PROCESS FOR THE PREPARATION OF PAROXETINE AND STRUCTURALLY RELATED COMPOUNDS

Abstract: The (-) trans isomer of 4-(4'-fluorophenyl)-3-(3, 4'-methylenedioxyphenoxymethyl)-piperidine(paroxetine) according to formula (1) is used in therapy as the hydrochloride salt to treat inter alia depression, obsessive compulsive disorder (OCD) and panic. There is described a process for the preparation of a compound of formula (1) or a phramaceutically acceptable salt thereof, in which R<1> is a substituted phenyl group, the process comprising hydrolysing a solution of a carbamate of formula (2) in which R<1> is as defined above and R<2> is a C1-6 alkyl group, a C3-6 cycloalkyl group, aralkyl group, phenyl or substituted phenyl group; with a base by forming a finely divided complex derived from the base and the carbamate and heating it in suspension in a solvent.

Description: PROCESS FOR THE PREPARATION OF PAROXETINE AND STRUCTURALLY RELATED COMPOUNDS The present invention relates to new processes for preparing pharmaceutically active compounds and intermediates therefor. Pharmaceutical products with antidepressant and anti-Parkinson properties are described in US-A-3912743 and US-A-4007196. An especially important compound among those disclosed is paroxetine, the (-) trans isomer of 4-(4'-fluorophenyl)-3- (3',4'- methylenedioxy-phenoxymethyl)-piperidine. This compound is used in therapy as the hydrochloride salt to treat inter alia depression, obsessive compulsive disorder (OCD) and panic. Previously published processes to paroxetine involve the hydrolysis of the carbamate: in which R >2 ; is typically an alkyl, aryl or arylalkyl group. In US 4 007 196, R 2 is Ph and the carbamate is hydro lysed by refluxing in benzene with potassium hydroxide with methyl cellosolve for 4 hours. Clearly it would be preferable to move away from the use of benzene and it has been found that the use of methyl cellosolve results in a transesterified intermediate which is slow to hydrolyse and which also leaves behind a difficult to remove residue from the hydrolysed product. EP-0 810 225 describes a preparation of paroxetine in which the N-ethoxycarbonyl derivative is hydrolysed by heating at 90°C in ethanol/water with KOH for 3 days. In EP 0 152 273, the phenyl carbamate of a paroxetine analogue is hydrolysed at 130-140°C in toluene with KOH and ethyleneglycol monomethylether for four hours. EP 0 223 403, an earlier application of the present applicant, treats the N- phenoxycarbonyl derivative in toluene with KOH for two hours at reflux. Serious difficulties have been encountered in attempts to scale up this process. Even with vigorous agitation during reflux, long reaction times and incomplete reactions were encountered. Whilst acceptable on a laboratory scale, these processes are not applicable to implementation on an industrial scale. Our investigations have led to the discovery that reaction conditions at temperatures well below reflux are critical for a successful reaction, and that by the time reflux temperature is reached the reaction may have failed irretrievably. In particular, we have discovered that at toluene reflux temperature potassium hydroxide melts and forms an almost insoluble complex mass with paroxetine carbamate derivatives such as, for example, 4- (4'-fluorophenyl)-3-(3",4"-methylenedioxyphenoxymethyl)- 1 - phenoxycarbonylpiperidine. Once this material is formed, it is not possible to obtain a complete reaction in a reasonable time. Furthermore, it is difficult and time-consuming to clean and prepare an industrial reactor for the next run. As a further result of our investigations, we have made surprising modifications to the reaction conditions which enable the reaction to be carried out in an efficient, robust, and reproducible manner, suitable for industrial-scale production. In its broadest sense, the present invention provides a process for the preparation of a paroxetine derivative of formula (1): in which R is a substituted phenyl group, preferably 3,4-methylenedioxyphenyl; by hydrolysing a carbamate of formula (2) in which R 2 is a Cι -6 alkyl group, a C 3-6 cycloalkyl group, aralkyl group, phenyl or substituted phenyl group and R 1 is as defined above. The process comprises formation of a finely divided, e.g.sand-like, complex of potassium hydroxide and the carbamate derivative at a temperature well below the reflux temperature of toluene (110.6°C), for example at between 70 and 90°C. The complex is easily stirrable and reacts quickly and cleanly to form paroxetine. Once formed, the well- stirred mixture is heated steadily to reflux temperature to complete the reaction, normally within