Fluphenazine

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

UNIIS79426A41Z

CAS number69-23-8

Product Ingredients

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

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

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

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

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

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

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

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

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

Synthesis Reference

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

US3058979

syn

syn

Antipsychotics (Neuroleptics)

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

Fluphenazine

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

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

Manufacturing Process

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

Chemical Synthesis

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

SYN

Indian Pat. Appl., 2014MU02033,

PATENT

CN 105153062

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

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

PATENT

WO 2015103587

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

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Medical use

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

Side effects

Discontinuation

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

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

Pharmacology

Pharmacodynamics

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

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

Pharmacokinetics

History

Fluphenazine came into use in 1959.^[6]

Availability

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

Other animals

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

References

1. ^ Jump up to:^{a b c d e f g h i j k l m n o} “fluphenazine decanoate”. The American Society of Health-System Pharmacists. Archived from the original on 8 December 2015. Retrieved 1 December 2015.
2. ^ “Product Information: Modecate (Fluphenazine Decanoate Oily Injection )” (PDF). TGA eBusiness Services. Bristol-Myers Squibb Australia Pty Ltd. 1 November 2012. Archived from the original on 2 August 2017. Retrieved 9 December 2013.
3. ^ Tardy M, Huhn M, Engel RR, Leucht S (August 2014). “Fluphenazine versus low-potency first-generation antipsychotic drugs for schizophrenia”. The Cochrane Database of Systematic Reviews. 8 (8): CD009230. doi:10.1002/14651858.CD009230.pub2. PMID 25087165.
4. ^ “Modecate Injection 25mg/ml – Patient Information Leaflet (PIL) – (eMC)”. http://www.medicines.org.uk. Retrieved 6 November 2017.
5. ^ “Fluphenazine”. livertox.nih.gov. Retrieved 6 November 2017.
6. ^ Jump up to:^a b McPherson EM (2007). Pharmaceutical Manufacturing Encyclopedia (3rd ed.). Burlington: Elsevier. p. 1680. ISBN 9780815518563.
7. ^ Jump up to:^a b World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
8. ^ Jump up to:^a b Rossi S, ed. (July 2017). “Fluphenazine – Australian Medicines Handbook”. Australian Medicines Handbook. Adelaide, Australia: Australian Medicines Handbook Pty Ltd. Retrieved 8 August 2017.
9. ^ Matar HE, Almerie MQ, Sampson SJ (June 2018). “Fluphenazine (oral) versus placebo for schizophrenia”. The Cochrane Database of Systematic Reviews. 6: CD006352. doi:10.1002/14651858.CD006352.pub3. PMC 6513420. PMID 29893410.
10. ^ Joint Formulary Committee, BMJ, ed. (March 2009). “4.2.1”. British National Formulary (57 ed.). United Kingdom: Royal Pharmaceutical Society of Great Britain. p. 192. ISBN 978-0-85369-845-6. Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse.
11. ^ Jump up to:^{a b c d e} Haddad P, Haddad PM, Dursun S, Deakin B (2004). Adverse Syndromes and Psychiatric Drugs: A Clinical Guide. OUP Oxford. pp. 207–216. ISBN 9780198527480.
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External links

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

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