-bromopyridin-3-yl)-l-(2,5- difluorophenyl)ethanol, 2 HC1 (2.019 g, 4.82 mmol) in tetrahydrofuran (98 ml) was added diisopropylethylamine (2.95 ml, 16.87 mmol) and the resultant solution was stirred for ten mintues at ambient temperature, cooled to 0 °C and

carbonyldiimidazole (1.094 g, 6.75 mmol) was added. After an additional three hours at 0 °C the reaction mixture was warmed to ambient temperature and allowed to stir for another 16 hours. 2M ¾ in methanol (5ml) was added and after ten mintues the suspension was filtered and concentrated to a pink oil which was purified by column chromatography (25% to 40 % EtO Ac/Hex) providing (4R,5R)-4-(5- bromopyridin-3-yl)-5-(2,5-difluorophenyl)oxazolidin-2-one (1.353 g, 3.62 mmol, 75 % yield) as an optically enriched white solid. ¾ NMR (500MHz, DMSO-d₆) δ 8.80 – 8.68 (m, 1H), 8.55 (d, J=2.1 Hz, 2H), 8.16 (t, J=2.1 Hz, 1H), 7.46 – 7.28 (m, 3H), 5.71 – 5.58 (m, 1H), 5.02 (d, J=6.7 Hz, 1H). MS Anal. Calcd. for [M+H]⁺ Ci₄H₁₀BrF₂ 2O2: 355.0; found 357.2.

Intermediate 79

(4R,5R)-4-(5-Bromopyridin-3-yl)-5-(2,5-difluorophenyl)oxazotidin-2-one. Method – 2 A mixture of tert-butyl ((lR,2R)-l-(54oromopyridin-3-yl)-2-(2,5- difluorophenyl)-2-hydroxyethyl)carbamate and tert-butyl ((lR,2R)-2-(5- bromopyridin-3-yl)-l-(2,5-difluorophenyl)-2-hydroxyethyl)carbamate (about 6: 1 ratio) (101 g, 236 mmol) in tetrahydrofuran (590 mL) was cooled to -7 °C with a methanol/ice bath. To this mixture was added a solution of 1 M potassium tert- butoxide in tetrahydrofuran (590 mL, 590 mmol) via an addition funnel while maintaining the internal temperature < 3 °C. The reaction mixture was stirred with a cooling bath for 30 min and then allowed to warm up to room temperature. After 20 h, the reaction was deemed complete by LC/MS. The reaction mixture was concentrated to dryness to give crude product. Another identical scale reaction was performed. The crude products of the two batches were combined to work up together. They were treated with ethyl acetate (1.75 L) and water (1.75 L). The layers were separated. The organic layer was washed with brine (1.75 L), dried (sodium sulfate), and evaporated to give 161.5 g of crude product as a brown solid. This was purified by ISCO to give 67.1 g (42% yield). LC/MS (ES+) 355/357 (M+H, 100; Br isotope pattern); ^XH NMR (400MHz, CDCl₃) δ 8.75 (d, J=2.2 Hz, 1H), 8.53 (d, J=1.8 Hz, 1H), 7.97 (t, J=2.0 Hz, 1H), 7.29 – 7.23 (m, 1H), 7.18 – 7.09 (m, 2H), 6.40 (s, 1H), 5.56 (d, J=5.7 Hz, 1H), 4.84 (d, J=5.5 Hz, 1H); Calcd for

Ci₄H₉N₂BrF₂0₂: C, 47.34; H, 2.55; N, 7.86; Br, 22.50; F, 10.69. Found: C, 47.29; H, 2.61; N, 7.87; Br, 22.40; F, 10.37. Note: Chiral HPLC of the above sample showed 4.7% of the enantiomer. The (4S, 55) enantiomer can be purged by recrystallization from methanol to give > 99.9 ee with 67% recovery.

Scheme 1.

Pd(0)/Cu(l)/ TBAF Scheme 2.

cheme 4.

R’ = H, alkyl

Scheme 8.

cheme 11.

Scheme 12.

Scheme 14.

Scheme 15.

R” = H, alkyl R” = alkyl

cheme 16.

R’ = alky I

R” = alkyl

Scheme 17.

R’ = H, alkyl

R” = H, alkyl

Scheme 18.

R’ = H, alkyl R’ = H, alkyl

P T/US2011/059339

COMPD IS 185

Example 185

(4R, 5R)-5-(2, 5-difluorophenyl)-4-(5-(phenylethynyl)-3-pyridinyl)-l, 3-oxazolidin-2- one.

To a stirred solution of optically enriched (4R,5R)-4-(5-bromopyridin-3-yl)-5- (2,5-difluorophenyl)oxazolidin-2-one (1.25 g, 3.25 mmol) in triethylamine (70 mL) was added ethynylbenzene (0.592 mL, 5.28 mmol), copper(I) iodide (67 mg, 0.352 mmol), and triphenylphosphine (653 mg, 2.464 mmol). Nitrogen was bubbled through the mixture for 10 mintues before adding dichlorobis(triphenylphosphine)- palladium(II) (202 mg, 0.282 mmol) with continued nitrogen gas bubbling. After an additional 10 mintues the reaction mixtrue was heated to reflux for 16 hours, cooled to ambient temperature, diluted with EtOAc, washed with water (3X), brine, dried over magnesium sulfate, and concentrated in vacuo. Column chromatography (25% – -> 40% EtO Ac/Hex) provided optically enriched (4R,5R)-5-(2,5-difluorophenyl)-4- (5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one which was separated by chiral SFC chromatography (Chiralcel OJ-H preparative column, 30 x 250mm, 5μιη, Mobile Phase: 40% MeOH (0.1%DEA) in C0₂ @ 150Bar, Temp: 35°C, Flow rate: 70.0 mL/min. for 16 min, UV monitored @ 280 nM . tR = 9.23 min) to provide (1.38 g, 2.99 mmol, 85 % yield) of pure single enantiomer (4R,5R)-5-(2,5-difluorophenyl)- 4-(5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one.

‘H NMR (500 MHz, DMSO-i¾) δ ppm 8.77 (d, J=2.21 Hz, 1 H) 8.57 (s, 1 H) 8.56 (d, J=2.20 Hz, 1 H) 8.07 (t, J=2.05 Hz, 1 H) 7.58 – 7.66 (m, 2 H) 7.44 – 7.52 (m, 3 H) 7.39 – 7.45 (m, 1 H) 7.28 – 7.39 (m, 2 H) 5.67 (d, J=6.62 Hz, 1 H) 5.04 (d, J=6.62 Hz, 1 H). ¹³C NMR (126 MHz,

DMSO-i¾) δ ppm 157.28; 157.24 (d, J=240.70 Hz) 155.92 (d, J=245.20 Hz) 151.63; 147.70; 136.78; 135.02; 131.57; 129.43; 128.89; 126.63 (dd, J=14.99, 7.72 Hz) 121.51; 119.47; 117.83 (dd, J=23.60, 9.10 Hz) 117.50 (dd, J=24.50, 8.20 Hz); 114.60 (dd, J=26.34, 4.54 Hz); 92.86; 85.76; 78.12; 59.43;

LCMS (ESI) m/z calcd for C₂₂H₁₅F₂N₂0₂: 377.11, found 377.20[M+H]⁺;

HRMS (ESI) m/z calcd for

C₂₂H₁₅F₂N₂0₂: 377.1096, found 377.1096 [M+H]+.

SEE

WO2015054103, OXAZOLIDINONES AS MODULATORS OF MGLUR5

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=15257519640294865E18C0BA057EADF3.wapp1nA?docId=WO2015054103&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

PAPER

Positive allosteric modulators (PAMs) of the metabotropic glutamate receptor subtype 5 (mGluR5) are of interest due to their potential therapeutic utility in schizophrenia and other cognitive disorders. Herein we describe the discovery and optimization of a novel oxazolidinone-based chemotype to identify BMS-955829 (4), a compound with high functional PAM potency, excellent mGluR5 binding affinity, low glutamate fold shift, and high selectivity for the mGluR5 subtype. The low fold shift and absence of agonist activity proved critical in the identification of a molecule with an acceptable preclinical safety profile. Despite its low fold shift, 4 retained efficacy in set shifting and novel object recognition models in rodents.

Discovery and Preclinical Evaluation of BMS-955829, a Potent Positive Allosteric Modulator of mGluR5

http://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.5b00450

http://pubs.acs.org/doi/suppl/10.1021/acsmedchemlett.5b00450/suppl_file/ml5b00450_si_001.pdf

SEE…………http://orgspectroscopyint.blogspot.in/2016/01/bms-955829.html

///////BMS 955829, mGluR5,  positive allosteric modulator,  schizophrenia,  cognition,  neurotoxicity, Bristol-Myers Squibb

FC1=CC=C(C=C1[C@H]([C@@H](C2=CC(C#CC3=CC=CC=C3)=CN=C2)N4)OC4=O)F

1-(6-bromoquinolin-4-yl)sulfanylcyclobutane-1-carboxylic acid

COMING………….

MS m/z (ESI): 338.0 [M+l]

1H NMR (400 MHz, DMSO) δ 13.17 (s, 1H), 8.75-8.79 (m, 1H), 8.24 (s, 1H), 7.87-7.98 (m, 2H), 7.21-7.25 (m, 1H), 2.83-2.95 (m, 2H), 2.30-2.41 (m, 2H), 2.16-2.27 (m, 1H), 1.97-2.08 (m, 1H)

WO-2014183555-A1 / 2014-11-20

http://www.google.co.in/patents/WO2014183555A1?cl=en

PROCEDURE

6-溴喹啉 -4-硫醇

将 6-溴 -4-氯喹啉 3a (260 mg， 1.1 mmol , 采用公知的方法 ” Bioorganic &

Medicinal Chemistry Letters, 2012, 22(4), 1569-1574 “制备而得)和硫化钠（100 mg， 1.3 mmol)加入到 4 mL的 N，N-二甲基甲酰胺中，加毕，加热至 80°C，搅拌反应 2小时。 向反应液中加入 50 mL水，滴加 1 M盐酸至反应液 pH为 5~6，用乙酸乙酯萃取 (50 mL X 3) , 合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题产物 6-溴喹啉 -4-硫醇 3b (257 mg，黄色油状物)，直接用于下步反应。

第二步

1 -((6-溴喹啉 -4-基)硫)环丁基甲酸乙酯

氩气氛下，将 6-溴喹啉 -4-硫醇 3b (257 mg， 1.1 mmol), 1-溴环丁垸甲酸乙酯 (266 mg， 1.3 mmol)和碳酸铯 (371 mg， 1.1 mmol)依次加入到 5 mL的 N，N-二甲基甲酰胺 中，加热至 60°C，搅拌反应 2小时。反应液过滤，滤饼用乙酸乙酯洗涤 (10 mL X 3)， 滤液减压浓缩，得到标题产物 1-((6-溴喹啉 -4-基)硫)环丁基甲酸乙酯 3c (300 mg， 棕色油状物)，产率： 77%。

MS m/z (ESI): 368.2 [M+l]

1H MR (400 MHz, CDC1₃) δ 8.67 (d, =4.77Hz, IH), 8.31 (d, =2.13Hz, IH), 7.94 (d, =8.91Hz, IH), 7.78 (dd, =9.03, 2.13Hz, IH), 7.15 (d, =4.89Hz, IH), 4.16 (q, =7.15Hz, 2H), 2.86-3.04 (m, 2H), 2.39-2.51 (m, 2H), 2.25-2.37 (m, IH), 2.00-2.15 (m, IH), 1.16 (t, =7.09Hz, 3H)

第三步

1 -((6-溴喹啉 -4-基)硫)环丁基甲酸

将 1-((6-溴喹啉 -4-基)硫)环丁基甲酸乙酯 3c (100 mg， 0.27 mmol)和水合氢氧化 锂 (23 mg， 0.55 mmol)溶解于 6 mL四氢呋喃，乙醇和水( ^=4: 1 : 1)的混合溶剂 中，搅拌反应 3小时。滴加 1M盐酸至反应液 pH为 5~6，分液，水相用二氯甲垸 萃取 (10 mL X 3)，合并有机相，有机相用饱和氯化钠溶液洗涤 (10 mL X I), 无水硫 酸钠干燥，过滤，滤液减压浓缩，用薄层层析以展开剂体系 A纯化所得残余物， 得到标题产物 1-((6-溴喹啉 -4-基)硫)环丁基甲酸 3 (20 mg，白色固体)，产率： 22%。

MS m/z (ESI): 338.0 [M+l]

1H NMR (400 MHz, DMSO) δ 13.17 (s, 1H), 8.75-8.79 (m, 1H), 8.24 (s, 1H), 7.87-7.98 (m, 2H), 7.21-7.25 (m, 1H), 2.83-2.95 (m, 2H), 2.30-2.41 (m, 2H), 2.16-2.27 (m, 1H), 1.97-2.08 (m, 1H)

L – ((6-bromo-quinolin-4-yl) thio) cyclobutyl acid

First step

6-bromo-quinoline-4-thiol

A mixture of 6-bromo-4-chloro-quinoline 3a (260 mg, 1.1 mmol, a known method of “Bioorganic &

Medicinal Chemistry Letters, 2012, 22 (4), 1569-1574 “prepared to give) and sodium sulfide (100 mg, 1.3 mmol) was added to 4 mL of N, N- dimethyl formamide, plus complete, heated 80 ° C, the reaction was stirred for 2 hours. To the reaction mixture was added 50 mL of water, 1 M hydrochloric acid was added dropwise to the reaction solution to pH 5-6, extracted with ethyl acetate (50 mL X 3), the combined organic phases, with no over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the title product 6-bromo-quinolin-4-thiol 3b (257 mg, yellow oil), it was used directly in the next reaction.