one hour. The sand-like complex of potassium hydroxide and carbamate derivative may be prepared by heating a mixture of the carbamate and potassium hydroxide, preferably in a finely divided form such as a flake, to a suitable temperature, and then discontinuing the heating while stirring vigorously. In the case of 4-(4'- fluorophenyl)-3-(3",4"-methylenedioxyphenoxymethyl)-l-phenoxycarbonylpiperidine a suitable temperature is between 70 and 90°C, whilst for other carbamates it may be determined by simple experiment. Preferably between 3 and 10 equivalents of base are used, more preferably, between 6 and 8 equivalents. Preferably the solvent is toluene. Commercial potassium hydroxide flake contains 10-20% water, and other sources of water may well be present in the reaction. We have found that the hydrolysis reaction is more rapid and gives lower levels of side-reaction products in the absence of excess water. These conditions may be achieved by modifying the apparatus to a Dean and Stark or similar configuration and carrying out the reaction in a dehydrating medium, so that water is removed during the reaction. Preferably, the dehydrating medium is toluene and excess water is removed by azeotropic distillation, preferably until the water content is below 30%, more preferably less than 20%, more preferably still below 10% by weight with respect to the weight of compound of formula (2). In reactions using toluene as the solvent, the concentration of carbamate is critical. Low concentration are undesirable because of vessel occupancy and other overheads, whereas high concentrations result in incomplete reactions. Suitable concentrations on a weight/weight basis are between 4 and 10 %, preferably between 5.5 and 9%, most preferably between 6.5 and 8.0%. Potassium phenate is a by-product of the above process and must be removed. The aqueous wash described in EP-0 223 403 has been found to be unsatisfactory on an industrial scale, even if high volumes of water are used, which is, of course, undesirable for efficient plant utilisation. If optimal reaction conditions have been applied to the reaction with KOH, most of the potassium phenate can be removed by filtration as a crystalline precipitate. Preferably, however, the prior art ambient temperature aqueous wash is replaced by a high temperature wash, using water which has been pre-heated, preferably to between 60 and 95°C, more preferably between 70 and 80 °C. The volume of water used is preferably between Vi and V 20 of the volume of toluene used in the reaction, more preferably between V 3 and V 5 . It has been found that this procedure achieves successful removal of potassium phenate, contrary to expectations in view of the large excess of potassium hydroxide used in the reaction. Such concentrated solutions of KOH at elevated temperatures would ordinarily be expected to be very aggressive and cause degradation of the desired product. Following washing, the paroxetine derivative product may be isolated in a sufficiently pure form from the toluene solution by evaporation, from which any of the known salts may be formed. Crystallisation of paroxetine hydrochloride from the toluene reaction solvent has been disclosed in the prior art, but has been found not to be applicable on an industrial scale. The product tends to be deposited initially as an oil which solidifies to form a lumpy product which is difficult to remove from the reaction vessel and includes unacceptable levels of impurities and solvent. We have developed an improved method of isolating a compound of formula (1) as a pharmaceutically acceptable salt,especially the hydrochloride, in which a co-solvent is added to a solution of the compound in toluene, benzene or xylene, prior to acidification with a pharmaceutically acceptable acid and crystallisation, optionallly seeding with seed crystals of the desired salt. Preferably the co-solvent is an alcohol, ketone, ester or chlorinated hydrocarbon. More preferably, it is an alcohol, most preferably ethanol, typically IMS. Preferably, the co- solvent is added to the reaction solvent after the aqueous wash, but before cooling to ambient temperature. Preferably, the co-solvent is added at between 50 and 60°C, typically at about 55°C. In the case of IMS, a volume equivalent to between V 20 and V 60 of the volume of the toluene solution is added, preferably between V 30 and V 40 . When preparing the hydrochloride salt, following addition of the co-solvent, the solution is suitably cooled to between 10°C and 30°C, preferably between 15 and 25°C and seeds of the desired paroxetine hydrochloride crystalline form, such as the hemihydrate, are