PROCESS FOR THE PREPARATION OF AN ACETATE SALT OF PAROXETINE OR PAROXETINE ANALOGUES

Abstract: The present invention relates to a new process for the preparation of an acetate salt of a compound of formula (1) in which R<1> is a substituted phenyl group, preferably 3,4-methylenedioxyphenyl; the process comprising treating a solution of the compound of formula (1) with acetic acid and a co-solvent. The (-) trans isomer of 4-(4'-fluorophenyl)-3-(3',4'-methylenedioxyphenoxymethyl)-piperidine (paroxetine) is an important compound having antidepressant and anti-Parkinson properties. This compound is used in therapy as the hydrochloride salt to treat inter alia depression obsessive compulsive disorder (OCD) and panic.

Description: PROCESS FOR THE PREPARATION OF AN ACETATE SALT OF PAROXETINE OR PAROXETINE ANALOGUES The present invention relates to a new process 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"-methylenedioxyphenoxymethyl)piperidine. This compound is used in therapy as the hydrochloride salt to treat inter alia depression, obsessive compulsive disorder (OCD) and panic. In Example 2 of EP 0 223 403, an earlier application of the present applicant, paroxetine is obtained from a toluene solution via an intermediate aqueous solution of the acetate. In Example 8 of the same disclosure, solid paroxetine acetate is isolated by addition of an excess of acetic acid and diethyl ether to an ether solution of the free base. The use of diethyl ether is hazardous, particularly in a manufacturing environment, due to its very high flammability and potential for explosive residues, especially during drying procedures. Consequently, manufacturing scale operation would involve expensive precautions and specialised apparatus, adding greatly to operating and capital costs. Furthermore, diethyl ether is not a convenient solvent for the manufacture of paroxetine free base. In the literature, toluene is typically used to manufacture the free base, but a distillation step is required to isolate the base and as a result it is produced in the form of a heavy viscous syrup. This distillation step is an inconvenient additional process and adds further to the production costs. Accordingly, there is a need for a process for the preparation of acetate salts of paroxetine and its analogues which is suitable for large scale manufacture. In its broadest sense, the present invention provides a process for the preparation of an acetate salt of a compound of formula (1): in which R 1 is a substituted phenyl group, preferably 3,4-methylenedioxyphenyl; the process comprising treating a solution of the compound of formula (1) with acetic acid and a co-solvent. In one embodiment, the co-solvent is added to the solution of the compound of formula (1). The acetic acid is then added to the solution. In an alternative embodiment, the co-solvent and acetic acid are mixed together and then added to the solution of the compound of formula (1). Preferably, the co-solvent is selected from ethyl acetate, propan-2-ol, propan-1-ol, acetone, butanone, methylisobutyl ketone and ethanol. Ethyl acetate is particularly suitable. Typically, the solution of the compound of formula (1) is in toluene or tetrahydrofuran. Following preparation of the acetate salt, it may be recrystallised from alcohols, ketones, esters, acetic acid or ethers. Particularly suitable solvents include ethyl acetate, ethanol, propan-1-ol, propan-2-ol, acetone, butanone, and isobutylmethyl ketone, either alone or in combination. The recrystallisation step may include, as required, heating, for example including removal of water using Dean & Stark apparatus, treatment with activated charcoal, silica or similar substances used for the removal of impurities, filtration, concentration, cooling and seeding. Alternatively or additionally, the acetate may be isolated as a solid by evaporation, freeze-drying or spray-drying. Spray drying from organic solvents or from mixtures of water with organic solvents are preferred in order to achieve satisfactory drying below the glass point. A preferred procedure is evaporation or spray drying directly onto a solid support, particularly one of use as an excipient for the formation of tablets or capsules. 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 hemihydrate. As an alternative to isolating the hemihydrate, solvated, amorphous, or anhydrate products may be isolated according to previously disclosed procedures. Paroxetine acetate may be 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-O 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. The Reference Example describes two suitable methods of 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. Examples Preparative Example 1 Preparation of paroxetine acetate from toluene/propan-2-ol. A solution of paroxetine base in toluene (5 ml of a 0.42 g/ml solution), which had previously been dried with anhydrous magnesium sulphate, was diluted with propan- 2-ol (20 ml) and seeded with crystalline paroxetine acetate. Acetic acid was added and the solution stirred at approximately 20°C overnight. The resulting solid was collected by filtration to give paroxetine acetate as a white crystalline solid. Preparative Example 2 Preparation of paroxetine acetate. A mixture of (-)-trans-N-phenoxycarbonyl-4-(4'-fluorophenyl)-3-(3 ",4"- methylenedioxyphenoxymethyl)piperidine (5.0 kg) and potassium hydroxide flake (4.5 kg) in toluene (75.0 litres) was heated at reflux under a