The second step

L – ((6-bromo-quinolin-4-yl) thio) ethyl cyclobutyl

Under an argon atmosphere, 6-bromo-quinolin-4-thiol 3b (257 mg, 1.1 mmol), 1- bromo-cyclobutyloxy embankment carboxylate (266 mg, 1.3 mmol) and cesium carbonate (371 mg, 1.1 mmol) were added to 5 mL of N, N- dimethylformamide and heated to 60 ° C, the reaction was stirred for 2 hours. The reaction mixture was filtered, the filter cake washed with ethyl acetate (10 mL X 3) and the filtrate was concentrated under reduced pressure to give the title product l – ((6-bromo-quinolin-4-yl) thio) ethyl cyclobutyl 3c ( 300 mg, brown oil). Yield: 77%.

MS m / z (ESI): 368.2 [M + l]

1H MR (400 MHz, CDC1 ₃₎ δ 8.67 (d, = 4.77Hz, IH), 8.31 (d, = 2.13Hz, IH), 7.94 (d, = 8.91Hz, IH), 7.78 (dd, = 9.03, 2.13Hz, IH), 7.15 (d, = 4.89Hz, IH), 4.16 (q, = 7.15Hz, 2H), 2.86-3.04 (m, 2H), 2.39-2.51 (m, 2H), 2.25-2.37 ( m, IH), 2.00-2.15 (m, IH), 1.16 (t, = 7.09Hz, 3H) Step

L – ((6-bromo-quinolin-4-yl) thio) cyclobutyl acid

L – ((6-bromo-quinolin-4-yl) thio) ethyl cyclobutyl 3c (100 mg, 0.27 mmol) and lithium hydroxide monohydrate (23 mg, 0.55 mmol) was dissolved in 6 mL of tetrahydrofuran, ethanol and water (^ = 4: 1: 1) mixed solvent, the reaction was stirred for 3 hours. 1M hydrochloric acid was added dropwise to the reaction solution pH of 5 to 6, liquid separation, the aqueous phase was extracted (10 mL X 3) with dichloromethane, the combined organic phases, the organic phase was washed with a saturated sodium chloride solution (10 mL XI), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, to the resulting thin layer chromatography using a developing solvent system A and the residue was purified to give the title product l – ((6-bromo-quinolin-4-yl) thio) cyclobutyl acid 3 (20 mg, white solid), yield: 22%. MS m / z (ESI): 338.0 [M + l]

1H NMR (400 MHz, DMSO) δ 13.17 (s, 1H), 8.75-8.79 (m, 1H), 8.24 (s, 1H), 7.87-7.98 (m, 2H), 7.21-7.25 (m, 1H), 2.83-2.95 (m, 2H), 2.30-2.41 (m, 2H), 2.16-2.27 (m, 1H), 1.97-2.08 (m, 1H)

Discovery of potent and orally bioavailable inhibitors of Human Uric Acid Transporter 1 (hURAT1) and binding mode prediction using homology model

• Jianbiao Peng^, ,

• Shanghai Hengrui Pharmaceutical Co. Ltd, 279 Wenjing Rd., Shanghai 200245, China

This Letter describes the discovery of a series of potent inhibitors of Human Uric Acid Transporter 1 (hURAT1). Lead generation and optimization via 3D pharmacophore analysis resulted in compound 41. With an IC₅₀ of 33.7 nM, 41 also demonstrated good oral bioavailability in rat (74.8%) and displayed a consistent PK profile across all species tested (rat, dog and monkey).

http://www.sciencedirect.com/science/article/pii/S0960894X1530353X

////////Shanghai Hengrui, inhibitors of Human Uric Acid Transporter 1 (hURAT1), 1-(6-bromoquinolin-4-yl)sulfanylcyclobutane-1-carboxylic acid

c13cc(ccc3nccc1SC2(C(=O)O)CCC2)Br

US-20160002275

CADILA HEALTHCARE LIMITED [IN]

(2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol is also known as Canagliflozin, is an inhibitor of subtype 2 sodium-glucose transport protein (SGLT2) which is chemically represented as compound of Formula (I).

U.S. Pat. No. 7,943,788 B2 discloses canagliflozin and a process for its preparation.

U.S. Pat. No. 7,943,582 B2 (the ‘582 patent) discloses crystalline form of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate and process for preparation thereof.

U.S. PG-Pub. No. 2011/0212905 discloses crystalline form of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate and process for preparation thereof.

U.S. PG-Pub. Nos. 2009/0233874, 2010/099883 and 2008/0146515 discloses similar process for the preparation of canagliflozin substantially as same as shown in scheme-1 below.

International (PCT) Publication No. WO 2011/079772 discloses a process for the preparation of canagliflozin by reduction of keto group of acetyl protected compound followed by hydrolysis.

U.S. PG-Publication No. 2014/0128595 discloses a process for the preparation of canagliflozin from anhydroglucopyranose derivative substantially as same as shown in scheme-2 below.

The prior-art processes requires sequence of protection/deprotection of canagliflozin obtained in the course of the reactions and further purification or crystallization to obtain canagliflozin in reasonably pure form. This sequences of processes results in high amount of yield loss.

In view of the above prior art, there is provided a novel, efficient and convenient process for preparation of canagliflozin which is at least a useful alternative to the prior art as well as an efficient and convenient method for purification of canagliflozin without sequence of protection and deprotection.

Scheme-3.

Ahmedabad-based pharma giant Cadila Healthcare’s chairman and managing director, Pankaj Patel,

EXAMPLES

Example-1Preparation of (3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (III)

In 500 mL three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel were added 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (Va) (5 g) and 150 mL toluene at 25° C. 1.5 mL (1.6M) n-butyl lithium in hexane was added dropwise at room temperature and the solution was stirred for 30 minutes. This solution was cooled to −78° C. and added dropwise to a solution of 3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (IV) (6.4 g) in 100 mL toluene and the mixture was stirred for 3 hours. The reaction mixture was treated with 2.5 g methanesulfonic acid in 100 mL methanol and stirred for 1 hour. The reaction mass was warmed to 25° C. and then added to pre-cool saturated sodium bicarbonate solution and resulting mass was extracted with ethyl acetate. The extract was washed with brine, dried over Na₂SO₄ and evaporated under reduced pressure to obtain compound of Formula (III).

Example-1APreparation of (3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (III)

In 500 mL three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel were added 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (Va) (5 g) and 150 mL toluene at 25° C. 1.5 mL (1.6M) n-butyl lithium in hexane was added dropwise at room temperature and the solution was stirred for 30 minutes. This solution was cooled to −78° C. and added dropwise to a solution of 3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (IV) (6.4 g) in 100 mL toluene and the mixture was stirred for 3 hours. The reaction mixture was treated with 2.5 g methanesulfonic acid in 100 mL methanol and stirred for 1 hour. The reaction mixture warmed to room temperature and stirred for 8 hours. Saturated sodium bicarbonate solution was added to the reaction mixture and the separated aqueous layer was extracted with toluene. The organic layer was distilled to remove toluene and the residue was dissolved in 50 mL methylene dichloride, washed with brine, dried over Na₂SO₄ and evaporated under reduced pressure to obtain residue. The residue was treated with 150 mL diisopropyl ether and stirred at 55° C. for 30 min, cooled, filtered and washed withdiisopropyl ether to obtain compound of Formula (III).

Example-1BPreparation of (3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (III)

In 5 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel were added 100 g 2-(5-iodo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (Vb), 114.35 g 3,4,5-tris((trimethylsilyl)oxy)-6-(((tri-methylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (IV), 2 L toluene and 1 Ltetrahydrofuran at 30° C. The reaction mixture was cooled to −78° C. and 171.45 mL n-butyl lithium in hexane (1.6M) was added and the solution was stirred for 3 hours. The reaction mixture was treated with 94.16 g methanesulfonic acid in 1500 mL methanol and stirred for 1 hour. The reaction mixture warmed to 25° C. and stirred for 8 hours. The reaction mixture was cooled to 5° C. and saturated sodium bicarbonate solution was added to the reaction mixture and stirred for 30 min. The separated aqueous layer was extracted with toluene. The organic layer was distilled to remove toluene and the residue was dissolved in 300 mL methylene dichloride and 200 g silica gel of 60-120 mesh was added. The reaction mixture was stirred for 30 min at 30° C., washed with brine, dried over Na₂SO₄ and evaporated under reduced pressure to obtain residue. The residue was treated with 1 L diisopropyl ether and stirred at 55° C. for 30 min, cooled, filtered and washed with diisopropyl ether to obtain compound of Formula (III).

Example-2APreparation of (3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-2-methoxy-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol (IIa1)

In 500 mL three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel were added 10 g compound of Formula (III), 80 mL methylene dichloride and 4.3 g N-methylmorpholine at −5 to 5° C. 2.7 g trimethylsilyl chloride was added slowly and stirred for 1 hour. After confirming the reaction completion TLC, 30 mL pre-cool water was slowly added, stirred and layers were separated. The separated aqueous layer was extracted with methylene dichloride and the combined organic layers were washed with 20% sodium dihydrogen phosphate dihydrate solution, water and brine. The organic layer was evaporated under reduced pressure to obtain compound of Formula (IIa).

Example-2BPreparation of (3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-2-methoxy-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol (IIa1)

In 1 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel were added 100 g compound of Formula (III) and 900 mL methanol at 30° C. and stirred for 1 hour. The reaction mixture was filtered to remove silica gel and washed with methanol. The filtrate was distilled under vacuum to remove methanol completely, 350 mL methylene dichloride and 42.63 g N-methylmorpholine were added to the residue and cooled to at −5 to 5° C., 34.34 g trimethylsilyl chloride was lot-wise added and stirred for 45 min. After confirming the reaction completion TLC, 300 mL pre-cool water was slowly added, stirred and layers were separated. The separated aqueous layer was extracted with methylene dichloride and the combined organic layers were washed with 20% sodium dihydrogen phosphate dihydrate solution, water and brine. The separated organic layer was dried over sodium sulfate and filtered to obtain compound of Formula (IIa1).

Example-3APreparation of Canagliflozin of Formula (I)

In 1 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel was added solution of compound (IIa) prepared in example-2B and cooled to −70° C. 8 mL triethylsilane and 5.5 mL boron trifluoridediethyl etherate were added dropwise within 1 hour maintaining the reaction temperature between −70° C. The reaction was warmed to −30° C. and stirred for 30 min. The reaction mixture was then added to freshly preparedsodium bicarbonate solution at 5° C. and then allowed to warm to room temperature and stirred for 20 mints to adjust the pH of 7-8. The reaction mass was then slowly added to cold water. The resulting mass was extracted with ethyl acetate. The combined organic layers were washed with saturated bicarbonatesolution, dried over Na₂SO₄ and evaporated under reduced pressure to obtain canagliflozin having purity 86% by HPLC.

Example-3BPreparation of Canagliflozin of Formula (I)

In 2 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel was added the solution of compound (IIa) prepared in example-2B and cooled to −70° C. 67.38 g triethylsilane and 83.08 g boron trifluoridediethyl etherate were added dropwise within 1 hour maintaining the reaction temperature between −70° C. The reaction was warmed to −30° C. and stirred for 3 hours. The reaction mixture was then added to freshly prepared sodium bicarbonate solution at 5° C. and then allowed to warm to room temperature and stirred for 20 mints to adjust the pH of 7-8. The reaction mixture was then slowly added to cold water. The separated aqueous layer was extracted with 200 mL methylene dichloride. The combined organic layer was washed with 300 mL water and distilled completely to remove methylene dichloride. The resulting residue extracted with 500 mL ethyl acetate and stirred to obtain clear solution. The reaction mixture was treated with brine and saturated bicarbonate solution to separate the layers. The separated organic layer was dried over sodium sulfate, charcoalized and filtered. The filtrate is distilled to remove ethyl acetate completely under vacuum. The residue was dissolved in 300 mL methylene dichloride and 200 g silica gel of 60-120 mesh was added. The reaction mixture was stirred for 30 min at 30° C. and distilled completely under reduced pressure to obtain residue. The residue was treated with 500 L diisopropyl ether and stirred at 55° C. for 30 min, cooled, filtered and washed with diisopropyl ether to obtain canagliflozin (I) having purity 87% by HPLC.

Example-4Preparation of (3R,4S,5R,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-2-methoxy-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triyl)tris(oxy)tris(trimethylsilane) (IIb1)

In 500 mL three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel were added 10 g compound of Formula (III), 100 mL methylene dichloride and 15 g N-methylmorpholine at 0 to 5° C. 12.7 g trimethylsilyl chloride was added slowly and stirred for 1 hour. After confirming the reaction completion by TLC, 300 mL pre-cool water was slowly added, stirred and layers were separated. The separated aqueous layer was extracted with methylene dichloride and the combined organic layers were washed with 20% sodium dihydrogen phosphate dihydrate solution, water and brine. The organic layer was evaporated under reduced pressure to obtain compound of Formula (IIb1).

Example-5Preparation of Canagliflozin

In 500 mL three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel was added 20 g compound (IIb1) prepared in example-4 and 100 mL methylene dichloride at −25° C. to −30° C. 11 mL triethylsilane and 7.8 mL boron trifluoridediethyl etherate was added drop wise within 1-2 hours maintaining the reaction temperature between −25° C. to −30° C. The reaction was stirred for 30 min and then allowed to warn to room temperature and stirred for 1.5-2 hours. The reaction mixture was then slowly added to cold water. The reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated bicarbonate solution, dried over sodium sulfate and evaporated under reduced pressure to obtain canagliflozin having purity 86% by HPLC.