added (preferably in an amount of between 0.05 and 1%, more preferably about 0.1% by weight). The solution is acidified with hydrochloric acid, suitably aqueous concentrated hydrochloric acid, with vigorous stirring. Advantageously, an amount of hydrochloric acid in excess of the theoretical amount required is added, typically between 1.1 and 2 equivalents, preferably between 1.3 and 1.8 equivalents, more preferably between 1.5 and 1.7 equivalents. Preferably, the acid is added very rapidly with vigorous stirring. As a result, crystallisation is rapid and gives a consistent form, avoiding lumpiness and variable purity. The mixture is preferably stirred for at least 30 minutes to complete crystallisation, following which, the temperature of the mixture may be reduced to 1-5°C for final crystallisation. As a result of the applicant's extensive investigations, it has been determined that hitherto unappreciated catechol impurities are formed during acidification from hydrolysis intermediates and are particularly problematic, being difficult to remove by crystallisation and resulting in coloured products. These products are typically caused by trace quantities of alcohols from earlier processing stages, or from plant washing protocols or by impurities in the solvents. The production of catechols can be reduced by first rinsing the reaction vessel with toluene and by washing the toluene phase with water. However, a more efficient process has also been developed, in which the step of an aqueous alkali wash, typically sodium hydroxide, is added following the acidification procedure. Preferably, this alkali wash is carried out at above ambient temperature, preferably in the range 40-60°C, more preferably about 50°C. In an industrial context, sodium hydroxide is available as a 50% by weight aqueous solution and so it is convenient to add heated water first, typically between 1/3 and l A of the volume of toluene, followed by an addition of 50% sodium hydroxide solution, preferably between 5 and 10 equivalents, more preferably between 6 and 8 equivalents. After the alkali wash, the previous treatment with co-solvent, seed and acid is repeated to isolate a purified paroxetine hemihydrate product. Optionally, the product may be subjected to a further purification by recrystallisation from propan-2-ol containing between 1% and 10% water, preferably between 2% and 4%. Between 5 and 10 parts of propan-2-ol are used relative to the weight of solid product, preferably between 7 and 8 parts. It has been found that a greatly improved form of product is obtained if the crystallisation is initiated at a relatively high temperature. Accordingly, the propan-2-ol solution is preferably cooled from reflux to between 50 and 60°C, more preferably in the region of 55°C, and the mixture seeded (1-5% by weight of expected product is used as seed). The mixture is then allowed to crystallise for 2-4 hours before gradually cooling to 0°C. After a further period of stirring (2-4 hours) the product is filtered, washed with aqueous propan-2-ol and dried The process of this invention may be used to prepare active compounds described in US- A-3912743 and US-A-4007196, and preferably to prepare paroxetine hydrochloride hemihydrate. As an alternative to isolating the hydrochloride hemihydrate, solvated, non- crystalline, or anhydrate hydrochloride salts or paroxetine salts with other acids may be isolated according to previously disclosed procedures. Paroxetine is preferably obtained as or converted to the hydrochloride salt and most preferably the hemihydrate of that salt, as described in EP-A-0223403. The present invention includes within its scope the compound paroxetine, particularly paroxetine hydrochloride, especially as the hemihydrate, when obtained via any aspect of this invention, and any novel intermediates resulting from the described procedures. Paroxetine is the (-)-trans isomer of 4-(4'-fluorophenyl)-3-(3',4'-methylenedioxy- phenoxymethyl)-piperidine. Following the procedure of EP-0 152 273, optical resolution may be carried out prior to coupling with the phenol. Alternatively, resolution may be carried out at other stages, such as after deprotection of the piperidine nitrogen. Example 2 illustrates resolution of the N-deprotected compound. Paroxetine obtained using this invention may be formulated for therapy in the dosage forms described in EP-A-0223403 or WO96/24595, either as solid formulations or as solutions for oral or parenteral use. Therapeutic uses of paroxetine, especially paroxetine hydrochloride, obtained using this invention include treatment of: alcoholism, anxiety, depression, obsessive compulsive