nitrogen atmosphere for four hours and then the mixture allowed to cool to 20-30°C. Water (50.0 litres) was added and the mixture stirred for 30 minutes and then allowed to settle for 30 minutes. The organic layer was separated, dried with magnesium sulphate (6.0 kg), stirred for 15 minutes and filtered. A solution of glacial acetic acid (0.67 kg) in ethyl acetate (15.0 litres) was added to the filtrate and the solution stirred at approximately 20°C for 30 minutes. The solution was then seeded with crystalline paroxetine acetate (10 g) and stirred for a further 1.5 hours. The resulting white crystalline solid was isolated by centrifugation, washed with ethyl acetate/toluene (volume ratio 1:5, 10 litres) and dried under vacuum at 40°C for 16 hours. Yield 2.8 Kg Preparative Example 3 Recrystallisation of paroxetine from propan-2-ol A suspension of paroxetine acetate (0.5 g), in propan-2-ol (5 ml) was heated to reflux with vigorous stirring to dissolve. The resulting solution was cooled to 0-5°C for 2 hours resulting in the formation of a white precipitate. The solid was collected by filtration, washed with propan-2-ol (1 ml) and dried in vacuo over phosphorous pentoxide to give paroxetine acetate. Paroxetine acetate was also recrystallised from propan-1-ol, acetone, butanone, and isobutylmethyl ketone by analogous procedures. Preparative Example 4 Paroxetine acetate (1 g) was dissolved in water (3 ml) with gentle heating. Isobutylmethyl ketone (15 ml) was added and the solution heated at reflux in a Dean and Stark apparatus until as much water as possible had been removed. The solution was then cooled to 0-5°C and a white crystalline precipitate formed. The solid was collected by filtration, washed with isobutylmethyl ketone and dried to give paroxetine acetate (0.84 g) as a granular white solid. Reference Example Preparation of paroxetine hydrochloride by the resolution of (±) trans 4-(4'- fluorophenyl)-3-(3",4"-methylenedioxyphenoxymethyl)piperidine. i) (±) trans 4-(4'-fluoropheny l)-3 -(3 " ,4 " -methylenedioxyphenoxymethy 1) 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 " -methy lenedioxyphenoxymethy 1) 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: O 00/39121 Claims 1. A process for the preparation of an acetate salt of a compound of formula ( 1 ) : in which R 1 is a substituted phenyl group, the process comprising treating a solution of the free base of formula (1) with acetic acid and a co-solvent. 2. A process as claimed in Claim 1 wherein the co-solvent is added to the solution of the compound of formula (1) followed by addition of the acetic acid. 3. A process as claimed in Claim 1 wherein the co-solvent and acetic acid are mixed together and then added to the solution of the compound of formula (1). 4. A process as claimed in any one of Claims 1 to 3 wherein the co-solvent is selected from ethyl acetate, propan-2-ol, propan-1-ol, acetone, butanone, methylisobutyl ketone and ethanol. 5. A process as claimed in Claim 4 wherein the co-solvent is ethyl acetate. 6. A process as claimed in any one of Claims 1 to 5 wherein the compound of formula ( 1 ) is in a toluene or tetrahydrofuran solution. 7. A process as claimed in any one of Claims 1 to 6 further comprising the step of recrystallisation from an alcohol, ketone, ester, or ether or from acetic acid; or a mixture thereof. 8. A process as claimed in Claim 7 comprising recrystallisation from ethyl acetate, ethanol, propan-1-ol, propan-2-ol, acetone, butanone, or isobutylmethyl ketone, or mixture thereof. 9. A process as claimed in any preceding claim further comprising the step of isolation of the solid by evaporation, freeze-drying or spray-drying. 10. A process as claimed in Claim 9 wherein the solid is isolated from an organic solvent; mixture of organic solvents; or mixture of water with one or more organic solvents. 11. A process as Claimed in Claim 9 or Claim 10 wherein the solid is isolated by evaporation or spray drying directly onto a solid support. 12. A process as claimed in any preceding claim wherein R is 3',4'- methylenedioxyphenyl. 13. A process for preparation of (-)tr< y-4-(4'-fluorophenyl)-3-(3",4"- methylenedioxyphenoxymethyl)piperidine that incorporates the process of any one of claims 1 to 12. 14. (-)trø«5-4-(4'-fluorophenyl)-3-(3",4"-methylenedioxyphenoxymethyl)- piperidine whenever obtained by a process including the process of any one of claims 1 to 13. O 00/39121 15. (-)trα«5-4-(4'-fluoropheny l)-3 -(3 " ,4 " -methylenedioxyphenoxymethyl)- piperidine as claimed in claim 14, in the form of a hydrochloride salt. 16. A pharmaceutical composition for treatment or prophylaxis of the disorders comprising a compound as claimed in claim 14 or 15 and a pharmaceutically acceptable carrier. 17. The use of a compound as claimed in claim 14 or 15 in the manufacture of a medicament for the treatment or prophylaxis of the disorders. 18. A method of treating the disorders which comprises administering an effective or prophylactic amount of a compound as claimed in claim 14 or 15 to a person suffering from one or more of the disorders.

Inventors: CRAIG ANDREW SIMON, JONES DAVID ALAN, MAN JOHN, CRAIG, ANDREW, SIMON, JONES, DAVID, ALAN, MAN, JOHN
Applicants: CRAIG ANDREW SIMON, JONES DAVID ALAN, MAN JOHN, SMITHKLINE BEECHAM PLC, CRAIG, ANDREW, SIMON, JONES, DAVID, ALAN, MAN, JOHN, SMITHKLINE BEECHAM P.L.C.
Application year: 1999
Main classification: C07D405
IPC codes: A61K31, A61P25, B01D9, C07D405, F26B5