Example-6Purification of Canagliflozin

In 250 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel 10 g canagliflozin (purity 85%) and 100 mLtoluene were stirred to obtain a clear solution. 10 g Polyvinylpyrrolidone was added to the solution and stirred for 2-3 hours. The reaction mixture was filtered and washed with toluene. The solid was stirred in ethyl acetate and water mixture for 30 min. The separated ethyl acetate layer was evaporated to dryness to obtain pure canagliflozin. (7.1 g. Purity 96.55% by HPLC).

Example-7Purification of Canagliflozin

In 250 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel 10 g canagliflozin (purity 87%) and 100 mLtoluene were stirred in in a round bottom flask to obtain a clear solution. 10 g β-cyclodextrin was added to the solution and stirred for 2-3 hours. The reaction mixture was filtered and washed with toluene. The solid was stirred in ethyl acetate and water mixture for 30 min. The separated ethyl acetate layer was treated with activated carbon, filtered and evaporated to dryness to obtain pure canagliflozin. (7.9 g, Purity 98.93% by HPLC).

Example-8Purification of Canagliflozin

In 250 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel 10 g canagliflozin (purity 87%) and 0.25 g activated carbon were stirred in 100 mL toluene for 15-20 min and filtered. 10 g β-cyclodextrin was added to the filtrate and stirred for 2-3 hours. The reaction mixture was filtered and washed with toluene. The solid was stirred in isopropyl acetate and water mixture for 30 min. The separated isopropyl acetate layer was evaporated to dryness to obtain pure canagliflozin. (7.7 g, Purity 99.12% by HPLC).

Example-9Purification of Canagliflozin

In 250 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel, 10 g canagliflozin (purity 87%) and 100 mLtoluene were stirred to obtain a clear solution. 10 g hydroxy propyl methyl cellulose was added to the solution and stirred for 2-3 hour. The reaction mixture was filtered, washed with toluene. The solid was stirred in isopropyl acetate and water mixture for 30 min and dried to obtain pure canagliflozin. (Purity 97-98% by HPLC).

Example-10Purification of Canagliflozin

In 2 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel, 100 g canagliflozin (purity 87%) obtained in example-3B and 900 mL methanol were stirred for 45 min at 30° C. The reaction mixture was filtered to remove silica gel. The filtrate was distilled under vacuum completely below 45° C. 400 mL toluene was added and heated to 55° C. to obtain a clear solution. The reaction mixture was filtered and the filtrate was added 100 g β-cyclodextrine. The reaction mixture was heated at 75° C. for 30 min and cooled to 30° C. and further stirred for 30 min. 5 g canagliflozin β-cyclodextrin complex was added to the solution and further cooled to 5° C. The reaction mixture was stirred for 3 hours and filtered. The wet-cake was treated with 300 mL isopropyl acetate and heated at 75° C. for 30 min. The reaction mixture was cooled to 30° C. and stirred for 6 hours and further cooled to 5° C. and stirred for 3 hours. The reaction mixture was filtered and washed with isopropyl acetate and dried at 30° C. to obtain crystalline canagliflozin β-cyclodextrine complex having 40 g pure canagliflozin with 99% purity by HPLC.

Example-11Preparation of Amorphous Canagliflozin

In 1 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel, 100 g canagliflozin β-cyclodextrine (purity 98%) obtained in example-10 and 400 mL acetone were stirred for 30 min at 30° C. The reaction mixture was filtered to remove β-cyclodextrine. The filtrate was distilled under vacuum completely below 45° C. 400 mL acetone was added to the residue to get clear solution at 30° C. 5 g activated charcoal was added and stirred for 20 min. The reaction mixture was filtered and the filtrate was spray dried using JISL Mini spray drier LSD-48 keeping feed pump at 30 rpm, inlet temperature at 60° C., outlet temperature at 40° C. and 2 Kg/cm2 hot air supply. The product was collected from cyclone and is further dried at 40° C.±5° C. under vacuum for 12 hours to get 80 g of amorphous canagliflozin having 99.6% purity by HPLC.

WO2014195966

https://www.google.co.in/patents/WO2014195966A2?cl=un

Canagliflozin is inhibitor of sodium dependent glucose transporter inhibitor (SGLT) which is chemically represented as (25′,3i?,4/?,55^,,6 ?)-2-{3-[5-[4-Fluoro-phenyl]-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol having (I).

Formula (I)

U.S. Patent No, 7,943,788 B2 (the ‘788 patent) discloses canagliflozin or salts thereof and the process for its preparation.

U.S. Patent Nos. 7,943,582 B2 and 8,513,202 B2 discloses crystalline form of 1 -(P-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] benzene hemihydrate and process for preparation thereof. The US ‘582 B2 and US ‘202 B2 further discloses that preparation of the crystalline form of hemi-hydrate canagliflozin typically involves dissolving in a good solvent (e.g. ketones or esters) crude or amorphous compound prepared in accordance with the procedures described in WO 2005/012326 pamphlet, and adding water and a poor solvent (e.g. alkanes or ethers) to the resulting solution, followed by filtration.

U.S. PG-Pub. No. 2013/0237487 Al (the US ‘487 Al) discloses amorphous dapagliflozin and amorphous canagliflozin. The US ‘487 Al also discloses 1:1 crystalline complex of canagliflozin with L-proline (Form CS1), ethanol solvate of a 1: 1 crystalline complex of canagliflozin with D-proline (Form CS2), 1 :1 crystalline complex of canagliflozin with L-phenylalanine (Form CS3), 1:1 crystalline complex of canagliflozin with D-proline (Form CS4).

The US ‘487 Al discloses preparation of amorphous canagliflozin by adding its heated toluene solution into n-heptane. After drying in vacuo the product was obtained as a white solid of with melting point of 54.7°C to 72.0°C. However, upon repetition of the said experiment, the obtained amorphous canagliflozin was having higher amount of residual solvents. Therefore, the amorphous canagliflozin obtained by process as disclosed in US ‘487 Al is not suitable for pharmaceutical preparations.

The US ‘487 Al further discloses that amorphous canagliflozin obtained by the above process is hygroscopic in nature which was confirmed by Dynamic vapor sorption (DVS) analysis. Further, it was observed that the amorphous form underwent a physical change between the sorption/desorption cycle, making the sorption/desorption behavior different between the two cycles. The physical change that occurred was determined to be a conversion or partial conversion from the amorphous state to a crystalline state. This change was supported by a change in the overall appearance of the sample as the humidity increased from 70% to 90% RH.

The canagliflozin assessment report EMA/718531/2013 published by EMEA discloses that Canagliflozin hemihydrate is a white to off-white powder^ practically insoluble in water and freely soluble in ethanol and non-hygroscopic. Polymorphism has been observed for canagliflozin and the manufactured Form I is a hemihydrate, and an unstable amorphous Form II. Form I is consistently produced by the proposed commercial synthesis process.

Therefore, it is evident from the prior art that the reported amorphous form of canagliflozin is unstable and hygroscopic as well as not suitable for pharmaceutical preparations due to higher amount of residual solvents above the ICH acceptable limits.

Hence, there is a need to provide a stable amorphous form of canagliflozin which is suitable for pharmaceutical preparations.

Crystalline solids normally require a significant amount of energy for dissolution due to their highly organized, lattice like structures. For example, the energy required for a drug molecule to escape from a crystal is more than from an amorphous or a non-crystalline form. It is known that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form (Econno T., Chem. Pharm. Bull., 1990; 38: 2003-2007). For some therapeutic indications, one bioavailability pattern may be favoured over another.

An amorphous form of some of the drugs exhibit much higher bioavailability than the crystalline forms, which leads to the selection of the amorphous form as the final drug substance for pharmaceutical dosage from development. Additionally, the aqueous solubility of crystalline form is lower than its amorphous form in some of the drugs, which may resulted in the difference in their in vivo bioavailability. Therefore, it is desirable to have amorphous forms of drugs with high purity to meet the needs of regulatory agencies and also highly reproducible processes for their preparation.

In view of the above, it is therefore, desirable to provide canagliflozin amorphous form as well as an efficient, economical and eco-friendly process for the preparation of highly pure canagliflozin amorphous form.

Example-l:

Preparation of amorphous form of Canagliflozin

In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel, 25.0 g of canagliflozin was dissolved in 250.0 mL of methanol mixture at 25°C to 30°C. The content was stirred for 30 minutes at 25°C to 30°C. To this, 1.0 g charcoal was added and stirred for 30 minutes at 25°C to 30°C. The content was filtered through Hyflo-supercel, and the Hyflo-supercel pad was washed with 50.0 mL methanol. The filtrate was concentrated under vacuum below 45°C followed by spray drying in JISL Mini spray drier LSD-48 under the below conditions. The product was collected from cyclone and is further dried at 55°C±5°C under vacuum for 16 hours to get 19.0 g of amorphous canagliflozin.

The spray-dried canagliflozin is amorphous in nature. The obtained product contains residual solvent well within ICH limit.

The obtained solid was amorphous canagliflozin as is shown by the X-ray diffraction pattern shown in FIG.1.

Example-2:

Preparation of amorphous form of Canagliflozin

In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel, 25.0 g of canagliflozin was dissolved in 250.0 mL of acetone mixture at 25°C to 3O°C. The content was stirred for 30 minutes at 25°C to 30°C. To this, 1.0 g charcoal was added and stirred for 30 minutes at 25°C to 30°C. The content was filtered through Hyflo-supercel, and the Hyflo-supercel pad was washed with 50.0 mL acetone. The filtrate was concentrated under vacuum below 45°C followed by spray drying in JISL Mini spray drier LSD-48 under the below conditions. The product was collected from cyclone and is further dried at 55°C±5°C under vacuum for 16 hours to get 20.0 g of amorphous canagliflozin.

The spray-dried canagliflozin is amorphous in nature. The compound is having residual acetone less than 0.5% by GC.

The obtained solid was amorphous canagliflozin as is shown by the X-ray diffraction pattern shown in FIG.2.

Example-3:

Preparation of amorphous form of canagliflozin

In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel, 10 g of canagliflozin was dissolved in 125 mL methanol and heated to obtain clear solution at 65°C. The solution was distilled to remove methanol completely. The compound thus obtained was amorphous canagliflozin.

Example-4:

Preparation of amorphous form of canagiiflozin

In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel, 10 g of canagiiflozin was dissolved in 125 mL acetone and heated to obtain clear solution at 65°C. The solution was distilled to remove acetone completely. The compound thus obtained was amorphous canagiiflozin. The compound is having residual acetone less than 0.5% by GC.

Example 5:

Preparation of amorphous form of canagiiflozin

In 100 ml three necked round bottom flask equipped with mechanical stirrer, thermometer and an addition funnel, canagiiflozin (0.5 gm, 1.02 mmol), PVP K-30 (4 gm, 8 times) and 88% methanol in water (12.5ml, 25V) were heated to 65-70°C to get clear solution. The reaction mixture was stirred for 1 hour, concentrated under vacuum (1.5 mbar) at 65-70°C and degassed under vacuum (1.5 mbar) for 1 hour at 70°C to obtain the title compound in amorphous form.

Example 6:

Preparation of amorphous form of canagiiflozin

In 100 ml three necked round bottom flask equipped with mechanical stirrer, thermometer and an addition funnel, canagiiflozin (0.5 gm, 1.02 mmol), HPMC-AS (1 gm, 2 times) in 88% methanol in water (12.5 ml, 25V) were heated at 65 to 70°C to get clear solution. The reaction mixture was stirred for 2 hours, concentrated under vacuum (1.5 mbar) at 70°C and degassed under vacuum (1.5 mbar) for lhr at 70°C to obtain the title compound in amorphous form.

Example-7:

Preparation of canagliflozin-L-Proline crystalline complex

In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel; 25.0 g of canagiiflozin, 6.06 g L-proline and 250 mL ethanol were heated to 75-80°C, stirred for 15 min and then cooled down to 25-30°C. The mass was filtered and washed with ethanol to obtain canagliflozin-L-proline crystalline complex.

Example-8:

Preparation of amorphous canagliflozin from canagliflozin-L-proline crystaUine complex

In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel 25.0 g of Canagliflozin-L-Proline Crystalline Complex and 250 mL of ethyl acetate were stirred to get a clear solution, washed with 2×150 mL of water and the organic layer was distilled. To the residue 100 mL of isopropyl acetate and 2.5 mL of water was added and heated to 75-80°C, stirred for 15 min and cooled down to 25-30°C. The mass filtered and washed with isopropyl acetate to obtain canagliflozin. The obtained canagliflozin was subjected to spray dyring under conditions of example-2 using acetone solvent to obtain amorphous canagliflozin. Purity > 99.5% by HPLC. The compound is having residual acetone less than 0.5% by GC.

The obtained solid was amorphous canagliflozin as shown by the X-ray diffraction pattern shown in FIG.2.

HPLC Purity of amorphous canagliflozin was measured by using following chromatographic conditions:

Equipment: Shimadzu LC2010C HPLC system equipped with a dual

wavelength UV-VIS detector or equivalent

Column: romasil C-8 (250mmx4.6 mm, 5 μπι) or equivalent

Flow rate: 1.5 mL/minute

Column oven temp.: 30°C

Wavelength: 210 nm

Injection Volume: 10 μΐ, .

Diluent: Mobile Phase A: Mobile Phase B (30:70)

Mobile Phase A: Buffer:Acetonitrile:Methanol (60:30: 10)

Mobile Phase B: Acetonitrile: Methanol (80:20)

Example-9:

Preparation of amorphous form of Canagliflozin as per Example-2 of US ‘487 Al In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel 25.0 g of canagliflozin and 150 mL of ethyl acetate were stirred to get clear solution. 100 mL of n-heptane was added to the solution and the reaction mixture was filtered and dried to obtain amorphous canagliflozin. The obtained amorphous canagliflozin were dried at 65°C under vacuum for 72 hours. The residual n-heptane was 44000 ppm by GC after 72 hours drying.