disorder, panic disorder, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, pre-menstrual syndrome (PMS), adolescent depression, trichotillomania, dysthymia, and substance abuse, referred to below as "the Disorders". Accordingly, the present invention also provides: a pharmaceutical composition for treatment or prophylaxis of the Disorders comprising paroxetine or paroxetine hydrochloride obtained using the process of this invention and a pharmaceutically acceptable carrier, the use of paroxetine or paroxetine hydrochloride obtained using the process of this invention to manufacture a medicament for the treatment or prophylaxis of the Disorders; and a method of treating the Disorders which comprises administering an effective or prophylactic amount of paroxetine or paroxetine hydrochloride obtained using the process of this invention to a person suffering from one or more of the disorders. This invention is illustrated by the following Examples. Example 1 4-(4'-fluorophenyl)-3-(3",4"-methylenedioxyphenoxymethyI) piperidine Potassium hydroxide flake (83 kg) and 4-(4'-fluorophenyl)-3-(3",4"- methylenedioxyphenoxymethyl)-l-phenoxycarbonylpiperidine (90 kg) in 1470 litres of toluene were heated carefully and in stages to 70°C, and stirred very vigorously. Heating was discontinued while a fine, sand-like suspension formed, and a controlled exothermic reaction commenced which brought the mixture to reflux temperature. Water was removed by means of Dean and Stark apparatus, and the mixture was allowed to reflux for 2 hours. The reaction mixture was then cooled to 70°C, washed twice with hot water at approximately 70°C (2 x 400 litres), and separated. The contents of the reactor were cooled to 55°C, treated with industrial methylated spirit (IMS) (40 litres), cooled further to 20°C, and seeded with paroxetine hydrochloride hemihydrate (60 g). Concentrated hydrochloric acid (28 litres) was added with vigorous stirring, and the stirring maintained for a further 30 minutes. Water (420 litres) and 50% aqueous sodium hydroxide solution (112 kg) was added, and the mixture heated to 50°C. The vessel contents were thoroughly stiπed, allowed to settle, and the aquous layer discharged to waste. The toluene layer was then washed with water (400 litres) and cooled to 20°C. The mixture was stirred vigorously while seeds of paroxetine hydrochloride hemihydrate (60 g) and concentrated hydrochloric acid (28 litres) were added. Stirring was maintained at a temperature of 20°C for 2 hours, then the vessel contents were cooled to approximately 0°C and stirred at this temperature for a further 2 hours. The crystalline product from toluene/IMS was filtered and then dissolved in propan-2-ol (570 litres) at 65°C. Water was added (15 litres) followed by seeds of paroxetine hydrochloride hemihydrate (60 g). The solution was then cooled to 55°C and stirred for 3 hours at this temperature before being cooled to 0-5°C and stirred for a further 2 hours. The slurry was filtered and the solid washed with aqueous isopropyl alcohol and dried under vacuum at 35°C to give paroxetine hydrochloride hemihydrate free of catechol impurities. Example 2 Preparation of paroxetine hydrochloride by the resolution of (±) trans 4-(4'- fluorophenyI)-3-(3",4"-methylenedioxyphenoxymethyl)piperidine. i) (±) trans 4-(4'-fluorophenyl)-3-(3",4"-methylenedioxyphenoxymethyl) piperidine (1.0 g) was dissolved in methanol (10 ml) and added to a solution of L(-)-di-p-toluoyl tartaric acid (1.25g) in methanol (10 ml). The mixture was seeded and allowed to stand at room temperature and the crystalline product examined by chiral HPLC, using the following system: Chiral HPLC analysis confirmed that substantially pure (-) trans L(-)-di-p-toluoyl tartrate salt had been isolated. The salt may be further purified by recrystallisation from methanol. ii) (±) trans 4-(4'-fluorophenyl)-3-(3",4"-methylenedioxyphenoxymethyl) piperidine (0.50 g) was dissolved in acetonitrile (10 ml) and added to a solution of L(-)-dibenzoyl tartaric acid (0.65g) in acetonitrile (10 ml). The mixture was seeded and stirred at room temperature. The crystalline product was shown by chiral HPLC to be significantly enriched with the (-) trans dibenzoyl tartrate salt. iii) Paroxetine free base is liberated from the (-) trans 4-(4'-fluoro-phenyl)-3-(3",4"- methylenedioxyphenoxymethyl) piperidine di-p-toluoyl or dibenzoyl tartrate salt by stirring in a mixture of toluene and dilute aqueous sodium hydroxide. The phases are separated and the toluene phase washed with water. Concentrated aqueous hydrochloric acid is then added and the crystalline precipitate collected by filtration and dried.