Example-10:

Replacing toluene with ethyl acetate in above example-9

In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel 25.0 g of canagliflozin and 150 mL of ethyl acetate were stirred to obtain clear solution. 100 mL of n-heptane was added to the solution and the reaction mixture was filtered and dried to obtain amorphous canagliflozin. The obtained amorphous canagliflozin were dried at 65°C under vacuum for 72 hours. The residual n-heptane was -44000 ppm by GC after 72 hours drying.

Example-11:

Replacing n-heptane with cyclohexane in above example-9

In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel 25.0 g of canagliflozin and 150 mL of ethyl acetate were stirred to obtain clear solution. 100 mL of cyclohexane was added to the solution and the reaction mixture was filtered and dried to obtain amorphous canagliflozin. The obtained amorphous canagliflozin were dried at 55°C under vacuum for 72 hours. The residual cyclohexane was >5000 ppm by GC after 72 hours drying.

Example-12:

Preparation of amorphous form of Canagliflozin

In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel; 25.0 g of canagliflozin and 250 mL of ethyl acetate were stirred to get clear solution and then ethyl acetate was removed under reduced pressure to obtain 20.0 g of amorphous canagliflozin. The obtained amorphous canagliflozin were dried at 55°C under vacuum for 72 hours. The residual ethyl acetate was -8450 ppm by GC after 72 hours drying.

///////////////New Patent, Zydus Cadila, Canagliflozin, US 20160002275

WO 2016001851

DR. REDDY’S LABORATORIES LIMITED [IN/IN]; 8-2-337, Road No. 3, Banjara hills, Hyderabad, Telangana Hyderabad 500034 (IN)

DAHANUKAR, Vilas; (IN).
ELATI, Ravi Ram Chandrasekhar; (IN).
ORUGANTI, Srinivas; (IN).
RAPOLU, Rajesh Kumar; (IN).
KURELLA, Sreenivasulu; (IN)

The drug compound having the adopted name “ticagrelor” has chemical names: [1 S-(1 α,2α,3β(1 S^*,2R^*),5p)]-3-[7-[2-(3,4-difluorophenyl-cyclopropyl] amino]-5-(propylthio)-3H-1 ,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-1 ,2-diol; or (1 S,2S,3fl,5S)-3-[7-{[(1 fl,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino}-5-(propylthio)-3H 1 ,2,3]-triazolo[4,5-c/|pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclope ed by Formula I.

Formula I

Ticagrelor is the active ingredient in the commercially available BRILINTA® tablets for oral administration.

Ticagrelor and related compounds are disclosed in International Patent Application Publication Nos. WO 00/34283 and WO 99/05143 as pharmaceutically active Ρ₂τ (which are now usually referred to as P2Y12) receptor antagonists. Such antagonists can be used, inter alia, as inhibitors of platelet activation, aggregation, or degranulation. International Patent Application Publication Nos. WO 01 /92263 and WO 2010/030224 A1 , WO 2012085665 A2, WO 2012138981 A2 and WO 2013037942 A1 disclose processes for preparing ticagrelor.

The processes for the preparation of traizolo [4,5-d] pyrimidine derivatives preferably Ticagrelor and related compounds, described in the above mentioned prior art suffer from disadvantages since the processes involve tedious and cumbersome procedures such as lengthy and multiple synthesis steps, reactions under pressure and high temperature, longer reaction times, tedious work up procedures and multiple crystallizations or isolation steps, column chromatographic purifications and thus resulting in low overall yields of the product. Ticagrelor obtained by the processes described in the prior art does not have satisfactory purity and unacceptable amounts of impurities are formed along with Ticagrelor at various stages of the processes that are difficult to purify and thus get carried forward in the subsequent steps thus affecting the purity of final compound. Thus, there remains a need to prepare compounds of Formula I of high purity and in good yield while overcoming the drawbacks presented by the previously described processes.

Formula V Formula V”

In a preferred embodiment, present application provide compounds of Formula IV with specific groups i.e. compounds of Formula IV and Formula IV”,

Formula IV Formula IV”

In a preferred embodiment, present application provides a compound of Formula II with specific groups i.e. compounds of Formula ΙΓ and Formula II”,

Formula ΙΓ Formula II”

In a preferred embodiment, present application provides a compound of Formula l la with specific grou

Formula lla

Formula VII’ Formula VII”

In a preferred embodiment, present application provides compounds of Formula Vila with specific groups i.e. compounds of Formula Vila’ and Formula “,

Formula Vila’ Formula Vila”

G.V. Prasad, chairman, Dr Reddy’s Laboratories

EXAMPLES

EXAMPLE 1 : Preparation of 2-bromo-N,N-diphenylacetamide (FORMULA Vile).

A flask is charged with Ν,Ν-diphenyl amine (25 g) and dichloromethane (350 mL) under nitrogen atmosphere. The reaction mixture is cooled to 0°C followed by addition of solution of triethyl amine (20.7 mL) and bromoacetyl chloride (38.72 mL) in dichloromethane (181 mL). The mixture is cooled to room temperature and then stirred for about 16 hours. The completion of the reaction is monitored by TLC. The reaction mixture is diluted with dichloromethane (250 mL) and then washed with 0.5N aqueous hydrochloric acid solution (3×150 mL), brine (100 mL). The organic layer is separated and subjected to distillation under vacuum at 45°C. The obtained compound is recrystallized from hexane (250 mL) and methanol (100 mL) to afford the title compound.

EXAMPLE 2: Preparation of benzyl ((3aS,4R,6S,6aR)-6-(2-(diphenylamino)-2-oxoethoxy)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)carbamate (FORMULA Vila).

A flask is charged with sodium hydride (2.85 mL, 60% dispersion in oil) and dimethyl formamide (10 mL) under nitrogen atmosphere. The reaction mixture is then cooled to -30°C followed by addition of a solution of benzyl

((3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)carbamate (20 g) in dimethyl formamide (40 mL). The mixture is stirred at -30°C for about 45 minutes, then a solution of 2-bromo-N,N-diphenylacetamide (22.65 g) in dimethyl formamide (60 mL) is added at the same temperature. The reaction mixture is allowed to attain room temperature and stirred at the same for 3 hours and completion of the reaction is monitored by TLC. The reaction mixture is quenched with ice-cold water (200 mL) and extracted with ethyl acetate (3×150 mL). The organic layer is combined and washed with water (3×100 mL), brine (100 mL) and then organic layer is then subjected to complete distillation under vacuum at 45°C. The crude so obtained is treated with MTBE (150 mL) and stirred at room temperature for overnight followed by filtration of obtained solid to afford the title compound.

EXAMPLE 3: Preparation of 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyl tetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (Formula VII)

A flask is charged with benzyl ((3aS,4R,6S,6aR)-6-(2-(diphenylamino)-2-oxoethoxy)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)carbamate (15 g), ethanol (300 mL), 10% Pd/C (1.5 g) and ammonium formate (5.49 g). The reaction mixture is stirred at 80°C for 8 hours and completion of the reaction is monitored by TLC. Then reaction mixture is cooled to room temperature and filtered through celite bed, bed is washed with ethyl acetate (100 mL). The filtrate is subjected to complete distillation under vacuum at 45°C. Then ethanol (120 mL), L-tartaric acid (4.88 g) is added to the crude compound and mixture is stirred for 4 hours at room temperature. To the mixture, MTBE (300 mL) is added at the same temperature. The solvent is distilled under vacuum at 35°C to afford the gummy solid. Then MTBE (100 mL) is added to the gummy solid and mixture is stirred for 10-12 hours. The solid obtained is filtered and washed with MTBE (50 mL). The solid obtained is dissolved in water and sodium bicarbonate solution (200 mL) is added, desired compound is extracted in ethyl acetate (100 mL). The solvent is subjected to distillation (upto 40%) followed by addition of hexane (150 mL) and ethyl acetate (20 mL). The mixture is stirred at -10°C, then solid is recovered followed by drying under vacuum at 40°C. The crude compound is purified by column chromatography using methanol and dichloromethane (5:95) to afford the title compound.

EXAMPLE 4: Preparation of 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2- (propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d]

[1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (Formula V)

A flask is charged with 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (6.5 g),

2- (((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (10.39 g), sodium bicarbonate (9.13 g) and water. The mixture is stirred at 95-100°C for 15-20 hours till completion of the reaction (as monitored by TLC). Then water (20 mL) and ethyl acetate (25 mL) are added at room temperature. The layers are separated and aqueous layer is extracted with ethyl acetate (20 mL). The organic layers are combined and washed with brine solution (2×25 mL). The organic layer is subjected to complete distillation under vacuum at 40-45°C. The obtained crude compound is purified by column chromatography using ethyl acetate and hexane (30:70) to afford the title compound.

EXAMPLE 5: Preparation of 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (Formula IV)

A flask is charged with 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (6 g), acetic acid (30 mL) and water (6 mL). The mixture is cooled to 0 to -5°C followed by addition of addition of sodium nitrite solution (768 mg in 6 mL of water). The mixture is stirred for 1 hour at the same temperature and then mixture is allowed to attain room temperature, and further stirred for 1 hour. The completion of the reaction is monitored by TLC and then toluene (60 mL) is added. The layers are separated, organic layer is washed with saturated solution of potassium carbonate and subsequently organic layer is dried with sodium sulphate and used for next reaction.

EXAMPLE 6: Preparation of 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin- 3- yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (Formula II)

A flask is charged with (1 R,2S)-2-(3,4-difluorophenyl)cyclopropan-1 -amine mandelate (3.25 g), diisopropylethyl amine (6.1 mL), toluene (60 mL) and stirred for 30 minutes at room temperature. Then slowly, toluene layer containing 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (60 mL) is added over a period of 10 minutes. The reaction mixture is stirred at room temperature for overnight and completion of the reaction is monitored by TLC. The reaction mixture is diluted with water (60 mL), layers are separated and aqueous layer is extracted with toluene (2×30 mL). The combined organic layers are washed with brine (60 mL) and then subjected to complete distillation under vacuum at 45°C to afford the crude compound. The crude compound is purified by column chromatography using ethyl acetate and hexane (80:20).

EXAMPLE 7: Preparation of 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)ethan-1 -ol (Formula lib)

A flask is charged with 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (3 g), THF (90 mL) and mixture is cooled to 0°C. Then portion wise, Lithium aluminium hydride (940 mg) is added over a period of 10 minutes and mixture is stirred at 0°C for 1 hour. The reaction mixture is then stirred at room temperature for 5 hours and progress of the reaction is monitored by TLC. Then mixture is cooled to 0-5°C and quenched with ice cold water (100 mL) and then diluted with ethyl acetate (30 mL). The layers are separated and organic layer after drying is used for next step.

EXAMPLE 8: Preparation of Ticagrelor (Formula I)

A flask is charged with organic layer containing 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3] triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)ethan-1 -ol (1 10 mL) and 2% hydrochloric acid solution (75 mL). The reaction mixture is stirred at room temperature for 48 hours and progress of the reaction is monitored by TLC. Then the reaction mixture is diluted with ethyl acetate (50 mL), layers are separated. The organic layer is sequentially washed with water (50 mL), brine solution (50 mL) followed by complete distillation under vacuum at 45°C. The crude compound is dissolved in ethyl acetate (12 mL) and then hexane (50 mL) is added. The mixture is stirred for 2 hours followed by isolation of solid by filtration. The obtained solid is dissolved in ethyl acetate (12 mL) and treated with charcoal followed by filtration. The filtrate is subjected to complete distillation and obtained solid is purified by column chromatography using ethyl acetate:hexane (1 :1 ) and methanohdichloromethane (5:95) to afford the title compound.

EXAMPLE 9: Preparation of 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)ethan-1 -ol (Formula lib)

A flask is charged with 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (100 mg), THF (3 mL) and cooled to 0-5°C followed by addition of Vitride (0.04 mL) at 0-5°C over a period of 5 minutes. The mixture is stirred at same temperature for 1 hour and progress of the reaction is monitored by TLC. Additional amount of Vitride (0.13 mL) is added to the mixture and stirred for additional 6 hours. After completion of reaction, reaction mixture is cooled to 0-5°C and quenched with saturated sodium potassium tartrate solution (10 mL) and extracted with ethyl acetate (20 mL). The organic layer is subjected to complete distillation under reduced pressure and obtained material is purified by column chromatography using ethyl acetate: hexane (1 :1 ) and methanohdichloromethane (5:95) to afford the title compound.

EXAMPLE 10: Preparation of 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)acetaldehyde (Formula lib’)

A flask is charged with 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (100 mg), THF (5 mL) and mixture is cooled to 0°C. Then portion wise, Lithium aluminium hydride (15 mg) is added over a period of 1 0

minutes and mixture is stirred at 0°C for 1 hour. The progress of the reaction is monitored by TLC. After completion of the reaction, mixture is quenched with ice cold water (5 mL) and diluted with ethyl acetate (10 mL). The layers are separated and organic layer after drying is subjected to complete distillation followed by purification using preparative TLC using 40% ethyl acetate in hexane to afford the title compound.

EXAMPLE 11 : Preparation of 2-bromo-1 -morpholinoethan-1 -one

A flask is charged with bromoacetyl bromide (25 mL), dichloromethane (500 mL) and mixture is stirred under nitrogen atmosphere. The reaction mixture is cooled to -25°C followed by slow addition of morpholine (72.7 mL in 500 mL of DCM) at the same temperature over a period of 30 minutes. The reaction mixture is stirred at -25°C for 15 minutes, then allowed to attain room temperature at which it is further stirred for 4 hours. The completion of the reaction is monitored by TLC and reaction mixture is sequentially washed with water (2×250 mL) and brine solution (2×100 mL). The organic solvent is subjected to distillation to afford the title compound.

EXAMPLE 12: Preparation of benzyl ((3aS,4R,6S,6aR)-2,2-dimethyl-6-(2-morpholino-2-oxoethoxy)tetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)carbamate (Formula Vila”)

A flask is charged with sodium hydride (60%, 4.29 g), DMF (90 mL) and cooled to -30°C. Then, benzyl ((3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)carbamate (30 g) is added to the reaction mixture at the same temperature over a period of 25 minutes and mixture is stirred at -30°C for 1 hour. Then 2-bromo-1 -morpholinoethan-1 -one (24.36 g) is added to the reaction mixture at -30°C over a period of 20 minutes and temperature is raised to room temperature. The mixture is stirred at RT for 1 hour. The progress of the reaction is monitored by TLC and after completion, the reaction mixture is quenched with ice cold water followed by extraction with ethyl acetate. The organic layer is separated and subjected to distillation to afford the title compound.

EXAMPLE 13: Preparation of 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-1 -morpholinoethan-1 -one (Formula VII”)

A flask is charged with benzyl ((3aS,4R,6S,6aR)-2,2-dimethyl-6-(2-morpholino-2-oxoethoxy)tetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)carbamate, ethanol (1 0 g), ammonium formate (4.35 g) and 10% Pd/C (1 g). The reaction mixture is heated to 80°C and then stirred for 2 hours. The progress of the reaction is monitored by TLC and after completion of the reaction, mixture is cooled to room temperature, filtered and washed with ethyl acetate (100 mL). The filtrate is distilled under reduced pressure and obtained compound is purified by column chromatography using methanol-DCM (5:95) to afford the title compound.

EXAMPLE 14: Preparation of 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2- (propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d]

[1 ,3]dioxol-4-yl)oxy)-1 -morpholinoethan-1 -one (Formula V”)

A flask is charged with 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-1 -morpholinoethan-1 -one (8 g), water (24 mL) and stirred for 10 minutes. Then sodium bicarbonate (8.9 g), 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (6.3 g) and water (24 mL) is added and mixture is heated to 95-100°C at which point it is stirred for 15 hours. The progress of the reaction is monitored by TLC and on completion reaction mixture is cooled to room temperature followed by addition of water (24 mL) and ethyl acetate (40 mL). The layers are separated and aqueous layer is extracted with ethyl acetate (20 mL). The organic layers are combined, washed with brine solution (2×40 mL) and subjected to distillation under vacuum at 45°C to afford the title compound.

EXAMPLE 15: Preparation of 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3] dioxol-4-yl)oxy)-1 -morpholinoethan-1 -one (Formula IV”)

A flask is charged with 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d]

[1 ,3]dioxol-4-yl)oxy)-1 -morpholinoethan-1 -one (4 g), acetic acid (20 mL) and stirred under nitrogen atmosphere for 10 minutes. Then water (8 mL) is added and mixture is cooled to -5 to 0°C followed by slow addition of sodium nitrite (650 mg). The mixture is stirred at 0°C for 1 hour and progress of the reaction is monitored by TLC. After completion of the reaction, mixture is extracted with toluene (40 mL and 20 mL). The combined toluene layer is sequentially washed with potassium

carbonate solution (40 mL) and brine solution (2×20 mL) followed by distillation under vacuum to afford the desired compound.

EXAMPLE 16: Preparation of 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-1 -morpholinoethan-1 -one (Formula II”)

A flask is charged with (1 R,2S)-2-(3,4-difluorophenyl)cyclopropan-1 -amine mandelate (2.5 g) and toluene (20 mL) followed by drop-wise addition of diisopropylethylamine (4.7 mL), then mixture is stirred for 10 minutes at RT. Then toluene layer containing 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3] dioxol-4-yl)oxy)-1 -morpholinoethan-1 -one (4 g in 55 mL) is added to the above mixture and reaction mass is stirred for 15 hours at room temperature. The progress of the reaction is monitored by TLC followed by addition of water (20 mL) on completion of reaction. The layers are separated, aqueous layer is extracted with toluene (20 mL). The organic layers are combined, washed with brine solution (2×20 mL) and then subjected to distillation under vacuum at 45°C to afford the crude compound. The crude compound is purified by column chromatography using hexane to afford the title compound.

EXAMPLE 17: Preparation of 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)ethan-1 -ol

A flask is charged with 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-1 -morpholinoethan-1 -one (1 g) in tetrahydrofuran (20 mL) and stirred under nitrogen atmosphere followed by addition of vitride (1 .53 mL) over a period of 10 minutes. The reaction mixture is stirred for 1 hour at room temperature and progress of the reaction is monitored by TLC. On completion, the mixture is quenched with sodium potassium tartrate (5 mL). The mixture is extracted with ethyl acetate (10 mL), then layers are separated and organic layer is subjected to distillation under vacuum at 45°C. The obtained material is dissolved in THF (20 mL) and slowly lithium aluminiumhydride (0.1 17 g) is added to the mixture at 0-5°C. Then mixture is stirred at room temperature for 1 hour and progress of the reaction is monitored by TLC. On completion of reaction, it is quenched with ice-cold water (20 mL) and extracted with ethyl acetate (15 mL). The layers are separated and organic layer is used for next step.

EXAMPLE 18: Preparation of Ticagrelor

A flask is charged with organic layer containing 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3] triazolo [4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy) ethan-1 -ol (30 mL) and 2% hydrochloric acid solution (30 mL). The reaction mixture is stirred at room temperature for overnight and progress of the reaction is monitored by TLC. Then the reaction mixture is diluted with ethyl acetate (20 mL), layers are separated. The organic layer is washed with brine solution (20 mL) followed by complete distillation under vacuum at 45°C. The crude compound is purified by column chromatography using ethyl acetate:hexane (7:10) and methanol :d ic h I oro methane (5:95) to afford the title compound.

EXAMPLE 19: Preparation of 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (Formula IV)

A flask is charged with 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d]

[1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (5 g) and acetonitrile (50 mL) for clear solution. To this, isoamyl nitrite (1 .5 g) is added over a period of 5 minutes. The reaction mixture is maintained at room temperature for 5 hours and completion of the reaction is monitored by TLC. Then water (50 mL) and toluene (50 mL) are added and layers are separated. The aqueous layer is extracted with toluene (50 mL) and total organic layers are combined, subjected to distillation under vacuum to afford the title compound.

Anji Reddy

Mr G.V. Prasad, CEO, Dr. Reddy’s Labs

G V Prasad and Mr K. Satish Reddy

///////////

NEW PATENT, TICAGRELOR, DR. REDDY’S LABORATORIES LIMITED, WO 2016001851

WO2016001844,

AMORPHOUS FORM OF AFATINIB DIMALEATE

SUN PHARMACEUTICAL INDUSTRIES LIMITED

VERMA, Shyam Sunder; (IN).
SINGH, Shravan Kumar; (IN).
SINGH, Kaptan; (IN).
PRASAD, Mohan; (IN)

Afatinib dimaleate is a tyrosine kinase inhibitor, chemically designated as 2-butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(35)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-,(2£)-, (2Z)-2-butenedioate (1:2) having the structure depicted by Formula I.

Formula I

U.S. Patent Nos. RE43,431 and 6,251,912 provide processes for the preparation of afatinib dimaleate.

U.S. Patent No. 8,426,586 and PCT Publication Nos. WO 2012/121764 and WO

2013/052157 provide processes for the preparation of crystalline forms of afatinib and their salts.

Example: Preparation of an amorphous form of afatinib dimaleate

In a round bottom flask, a mixture of afatinib (3 g) and ethyl acetate (30 mL) was heated to about 65°C to obtain a turbid solution. In another round bottom flask, a mixture of maleic acid (1.6 g) and ethyl acetate (30 mL) was heated to about 50°C to obtain a clear solution. The maleic acid solution was added to the afatinib solution, and then the reaction mixture was heated at about 75°C to about 80°C. The reaction mixture was stirred at about 75°C to about 80°C for about 1 hour. The reaction mixture was cooled to about

20°C to obtain a sticky material. The sticky material was scratched with a spatula, and then the reaction mixture was further stirred at about 20°C to about 25°C for about 1 hour. The material obtained was filtered, and then washed with ethyl acetate (20 mL). The solid obtained was dried under vacuum at about 45°C to about 50°C for about 15 hours to obtain the amorphous form of afatinib dimaleate.

Yield: 2.5 g (56%)

Sun Pharma chief Dilip Shanghvi

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Catal. Sci. Technol., 2016, Advance Article
DOI: 10.1039/C5CY01883H, Paper

Stefan Christiaan Stouten, Timothy Noel, Qi Wang, Matthias Beller, Volker Hessel
The methoxycarbonylation of cyclohexene with carbon dioxide over a ruthenium catalyst was realized in a micro flow system under supercritical conditions.

Continuous ruthenium-catalyzed methoxycarbonylation with supercritical carbon dioxide

http://pubs.rsc.org/en/Content/ArticleLanding/2016/CY/C5CY01883H?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2Fcy+%28RSC+-+Catalysis+Science+%26+Technology+latest+articles%29#!divAbstract

The methoxycarbonylation of cyclohexene with carbon dioxide over a ruthenium catalyst was realized in a micro flow system under supercritical conditions. Instead of the toxic and flammable carbon monoxide, this process utilizes carbon dioxide, thereby avoiding issues with bulk transportation of carbon monoxide as well as eliminating the need for safety precautions associated with the use of carbon monoxide. Obtained was a 77% yield of the ester product at 180 °C, 120 bar and with a 90 min residence time, which is over five times faster than for the same reaction performed under subcritical conditions in batch. An important factor for the performance of the system was to have a sufficiently polar supercritical mixture, allowing the catalyst to dissolve well. The optimal temperature for the reaction was 180 °C, as the activity of the system dropped considerably at higher temperatures, most likely due to catalyst deactivation.

Department of Chemical Engineering and Chemistry

ir. S.C. (Stefan) Stouten –

Address:

Technische Universiteit Eindhoven
P.O. Box 513
5600 MB EINDHOVEN

Department:

Department of Chemical Engineering and Chemistry

Section:

Micro Flow Chemistry and Process Technology

Positioncategory:

doctoral candidate (PhD) (PhD Stud.)

Position:

doctoral candidate

Room:

STW 0.

Email:

s.stouten@tue.nl

Volker Hessel

Address:

Technische Universiteit Eindhoven
P.O. Box 513
5600 MB EINDHOVEN

Chair:

Micro Flow Chemistry and Process Technology

Department:

Department of Chemical Engineering and Chemistry

Section:

Micro Flow Chemistry and Process Technology

Positioncategory:

Professor (HGL)

Position:

Full Professor

Room:

STW 1.45

Tel:

+31 40-247 2973

Tel (internal):

2973

Email:

v.hessel@tue.nl

////////Continuous,  ruthenium-catalyzed,  methoxycarbonylation, supercritical carbon dioxide, flow reactor

WO 2016001885

DR. REDDY’S LABORATORIES LIMITED [IN/IN]; 8-2-337, Road No. 3, Banjara Hills, Telangana, India Hyderabad 500034 (IN)

VELAGA, Dharma Jagannadha Rao; (IN).
PEDDY, Vishweshwar; (IN).
VYALA, Sunitha; (IN)

(WO2016001885) AMORPHOUS FORM OF ELIGLUSTAT HEMITARTARATE

Chemically Eliglustat is named N-[(1 R,2R)-2-(2,3-dihydro-1 ,4-benzodioxin-6-yl)-2-hydroxy-1 -(1 -pyrrolidinylmethyl)ethyl]-Octanamide(2R_!3R)-2,3-dihydroxybutanedioate and the hemitartarate salt of eliglustat has the structural formula as shown in Formula I.

Formula I

Eliglustat hemitartrate (Genz-1 12638), currently under development by Genzyme, is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of Gaucher disease and other lysosomal storage disorders. Eliglustat hemitartrate is orally active with potent effects on the primary identified molecular target for type 1 Gaucher disease and other glycosphingolipidoses, appears likely to fulfill high expectations for clinical efficacy. Gaucher disease belongs to the class of lysosomal diseases known as glycosphingolipidoses, which result directly or indirectly from the accumulation of glycosphingolipids, many hundreds of which are derived from glucocerebroside. The first step in glycosphingolipid biosynthesis is the formation of glucocerebroside, the primary storage molecule in Gaucher disease, via glucocerebroside synthase (uridine diphosphate [UDP] – glucosylceramide glucosyl transferase). Eliglustat hemitartrate is based on improved inhibitors of glucocerebroside synthase, and is currently under development by Genzyme.

U.S. patent No. 7,196,205 discloses a process for the preparation of Eliglustat or a pharmaceutically acceptable salt thereof.

U.S. patent No. 6855830, 7265228, 7615573, 7763738, 8138353, U.S. patent application publication No. 2012/296088 discloses process for preparation of Eliglustat and intermediates thereof.

U.S. patent application publication No. 2013/137743 discloses (i) a hemitartrate salt of Eliglustat, (ii) a hemitartrate salt of Eliglustat, wherein at least 70% by weight of the salt is crystalline, (iii) a hemitartrate salt of Eliglustat, wherein at least 99% by weight of the salt is in a single crystalline form.

It has been disclosed earlier that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailablity patterns compared to crystalline forms [Konne T., Chem pharm Bull., 38, 2003(1990)]. For some therapeutic indications one bioavailabihty pattern may be favoured over another. An amorphous form of Cefuroxime axetil is a good example for exhibiting higher bioavailability than the crystalline form.

Solid amorphous dispersions of drugs are known generally to improve the stability and solubility of drug products. However, such dispersions are generally unstable over time. Amorphous dispersions of drugs tend to convert to crystalline forms over time, which can lead to improper dosing due to differences of the solubility of crystalline drug material compared to amorphous drug material. The present invention, however, provides stable amorphous dispersions of eliglustat hemitartrate. Moreover, the present invention provides solid dispersions of eliglustat hemitartrate which may be reproduced easily and is amenable for processing into a dosage form.