Claims: CLAIMS 1. A process for the preparation of a compound of formula ( 1 ): or a pharmaceutically acceptable salt thereof, in which R ! is a substituted phenyl group, the process comprising hydrolysing a solution of a carbamate of formula (2) in which R 1 is as defined above and R 2 is a Cι -6 alkyl group, a C -6 cycloalkyl group, aralkyl group, phenyl or substituted phenyl group; with a base, which process comprises forming a finely divided complex of the base with the carbamate, and heating the complex in suspension in a solvent. A process as claimed in Claim 1 wherein the base is potassium hydroxide. 3. A process as claimed in Claim 1 or Claim 2 wherein between 3 and 10 equivalents of base are used, more preferably, between 6 and 8 equivalents. 4. A process as claimed in any one of Claims 1 to 3 wherein the solvent is toluene, benzene, or xylene, preferably toluene. 5. A process as claimed in any preceding claim wherein R 1 is 3,4- methylenedioxyphenyl. 6. A process as claimed in any preceding claim wherein R is phenyl. 7. A process for the preparation of finely divided complex derived from potassium hydroxide and a carbamate of formula (2) by heating a mixture of the carbamate and potassium hydroxide to a suitable temperature and then discontinuing the heating while stirring vigorously in a solvent. 8. A process according to claim 7 wherein the the reaction is carried out under anhydrous or dehydrating conditions. 9. A process as claimed in Claim 8 wherein the dehydrating conditions include removal of water by azeotropic distillation. 10. A process as claimed in any one claims 7 to 9 wherein the carbamate is 4-(4'- fluorophenyl)-3-(3",4"-methylenedioxyphenoxymethyl)-l-phenoxycarbonylpiperidine and the temperature is between 70 and 90°C. 11. A process as claimed in any one of claims 7 to 10 wherein the solvent is toluene. 12. A process as claimed in any one of Claims 2 to 6 wherein the base is KOH and the complex derived from the carbamate is prepared in situ in accordance with the process of any one of Claims 7 to 11. 13. A process as claimed in Claim 12 wherein water is removed by azeotropic distillation at reflux until the water content is less than 30%, preferably less than 20%, more preferably less than 10%. 14. A process as claimed in any one of the preceding Claims wherein the carbamate concentration on a weight/weight basis is between 4 and 10 %, preferably between 5.5 and 9%, most preferably between 6.5 and 8.0%). 15. A process as claimed in any one of the preceding Claims further comprising a subsequent step of a high temperature aqueous wash using water at a temperature of between 60 and 95°C, preferably between 70 and 80°C. 16. A process as claimed in Claim 15 wherein the aqueous wash uses a volume of water between A and 1/20 that of the solvent, preferably between 1/3 and 1/5. 17. A process as claimed in Claim 15 or Claim 16 wherein the step of an aqueous wash is preceded by a step of filtration. 18. A process for the crystallisation of a compound of formula (1) as a pharmaceutically acceptable salt, in which a co-solvent is added to a solution of the compound in toluene, benzene or xylene, and the solution is acidified, prior to crystallisation. 19. A process as claimed in Claim 18 wherein the co-solvent is an alcohol, ketone, ester or chlorinated hydrocarbon. 20. A process as claimed in Claiml9 wherein the co-solvent is an alcohol, preferably ethanol. 21. A process according to any one of claims 18 to 20 in which the co-solvent is added in a volume equivalent to between 2 o and / 60 of the volume of the toluene solution, preferably between V 30 and V 0 . 22. A process as claimed in any one of Claims 18 to 21 wherein following addition of the co-solvent, the solution is cooled to between 10 and 30°C, preferably between 15 and 25°C and optionally seeded. 23. A process as claimed in Claim 22 wherein seed crystals are added in an amount of between 0.05% and 1%, preferably about 0.1% by weight. 24. A process as claimed in any one of claims 18 to 23 for the preparation of a hydrochloride salt of a compound of formula (1) wherein following addition of cosolvent and, optionally, seeding, hydrochloric acid, preferably concentrated aqueous hydrochloric acid, is added in an amount in excess of the theoretical amount. 25. A process as claimed in Claim 24 wherein between 1.1 and 2 equivalents, preferably between 1.3 and 1.8 equivalents, more preferably about 1.7 equivalents of hydrochloric acid are added. 26. A process as claimed in Claim 24 or 25 wherein the acid is added rapidly with vigorous stirring. 27. A process as claimed in any one of Claims 24 to 26 further comprising the step of an aqueous alkali wash following the acidification step. 28. A process as claimed in Claim 27 wherein the alkali wash is carried out at an elevated temperature, preferably between 40 and 60°C, more preferably at about 50°C. 29. A process as claimed in Claim 27 or 28, wherein the alkali is sodium hydroxide. 30. A process as claimed in Claim 29 wherein the alkali wash step comprises adding heated water to the toluene solution in an amount of between 1/3 and % the volume of the toluene present and thereafter adding a concentrated solution of sodium hydroxide thereto such that the quantity of alkali added is between 5 and 10 equivalents, preferably between 6 and 8 equivalents. 31. A process as claimed in any one of Claims 27 to 30 wherein the alkali wash step is followed by a repeat step of addition of a co -solvent, optional seeding and acidification as described in any one of claims 18 to 26. 32. A process according to any one of claims 1 to 17, wherein the hydrolysis step is carried out in the absence of alcohols. 33. A process as claimed in claim 32 in which trace quantities of alcohols are reduced by first rinsing the reaction vessel with toluene and by washing the toluene phase with water. 34. A process as claimed in any one of the preceding Claims comprising a further step of recrystallisation from propan-2-ol containing between 1 and 10% water, preferably from 2 to 4% following isolation of the solid compound of formula (1). 35. A process as claimed in Claim 34 wherein between 5 and 10 parts by weight of propan-2-ol are used relative to solid product, preferably between 7 and 8 parts. 36. A process as claimed in Claim 34 or Claim 35 wherein the solid product is dissolved in the propan-2-ol at reflux, the solution is then cooled to between 50 and 60°C, preferably about 55°C, and seeded with about 1-5% by weight of the anticipated product as seed, following which, the mixture is left to crystallise before gradual cooling to 0°C. 37. A process for the removal of catechols from a solution of a compound of formula (1) comprising the step of an aqueous alkali wash. 38. A process as claimed in Claim 37 wherein the alkali wash is carried out at an elevated temperature, preferably between 40 and 60°C, more preferably at about 50°C. 39. A process as claimed in Claim 37 or 38, wherein the alkali is sodium hydroxide. 40. A process as claimed in Claim 39 wherein the alkali wash step comprises adding heated water to the solution in an amount of between 1/3 and V* the volume of the solvent present and thereafter adding a concentrated solution of sodium hydroxide thereto such that the quantity of alkali added is between 5 and 10 equivalents, preferably between 6 and 8 equivalents . 41. A process for preparation of (-)trα«.y-4-(4'-fluorophenyl)-3-(3",4"- methylenedioxyphenoxymethyl)piperidine that incorporates the process of any one of claims 1 to 40. 42. (-)tra«5-4-(4 , -fluorophenyl)-3-(3"',4"-methylenedioxy-phenoxymethyl)-piperidine whenever obtained by a process including the process of any one of claims 1 to 40. 43. (-)trα«5-4-(4'-fluorophenyl)-3-(3",4"-methylenedioxy-phenoxymethyl)-piperidine as claimed in claim 42, in the form of a hydrochloride salt. 44. A pharmaceutical composition for treatment or prophylaxis of the Disorders comprising a compound as claimed in claim 42 or 43 and a pharmaceutically acceptable carrier. 45. The use of a compound as claimed in claim 42 or 43 in the manufacture of a medicament for the treatment or prophylaxis of the Disorders. 46. A method of treating the disorders which comprises administering an effective or prophylactic amount of a compound as claimed in claim 42 or 43 to a person suffering from one or more of the Disorders.

Inventors: LUCAS EDWARD, LUCAS, EDWARD
Applicants: LUCAS EDWARD, SMITHKLINE BEECHAM PLC, LUCAS, EDWARD, SMITHKLINE BEECHAM P.L.C.
Application year: 2000
Main classification: C07D405
IPC codes: A61K31, A61P3, A61P15, A61P17, A61P25, C07D211, C07D405