There remains a need to provide solid state forms of eliglustat hemitartarate which are advantageous in a cost effective and environment friendly manner.

EXAMPLES

Example 1 : Preparation of amorphous form of eliglustat hemitartarate.

500mg of eliglustat hemitartarate was dissolved in 14 mL of dichloromethane at 26°C and stirred for 15 min. The solution is filtered to remove the undissolved particles and the filtrate is distilled under reduced pressure at 45°C. After distillation the solid was dried under vacuum at 45°C.

Example 2: Preparation of amorphous form of eliglustat hemitartarate.

500mg of eliglustat hemitartarate was dissolved in 70 mL of ethanol and stirred for 15 min at 25° – 30°C. The solution is filtered to remove the undissolved particles and the filtrate is distilled under reduced pressure at 48°C. After distillation the solid was dried under vacuum at 48°C.

Example 3: Preparation of amorphous form of eliglustat hemitartarate.

500mg of eliglustat hemitartarate was dissolved in 20 mL of methanol and stirred for 15 min at 25° – 30°C. The solution is filtered to remove the undissolved particles and the filtrate is distilled under reduced pressure at 48°C. After distillation the solid was dried under vacuum at 48°C.

Example 4: Preparation of a solid dispersion comprising an amorphous form of eliglustat hemitartarate and PVP-K30.

500mg of eliglustat hemitartarate and 500mg of PVP-K30 was dissolved in 20 mL of methanol and stirred for 10 min at 25° – 30°C. The solution is filtered to remove the undissolved particles and the filtrate is distilled under reduced pressure at 48°C. After distillation the solid is dried under vacuum at 48°C.

Example 5: Preparation of a solid dispersion comprising an amorphous form of eliglustat hemitartarate and hydroxy propyl cellulose.

500mg of eliglustat hemitartarate and 500 mg of hydroxy propyl cellulose was dissolved in 30 ml of methanol and stirred for 10 min at 25° – 30°C. The solution is distilled under reduced pressure at 49°C. After distillation the solid is dried under vacuum at 49°C.

Example 6: Preparation of a solid dispersion comprising an amorphous form of eliglustat hemitartarate and hydroxy propyl methyl cellulose.

500mg of eliglustat hemitartarate and 500 mg of hydroxy propyl methyl cellulose was dissolved in 30 mL of methanol and stirred for 10 min at 25° – 30°C. The solution is distilled under reduced pressure at 48°C. After distillation the solid is dried under vacuum at 48°C.

Example 7 Preparation of amorphous form of eliglustat hemitartarate.

3g of eliglustat hemitartarate was dissolved in 75 mL of methanol and stirred at 25°C for dissolution. The solution was filtered to remove the undissolved particles and the filtrate is subjected for spray drying at inlet temperature of 70°C and outlet temperature of 42°C to afford the title compound.

Example 8: Preparation of amorphous form of eliglustat hemitartarate.

500mg of eliglustat hemitartarate was dissolved in 30 mL of isopropanol and stirred at 56°C for dissolution. The solution was filtered to remove the undissolved particles and the filtrate is subjected to complete distillation under reduced pressure and drying at about 56°C to afford the title compound.

Example 9: Preparation of amorphous form of eliglustat hemitartarate.

1 g of eliglustat hemitartarate was provided in 40 mL of ethyl acetate and stirred at about 63°C. Then methanol (5 mL) is added at the same temperature to obtain clear solution which was filtered to remove the undissolved particles. Then additional quantity of methanol (5mL) is added to the filtrate and the filtrate was again filtered to remove particles. The obtained filtrate was subjected to complete distillation under reduced pressure and drying at about 57°C to afford the title compound.

Example 10: Preparation of amorphous form of eliglustat hemitartarate.

1 g of eliglustat hemitartarate was provided in 40 mL of acetone and stirred at about 55°C followed by addition of methanol (15 mL). The mixture is stirred at 55°C for clear solution and filtered to remove the undissolved particles. The obtained filtrate was subjected to complete distillation under reduced pressure and drying at about 57°C to afford the title compound.

Example 11 : Preparation of amorphous form of eliglustat hemitartarate.

1 g of eliglustat hemitartarate was provided in 25 mL of isopropyl alcohol and 25 mL of ethanol. The mixture was stirred at about 58°C for dissolution and filtered to remove the undissolved particles. The obtained filtrate was subjected to complete distillation under reduced pressure and drying at about 57°C to afford the title compound.

Example 12 Preparation of amorphous form of eliglustat hemitartarate.

5g of eliglustat hemitartarate was provided in 300 mL of isopropyl alcohol and stirred at about 59°C for dissolution. The solution was filtered to remove the undissolved particles and the filtrate is subjected for spray drying at inlet temperature of 65°C and outlet temperature of 37°C to afford the title compound according to Fig. 6

Example 13: Preparation of a solid dispersion comprising an amorphous form of eliglustat hemitartarate and Copovidone

500mg of eliglustat hemitartarate and 500mg of Copovidone were dissolved in 30 mL of methanol and stirred for clear solution, then filtered to make it particle free. The solvent from the filtrate was evaporated under reduced pressure at 45°C and obtained solid was subjected to drying at 45°C to afford the title solid. The resulting dispersion was found to be amorphous by X-ray powder diffraction.

Example 14: Preparation of a solid dispersion comprising an amorphous form of eliglustat hemitartarate and Copovidone

2g of eliglustat hemitartarate and 2g of Copovidone were dissolved in 100 mL of methanol and stirred for clear solution, then filtered to make it particle free. The solvent from the filtrate was subjected to spray drying at inlet temperature of 70 at 45°C and outlet temperature of 42°C to afford the title compound. The resulting dispersion was found to be amorphous by X-ray powder diffraction.

Example 15: Preparation of a solid dispersion comprising an amorphous form of eliglustat hemitartarate

2g of eliglustat hemitartarate was charged in 40 mL of methanol followed by addition of 2g of PVP K-30. The mixture was stirred for clear solution and filtered to make it particle free, the bed was washed with 20 mL of methanol. Then 2g of Syloid is added to the filtrate and filtrate is subjected to distillation under reduced pressure at about 57°C and obtained solid was subjected to drying at about 57°C to afford the title solid. The resulting dispersion was found to be amorphous by X-ray powder diffraction according to Fig. 7a. The said dispersion is kept at 25°C under 40% relative humidity for 24 hours and PXRD was recorded and found to be amorphous according to Fig 7b.

Example 16: Preparation of a solid dispersion comprising an amorphous form of eliglustat hemitartarate

2g of eliglustat hemitartarate was charged in 40 mL of methanol followed by addition of 2g of Copovidone. The mixture was stirred for clear solution and filtered to make it particle free, the bed was washed with 20 mL of methanol. Then 2g of Syloid is added to the filtrate and filtrate is subjected to distillation under reduced pressure at about 57°C and obtained solid was subjected to drying at about 57°C to afford the title solid. The resulting dispersion was found to be amorphous by X-ray powder diffraction according to Fig. 8a. The said dispersion is kept at 25°C under 40% relative humidity for 24 hours and PXRD was recorded and found to be amorphous according to Fig. 8b and D₉₀ of the resultant solid is about 437 microns.

Example 17: Preparation of a solid dispersion comprising an amorphous form of eliglustat hemitartarate and Syloid

1 g of eliglustat hemitartarate was dissolved in 25 ml_ of methanol and filtered to make it particle free. Then 1 g of Syloid 244 FPNF was added to the filtrate and solvent from the filtrate was evaporated under reduced pressure at 56°C and obtained solid was subjected to drying at 56°C to afford the title solid. The resulting dispersion was found to be amorphous by X-ray powder diffraction according to Fig. 9 and D₉₀ of the resultant solid is about 4 microns.

Example 18: Preparation of a solid dispersion comprising an amorphous form of eliglustat hemitartarate and Syloid

1 g of eliglustat hemitartarate was dissolved in 25 ml_ of methanol and filtered to make it particle free. Then 500mg of Syloid 244 FPNF was added to the filtrate and solvent from the filtrate was evaporated under reduced pressure at 56°C and obtained solid was subjected to drying at 56°C to afford the title solid. The resulting dispersion was found to be amorphous by X-ray powder diffraction.

PATENT

(WO2015059679) IMPROVED PROCESS FOR THE PREPARATION OF ELIGLUSTAT

WO2015059679

DR. REDDY’S LABORATORIES LIMITED [IN/IN]; 8-2-337, Road No. 3, Banjara Hills Hyderabad 500034 (IN)

JAVED, Iqbal; (IN).
DAHANUKAR, Vilas Hareshwar; (IN).
ORUGANTI, Srinivas; (IN).
KANDAGATLA, Bhaskar; (IN)

Eliglustat tartrate (Genz-1 12638) is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of gaucher disease and other lysosomal storage disorders, which is currently under development.

Eliglustat is chemically known as 1 R, 2R-Octanoic acid [2-(2′, 3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-2-hydroxy-1 -pyrrolidin-1 -ylmethyl]-ethyl]-amide, having a structural formula I depicted here under.

Formula I

Eliglustat hemitartrate (Genz-1 12638) development by Genzyme, is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of Gaucher disease and other lysosomal storage disorders. Eliglustat hemitartrate is orally active with potent effects on the primary identified molecular target for type 1 Gaucher disease and other glycosphingolipidoses, appears likely to fulfill high expectations for clinical efficacy. Gaucher disease belongs to the class of lysosomal diseases known as glycosphingolipidoses, which result directly or indirectly from the accumulation of glycosphingolipids, many hundreds of which are derived from glucocerebroside. The first step in glycosphingolipid biosynthesis is the formation of glucocerebroside, the primary storage molecule in Gaucher disease, via glucocerebroside synthase (uridine diphosphate [UDP] – glucosylceramide glucosyl transferase). Eliglustat hemitartrate is based on improved inhibitors of glucocerebroside synthase.

U.S. patent No. 7,196,205 (herein described as US’205) discloses a process for the preparation of eliglustat or a pharmaceutically acceptable salt thereof. In this patent, eliglustat was synthesized via a seven-step process involving steps in that sequence: (i) coupling S-(+)-2-phenyl glycinol with phenyl bromoacetate followed by column chromatography for purification of the resulting intermediate, (ii) reacting the resulting (5S)-5-phenylmorpholin-2-one with 1 , 4-benzodioxan-6-carboxaldehyde to obtain a lactone, (iii) opening the lactone of the oxazolo-oxazinone cyclo adduct via reaction with pyrrolidine, (iv) hydrolyzing the oxazolidine ring, (v) reducing the amide to amine to obtain sphingosine like compound, (vi) reacting the resulting amine with octanoic acid and N-hydroxysuccinimide to obtain crude eliglustat, (vii) purifying the crude eliglustat by repeated isolation for four times from a mixture of ethyl acetate and n-heptane.

U.S. patent No. 6855830, 7265228, 7615573, 7763738, 8138353, U.S. patent application publication No. 2012/296088 disclose processes for preparation of eliglustat and intermediates thereof.

U.S. patent application publication No. 2013/137743 discloses (i) a hemitartrate salt of eliglustat, (ii) a hemitartrate salt of eliglustat, wherein at least 70% by weight of the salt is crystalline, (iii) a hemitartrate salt of Eliglustat, wherein at least 99% by weight of the salt is in a single crystalline form.

It is also an objective of the present application to provide an improved process for the preparation of eliglustat and a pharmaceutically acceptable salt thereof which is high yielding, simple, cost effective, environment friendly and commercially viable by avoiding repeated cumbersome and lengthy purification steps. It is a further objective of the present application to provide crystalline forms of eliglustat free base and its salts.

Example 6: Preparation of Eliglustat {(1 R, 2R)-Octanoic acid[2-(2′,3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-2-hydroxy-1 -pyrrolidin-1-ylmethyl-ethyl]-amide}.

(1 R, 2R)-2-Amino-1 -(2′, 3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-3-pyrrolidin-1 -yl-propan-1 -ol (15g) obtained from above stage 5 was dissolved in dry dichloromethane (150ml) at room temperature under nitrogen atmosphere and cooled to 10-15^° C. Octanoic acid N-hydroxy succinimide ester (13.0 g)was added to the above reaction mass at 10-15^° C and stirred for 15 min. The reaction mixture was stirred at room temperature for 16h-18h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was cooled to 15°C and diluted with 2M NaOH solution (100 ml_) and stirred for 20 min at 20 °C. The organic layer was separated and washed with 2M sodium hydroxide (3x90ml).The organic layer was dried over anhydrous sodium sulphate (30g) and concentrated under reduced pressure at a water bath temperature of 45^°C to give the crude compound (20g).The crude is again dissolved in methyl tertiary butyl ether (25 ml_) and precipitated with Hexane (60ml). It is stirred for 10 min, filtered and dried under vacuum to afford Eliglustat as a white solid (16g). Yield: 74%, Mass (m/zj: 404.7 HPLC (% Area Method): 97.5 %, ELSD (% Area Method): 99.78%, Chiral HPLC (% Area Method): 99.78 %.

Example 7: Preparation of Eliglustat oxalate.

Eliglustat (5g) obtained from above stage 6 is dissolved in Ethyl acetate (5ml) at room temperature under nitrogen atmosphere. Oxalic acid (2.22g) dissolved in ethyl acetate (5ml) was added to the above solution at room temperature and stirred for 14h. White solid observed in the reaction mixture was filtered and dried under vacuum at room temperature for 1 h to afford Eliglustat oxalate as a white solid (4g). Yield: 65.46%, Mass (m/zj: 404.8 [M+H] ^+> HPLC (% Area Method): 95.52 %, Chiral HPLC (% Area Method): 99.86 %

G.V. Prasad, chairman, Dr Reddy’s Laboratories

//////////////New patent, WO 2016001885, Dr Reddy’s Laboratories Ltd, Eliglustat hemitartarate, WO 2015059679

SKLB 1028

9-isopropyl-N²-(4-(4-methylpiperazin-1-yl)phenyl)-N⁸-(pyridin-3-yl)-9H-purine- 2,8-diamine. Yield 65.6 %. HPLC>98.6%. ¹H NMR(400 MHz, DMSO-d₆)： δ 9.22(s, 1H), 9.05(s, 1H), 8.94(d, J=2.8Hz, 1H), 8.39(s, 1H), 8.34(d, J=8.4Hz, 1H), 8.20(m, 1H), 7.63(d, J=8.8Hz, 2H), 7.37(m, 1H), 6.88 (d, J=8.8Hz, 2H), 4.88(m, 1H), 3.05(m, 4H), 2.45(m, 4H), 2.22(s, 3H), 1.69(s, 3H), 1.68(s, 3H)ppm。HRMS (ESI) m/z [M-H]- calcd for C₂₄H₂₉N₉: 443.2546, found: 442.2538………..Leukemia (2012), 26(8)

PATENT

WO 2011147066

Synthetic route is as follows:

Example reaction is as follows:

8

Preparation of chloro-4-amino-5-nitro pyrimidine of Example 12-

Was added dropwise 2,4-dichloro-5-nitro-pyrimidine (lO Aqueous ammonia (8.0ml) and Ν, Ν- diisopropylethylamine (13.2ml) was dissolved in 150ml dichloromethane, 0 ° C when .Og) in dichloromethane (30ml) solution, after dropwise, maintaining the temperature of the reaction one hour, the precipitate was filtered off, the filter cake was recrystallized to give a yellow solid 8.1g, yield 90.1%

Product 1HNMR (400MHz, DMSO-i¾): δ 9.20 (s, 1H), 9.02 (s, 1H), 8.60 (s, lH) ppm

Preparation of pyrimidine

Isopropylamine (4.5ml) and Ν, Ν- diisopropylethylamine (13.2ml) was dissolved in 150ml of dichloromethane, was added dropwise 2,4-dichloro-5-nitro-pyrimidine at 0 ° C ( lO.Og) in dichloromethane (30ml) solution, after dropwise, maintaining the reaction temperature for half an hour, and purified by column chromatography to give a light yellow solid was 10.1g, 90.4% yield of product 1H NMR (400 MHz, CDCl ₃ ): [delta] 9.03 (s, 1H), 8.24 (s, 1H), 4.53 (m, 1H), 1.34 (d, J = 6.8 Hz, 6H) ppm ₀

Example 16, 4-amino-2- (4- (4-methyl-piperazin-1-yl) anilino) -5-nitro-pyrimidin embodiment

4- (4-methylpiperazine) aniline (3.8g) was added to the compound 2-l (3.5g) in n-butanol (150ml) solution, the reaction for 4.5 hours at 90 ° C, cooled to room temperature, filtered , washed, and dried to give a red solid (5.2g), a yield of 79.5%. Product ‘H NMR (400 MHz, CDCl ₃ ): [delta] 9.07 (s, 1H), 8.52 (s, 2H), 8.40 (s, 1H), 7.57 (s, 1H), 7.51 (s, 1H), 7.10 (m, 2H), 3.3 l (t, J = 4.8Hz, 4H), 2.81 (t, J = 4.8Hz, 4H), 2.30 (s, 3H) ppm.

Example 90,

9-isopropyl-2- (4- (4-methyl-piperazin-1-yl) anilino) -8- (pyridin-3-yl) -9H- purine

The compound 5- 7 (2.05g) was dissolved in dichloromethane (90ml), were added sequentially EDCI (2.3g), Ν, Ν- diisopropylethylamine (4.9ml), 3- pyridyl isothiocyanate ester (1.0g), stirred at room temperature for half an hour, then refluxed for 10 hours, TLC monitoring completion of the reaction the raw material 5-7 was cooled and purified by column chromatography to give a light red solid, yield 65.7%.

Product ESI-MS (m / z,%) 442.26 (MH) -. Ή NMR (400 MHz, DMSO-d ₆ ): [delta] 9.38 (s, IH), 9.13 (s, IH), 8.99 (s, IH), 8.40 (s, IH), 8.36 (d, J = 8.4 Hz, IH), 8.20 (d, J = 4.4Hz, IH), 7.70 (d, J = 8.8Hz, 2H), 7.37 (m, IH), 6.96 (d, J = 8.8Hz, 2H), 4.97-4.92 ( m, IH), 3.35 (s, 6H), 2.80 (s, 3H): 2.53 (s, 2H), 1.69 (s, 6H) ppm.

/////////SKLB 1028, IND Filed, Preclinical

CN1CCN(CC1)c5ccc(Nc3nc4n(C(C)C)c(Nc2cccnc2)nc4cn3)cc5

Acotiamide hydrochloride trihydrate
CAS#: 773092-05-0 (Acotiamide HCl hydrate, 1:1:3); 185104-11-4(Acotiamide HCl, 1:1); 185106-16-5 (Acotiamide free base)
Chemical Formula: C21H37ClN4O8S

Molecular Weight: 541.06
Elemental Analysis: C, 46.62; H, 6.89; Cl, 6.55; N, 10.36; O, 23.66; S, 5.93

Acotiamide, also known as YM-443 and Z-338, is a drug approved in Japan for the treatment of postprandial fullness, upper abdominal bloating, and early satiation due to functional dyspepsia. It acts as an acetylcholinesterase inhibitor. Note: The Approved drug API is a cotiamide HCl trihydrate (1:1:3)

N-(2-(diisopropylamino)ethyl)-2-(2-hydroxy-4,5-dimethoxybenzamido)thiazole-4-carboxamide hydrochloride trihydrate.

YM443; YM-443; YM 443; Z338; Z-338; Z 338; Acotiamide; Acotiamide hydrochloride trihydrate; Brand name: Acofide.

A peripheral acetylcholinesterase (AChE) inhibitor used to treat functional dyspepsia.

Acotiamide (YM-443, Z-338) is a drug approved in Japan for the treatment of postprandial fullness, upper abdominal bloating, and early satiation due to functional dyspepsia.^[1] It acts as an acetylcholinesterase inhibitor.

Acotiamide hydrochloride (acotiamide; N-[2-[bis(1-methylethyl) amino]ethyl]-2-[(2-hydroxy-4,5-dimethoxybenzoyl) amino] thiazole-4-carboxamide monohydrochloride trihydrate, Z-338) has been reported to improve meal-related symptoms of functional dyspepsia in clinical studies.

Acotiamide (Acofide(®)), an oral first-in-class prokinetic drug, is under global development by Zeria Pharmaceutical Co. Ltd and Astellas Pharma Inc. for the treatment of patients with functional dyspepsia. The drug modulates upper gastrointestinal motility to alleviate abdominal symptoms resulting from hypomotility and delayed gastric emptying. It exerts its activity in the stomach via muscarinic receptor inhibition, resulting in enhanced acetylcholine release and inhibition of acetylcholinesterase activity. Unlike other prokinetic drugs that are utilized in the management of functional dyspepsia, acotiamide shows little/no affinity for serotonin or dopamine D2 receptors. Acotiamide is the world’s first approved treatment for functional dyspepsia diagnosed by Rome III criteria, with its first approval occurring in Japan. Phase III trials in this patient population are in preparation in Europe, with phase II trials completed in the USA and Europe.

SYNTHESIS

Acylation of 2-aminothiazole-4-carboxylic acid ethyl ester (I) with 2,4,5-trimethoxybenzoyl chloride (II) produced the corresponding amide (III). The 2-methoxy group of (III) was then selectively cleaved by treatment with pyridine hydrochloride, yielding the 2-hydroxybenzamide (IV). Finally, displacement of the ethyl ester group of (IV) by N,N-diisopropyl ethanediamine (V) upon heating at 120 C furnished the target compound, which was isolated as the corresponding hydrochloride salt.

EP 0994108; WO 9858918

In a closely related procedure, acid chloride (II), prepared by treatment of 2,4,5-trimethoxybenzoic acid (VI) with SOCl2 in hot toluene, was condensed with aminothiazole (I), yielding amide (III). Displacement of the ethyl ester group of (III) by N,N-diisopropyl ethanediamine (V) furnished diamide (VII). Finally, upon formation of the hydrochloride salt of (VII) in isopropanol, the 2-methoxy group was simultaneously cleaved, directly leading to the title compound.

CN103709191A

Acotiamide hydrochloride, chemical name: N_ [2_ (diisopropylamino) ethyl] -2- [(2-hydroxy-4,5-dimethoxybenzoyl) amino ] thiazole-4-carboxamide hydrochloride, the following structure:

  A test for the amine hydrochloride Japan Zeria Pharmaceutical Company and Astellas jointly developed acetylcholinesterase inhibitor class of prokinetic drugs, namely the treatment of functional dyspepsia drugs, is the world’s first approved specifically for the treatment of FD drugs, in June 2013 for the first time launched in Japan, under the trade name Acofide. Functional dyspepsia (Functional dyspepsia, FD) is a group of common symptoms include bloating, early satiety, burning sensation, belching, nausea, vomiting and abdominal discomfort and so difficult to describe, and no exact organic disease. Organic diseases because of lack of basic, functional dyspepsia harm to patients focus on the performance of gastrointestinal symptoms caused discomfort and possible impact on the quality of life in. Because some patients with functional dyspepsia symptoms caused by eating less, digestion and absorption efficiency is reduced, resulting in varying degrees of malnutrition (including nutrients are not full). With the people’s demands and improve the quality of life for functional dyspepsia know, the number of visits of the disease gradually increased, to become one of the most common disease of Gastroenterology partner waiting group. Such a high prevalence of functional dyspepsia treatment provides a huge market.

  The present synthesis method has been reported in less divided into four methods are described below:

  1, reference CN1084739C, synthetic route as shown below. Disadvantage of this patent is that: (I) using thionyl chloride and dichloroethane toxic, environmentally damaging substances; (2) demethylation low yield (64.6% to 86 reported in the literature %). Examples reported in this patent first and second step total yield was 84.6% and the total yield of the third-step reaction and recrystallization of 61%, the total yield of 51.6%.

  The method, reported in the patent CN1063442C preparation A (page 25) reports (without reference to examples I and 6, referring to its general method). Patent CN102030654B (page 3) above: Step demethylation reaction generates a lot of by-products, it is difficult to take off only a selective protection of hydroxy groups, poor selectivity. Specific synthetic examples are shown below:

  Preparation Method B 3 mentioned patent CN1063442C (prepared unprotected, p. 25), where the yield is very low two-step reaction. A test method for the preparation of amines referenced above example (Example 38) A test for specific preparation yield amine not mentioned in the text, but if you use the above method starting materials primary amino side reactions occur. Synthesis of solid concrete

Following is an example:

reported that patent CN101006040B in Method 4. The first step demethylation can also use titanium tetrachloride and aluminum chloride; the second reaction can also be used phenol / thionyl chloride. Synthetic route are higher yield and purity (total yield 73%).

  The method of synthesis of the above methods 3 patent CN1063442C reported, though not suitable for the synthesis of amine A test, but may be modified on this basis.

the above patents, CN1084739 reagents using dichloroethane, toxic, environmentally destructive, and the total yield is low, is not conducive to industrial production; patent CN102030654B mentioned Step demethylation The reaction produces a lot of by-products, it is difficult to take off only selective hydroxy protecting group, the reaction selectivity, more side effects.

Example 4

[Amino-N- (2- tert-butoxycarbonyl group -4,5_ dimethoxybenzoyl)] _4_ Preparation of 2-methoxycarbonyl-1,3-thiazole: [0062] Step 1

  2-hydroxy-4,5-dimethoxy-benzoic acid (100 g) was dissolved in dry toluene (400 ml) was added Boc20 (132 g) was stirred at rt for 3 hours at room temperature, was added a 10% aqueous citric acid (100 ml) and washed three times with purified water until neutral, dried over anhydrous sodium sulfate was added (20 g) and dried 8 hours, filtered, and the filtrate was added thionyl chloride (64 g) and N, N-dimethyl- carboxamide (0.19 ml), followed by stirring 80 ° C for 4 hours, the compound was added 2-amino-4-methoxycarbonyl-1,3-thiazole (85 g), stirred for 5 hours at 100 ° C, the reaction was completed After cooling to room temperature, the precipitated crystals were collected by filtration, crystals were added to 1.6 liters of water, 400 g of ice was added with stirring, and added a mass ratio of 10% sodium hydroxide aqueous solution adjusted to pH 7.5, followed by stirring for 3 hours at room temperature, filtered The crystals were collected, washed with water, 60 ° C and dried to give the title compound (170 g).

Hl-NMR (DMSO, 400MHz) δ: 1.34 (s, 3H), 1.37 (s, 3H), 1.40 (s, 3H), 3.77 (s, 3H),

3.82 (s, 3H), 3.88 (s, 3H), 7.17 (s, 1H), 7.50 (s, 1H), 7.95 (s, 1H), 11.45 (bs, 1H).

Step 2: 2- [N- (2- hydroxy-4,5-dimethoxybenzoyl) amino] -4- [(2_ diisopropylamino ethyl) – aminocarbonyl] -1 , Preparation of 3-thiazole hydrochloride

The 2- [N- (2- tert-butoxycarbonyl group -4,5_ dimethoxybenzoyl) amino] _4_ methoxycarbonyl _1,3_ thiazole prepared (170 g) and N , N- diisopropyl-ethylenediamine (162 ml), N, N- dimethylacetamide (162 ml) was stirred at 135 ° C for 8 hours and cooled, 1-butanol (1.7 liters), with 0.5N aqueous sodium hydroxide solution and washed with saturated brine, the mixture was concentrated under reduced pressure, methanol (1.7 l), hydrogen chloride gas under cooling and stirred for 5 hours, the precipitate was collected by filtration, the crystals were washed with 2-propanol and water do recrystallized from a mixed solvent, to give the title compound. Melting point: 160 ° C.

[0067] Hl- bandit R (DMSO, 400ΜΗζ) δ: 1.33 (d, J = 6.4Hz, 6H); 1.36 (d, J = 6.4,6H), 3.17-3.20 (m, 2H); 3.57-3.69 ( m, 4H), 3.77 (s, 3H), 3.82 (s, 3H), 6.89 (s, 1H), 7.50 (s, 1H), 7.91 (s, 1H); 8

• 74 (t, 1H, J = 5.9Hz); 9.70 (s, 1H); 11.80 (s, 1H); 12.05-12.15 (bs, 1H).

CN103387552A

A test for the amine hydrochloride (Z-338) is a new Ml Japan Zeria company’s original research, M2 receptor antagonist, for the treatment of functional dyspepsia clinic.

Chinese patent application describes doxorubicin hydrochloride CN200580028537 test for amines (Z-338) preparation, reaction

Process is as follows.

A test for the amine hydrochloride (z-338) Compound Patent Application (CN96194002.6) choosing 2,4,5-trimethoxy benzoic acid as a starting material first with 2-aminothiazol-4-carboxylate reacts 2- [(2-hydroxy-4,5-dimethoxybenzoyl) amino] -1,3-thiazole-4-carboxylate, 2-methyl-benzene and then removed, the yield of this method lower demethylation selectivity bad. So choose the first 2-methyl-removal before subsequent reaction better.

The first patent application CN200580028537 2_ hydroxyl _4,5_ dimethoxy benzoic acid and triphenyl phosphite placed in toluene, was added a few drops of concentrated sulfuric acid as a catalyst under reflux to give the intermediate 2-hydroxy – 4,5-dimethoxy-phenyl benzoate. After the above intermediate with 2-aminothiazol-4-carboxylate in place of toluene, was added triphenyl borate reacted, treated to give 2- [(2-hydroxy-4,5-dimethoxy- benzoyl) amino] -1,3-thiazole-4-carboxylate, and finally with N, N- diisopropylethylamine in toluene diamine salt in the system after the reaction.

Example 1

  2 – [(2-hydroxy-4,5-dimethoxybenzoyl) amino] thiazole Synthesis _1,3_ _4_ carboxylate

[0030] triphosgene dissolved in 90ml CH2Cl2 19.0g placed in a four-necked flask, under N2 stream, the 2_ hydroxyl _4,5_ dimethoxy benzoic acid (22.2g) was dissolved in 150ml CH2Cl2 and 45ml pyridine, at four-necked flask temperature dropped 0_5 ° C under ice-salt bath. Dropping finished within 45min, kept cold stirred lOmin. After warm to room temperature (20 ° C) was stirred for 50min, the reaction was stopped. Pressure filtration, and the filtrate by rotary evaporation at room temperature to a constant weight, adding 35g 2- aminothiazol-4-carboxylate and 240ml 1,2_ dichloroethane and heated to reflux, the reaction 6h. After stopping the cooling, suction filtration, washed with methanol and the resulting solid was refluxed in 40ml, hot filtration to give a white solid 32.18g, yield 85%. M + Na + 361; 2M + Na + 699. [0031] Example 2

2 – [(2-hydroxy-4,5-dimethoxybenzoyl) amino] thiazole Synthesis _1,3_ _4_ carboxylate

triphosgene dissolved in 15ml CH2Cl2 placed 3.0g four-necked flask, under N2 stream, the 2_ hydroxyl _4,5_ dimethoxy benzoic acid (3.0g) was dissolved in pyridine 30ml CH2Cl2 and 61,111, in four-necked flask temperature dropped 0_5 ° C under ice-salt bath. 20min Upon completion, kept cold stirring lh. After warm to room temperature (20 ° C) and stirred overnight, 24h after stopping the reaction. Rotary evaporation at room temperature to a constant weight is added 3.5g 2- aminothiazol-4-carboxylate and 30ml 1,2- dichloroethane burning, heated to reflux, the reaction 6h. The solvent was evaporated after stopping, add 30ml methanol reflux filtration to give a white solid 4.1g, 20ml methanol was added to the mother liquor evaporated leaching and washing a white solid 0.85g. After the merger was solid 4.95g, yield 97%.

Example 3

  2 – [(2-hydroxy-4,5-dimethoxybenzoyl) amino] thiazole Synthesis _1,3_ _4_ carboxylate

The diphosgene 3.0g was dissolved into 15ml CH2Cl2 four-necked flask, under N2 stream, the 2_ hydroxyl _4,5_ dimethoxy benzoic acid (3.0g) was dissolved in 30ml CH2Cl2 and 61,111 pyridine, Under ice-salt bath temperature dropped a four-necked flask 0_5 ° C. 20min Upon completion, kept cold stirring lh. After warm to room temperature (20 ° C) and stirred overnight, 24h after stopping the reaction. Rotary evaporation at room temperature to a constant weight is added 3.5g 2- aminothiazol-4-carboxylate and 30ml 1,2- dichloroethane burning, heated to reflux, the reaction 6h. After the solvent was evaporated and stopped by adding 30ml of methanol was refluxed for leaching to give a white solid 4.57g, yield 89.6%.

  Example 4

  2 – [(2-hydroxy-4,5-dimethoxybenzoyl) amino] thiazole Synthesis _1,3_ _4_ carboxylate

  triphosgene dissolved in 15ml CH2Cl2 placed 3.0g four-necked flask, under N2 stream, the 2_ hydroxyl _4,5_ dimethoxy benzoic acid (3.0g) `pyridine was dissolved in 30ml CH2Cl2 and 61 111, Under ice-salt bath temperature dropped a four-necked flask 0_5 ° C. 20min Upon completion, kept cold stirring lh. After warm to room temperature (20 ° C) and stirred overnight, 24h after stopping the reaction. Rotary evaporation at room temperature to a constant weight is added 3.7g 2- aminothiazol-4-carboxylic acid ethyl ester and 30ml 1,2- dichloroethane burning, heated to reflux, the reaction 6h. The solvent was evaporated after stopping, add 30ml methanol reflux filtration to give a white solid 3.8g, 20ml methanol was added to the mother liquor evaporated leaching and washing a white solid 0.54g. After the merger was solid 4.34g, yield 81.4%. M + Na + 375.

Example 5

  N- [2_ (diisopropylamino) ethyl] -2 – [(hydroxy -4,5_ 2_ dimethoxybenzoyl) amino] -1,3-thiazol-4-carboxamide amide hydrochloride

  2 – [(2-hydroxy-4,5-dimethoxybenzoyl) amino] thiazole _4_ _1,3_ carboxylate and 1.5g IOml 1,4- dioxane placed in a four-necked flask, N2 gas shielded at 75 ° C was added dropwise 1.5ml N, N- diisopropyl-ethylenediamine, rose after reflux, the reaction was stirred for 6 hours. The reaction was stopped, the solvent was evaporated to dryness under reduced pressure, 30ml CH2Cl2 was added dissolved in 20ml10% NaCl solution was washed twice, and then the organic solvent was evaporated to dryness. IOml methanol was added, concentrated hydrochloric acid was added to adjust Xeon acidic. Evaporated methanol, washed with acetone to give the product 2.08g, yield 96.3%. M + H 451, MH 449.

Example 6

[0044] N- [2- (diisopropylamino) ethyl] -2 – [(hydroxy _4,5_ 2_ dimethoxybenzoyl) amino] -1,3-thiazol-4-carboxamide amide hydrochloride

2 – [(2-hydroxy-4,5-dimethoxybenzoyl) amino] thiazole _4_ _1,3_ carboxylate and 1.5g IOml 1,4- dioxane placed in a four-necked flask, N2 gas shielded at 75 ° C was added dropwise 1.5ml N, N- diisopropyl-ethylenediamine, rose after reflux, the reaction was stirred for 6 hours. The reaction was stopped, the solvent was evaporated to dryness under reduced pressure, 30ml CH2Cl2 was added dissolved in 20ml10% NaCl solution was washed twice, and then the organic solvent was evaporated to dryness. IOml methanol was added, concentrated hydrochloric acid was added to adjust Xeon acidic. Evaporated methanol, washed with acetone to give the product 1.76g, yield 84.7%.

PAPER

A Three-Step Synthesis of Acotiamide for the Treatment of Patients with Functional Dyspepsia

Abstract

A three-step synthesis of acotiamide is described. The agent is marketed in Japan for treatment of patients with functional dyspepsia. We designed a one-pot method to prepare the key intermediate 5a from 2 via an acyl chloride and amide and then reacted with 6 to obtain 1 under solvent-free condition. With the use of DCC, the unavoidable impurity 5b was also successfully converted into the desired 1. After isolation of 1, we carried forward to the next step of HCl salt formation, which was proved to be a very effective procedure for the removal of practically all major impurities. The process is cost-effective, simple to operate, and easy to scale-up.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00256

see………….http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.5b00256/suppl_file/op5b00256_si_001.pdf

References

Matsueda K, Hongo M, Tack J, Aoki H, Saito Y, Kato H (January 2010). “Clinical trial: dose-dependent therapeutic efficacy of acotiamide hydrochloride (Z-338) in patients with functional dyspepsia – 100 mg t.i.d. is an optimal dosage”. Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society 22 (6): 618–e173. doi:10.1111/j.1365-2982.2009.01449.x. PMID 20059698.

: Mayanagi S, Kishino M, Kitagawa Y, Sunamura M. Efficacy of acotiamide in combination with esomeprazole for functional dyspepsia refractory to proton-pump inhibitor monotherapy. Tohoku J Exp Med. 2014;234(3):237-40. PubMed PMID: 25382232.

2: Zai H, Matsueda K, Kusano M, Urita Y, Saito Y, Kato H. Effect of acotiamide on gastric emptying in healthy adult humans. Eur J Clin Invest. 2014 Dec;44(12):1215-21. doi: 10.1111/eci.12367. PubMed PMID: 25370953.

3: Xiao G, Xie X, Fan J, Deng J, Tan S, Zhu Y, Guo Q, Wan C. Efficacy and safety of acotiamide for the treatment of functional dyspepsia: systematic review and meta-analysis. ScientificWorldJournal. 2014;2014:541950. doi: 10.1155/2014/541950. Epub 2014 Aug 12. PubMed PMID: 25197703; PubMed Central PMCID: PMC4146483.

4: Sun Y, Song G, McCallum RW. Evaluation of acotiamide for the treatment of functional dyspepsia. Expert Opin Drug Metab Toxicol. 2014 Aug;10(8):1161-8. doi: 10.1517/17425255.2014.920320. Epub 2014 May 31. PubMed PMID: 24881488.

5: Matsunaga Y, Tanaka T, Saito Y, Kato H, Takei M. [Pharmacological and clinical profile of acotiamide hydrochloride hydrate (Acofide(®) Tablets 100 mg), a novel therapeutic agent for functional dyspepsia (FD)]. Nihon Yakurigaku Zasshi. 2014 Feb;143(2):84-94. Review. Japanese. PubMed PMID: 24531902.

6: Nowlan ML, Scott LJ. Acotiamide: first global approval. Drugs. 2013 Aug;73(12):1377-83. doi: 10.1007/s40265-013-0100-9. Erratum in: Drugs. 2014 Jun;74(9):1059. Nolan, Mary L [corrected to Nowlan, Mary L]. PubMed PMID: 23881665.

7: Altan E, Masaoka T, Farré R, Tack J. Acotiamide, a novel gastroprokinetic for the treatment of patients with functional dyspepsia: postprandial distress syndrome. Expert Rev Gastroenterol Hepatol. 2012 Sep;6(5):533-44. doi: 10.1586/egh.12.34. Review. PubMed PMID: 23061703.

8: Nagahama K, Matsunaga Y, Kawachi M, Ito K, Tanaka T, Hori Y, Oka H, Takei M. Acotiamide, a new orally active acetylcholinesterase inhibitor, stimulates gastrointestinal motor activity in conscious dogs. Neurogastroenterol Motil. 2012 Jun;24(6):566-74, e256. doi: 10.1111/j.1365-2982.2012.01912.x. Epub 2012 Mar 19. PubMed PMID: 22429221.

9: Kusunoki H, Haruma K, Manabe N, Imamura H, Kamada T, Shiotani A, Hata J, Sugioka H, Saito Y, Kato H, Tack J. Therapeutic efficacy of acotiamide in patients with functional dyspepsia based on enhanced postprandial gastric accommodation and emptying: randomized controlled study evaluation by real-time ultrasonography. Neurogastroenterol Motil. 2012 Jun;24(6):540-5, e250-1. doi: 10.1111/j.1365-2982.2012.01897.x. Epub 2012 Mar 4. PubMed PMID: 22385472.

10: McLarnon A. Dyspepsia: Acotiamide can relieve symptoms of functional dyspepsia. Nat Rev Gastroenterol Hepatol. 2012 Jan 17;9(2):62. doi: 10.1038/nrgastro.2011.262. PubMed PMID: 22249733.

Acotiamide

Systematic (IUPAC) name
N-{2-[Bis(1-methylethyl)amino]ethyl}-2-{[(2-hydroxy-4,5-dimethoxyphenyl)carbonyl]amino}-1,3-thiazole-4-carboxamide
Clinical data
Legal status	Uncontrolled
Routes of administration	Oral
Identifiers
CAS Number	185106-16-5
ATC code	None
PubChem	CID: 5282338
ChemSpider	4445505
UNII	D42OWK5383
ChEMBL	CHEMBL2107723
Chemical data
Formula	C21H30N4O5S
Molecular mass	450.55 g/mol

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