WO2001029032A1

WO2001029032A1 - Process for the preparation of paroxetine

Info

Publication number: WO2001029032A1
Application number: PCT/GB2000/004066
Authority: WO
Inventors: David Crowe; Neal Ward; Andrew Stephen Wells
Original assignee: Smithkline Beecham Plc
Priority date: 1999-10-20
Filing date: 2000-10-20
Publication date: 2001-04-26
Also published as: GB9924882D0; AU1038501A; WO2001029032A8

Abstract

Three process schemes (1, 2, and 3) for a complete route to paroxetine starting from arecoline are disclosed.

Description

PROCESS FOR THE PREPARATION OF PAROXETINE

This invention relates to processes for the manufacture of paroxetine and pharmaceutically acceptable salts thereof which are suitable for large scale commercial operation.

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 ter alia depression, obsessive compulsive disorder (OCD) and panic.

Various processes have been described for the preparation of paroxetine, for example in US 4,007,196, EP 0219,934, EP 0223, 334, EP 223, 403, EP 0300,617 and Acta Chemica Scandinavica (1996) volume 50 page 164. A particularly useful starting material employed in processes described therein is the alkaloid arecoline (1)

In these processes, arecoline is used to prepare piperidines using a literature procedure (J.T. Plati, A.K Ingerman and W Wenner, Journal of Organic Chemistry (1957) Volume 22 pages 261-265). Plati et al describe the reaction of arecoline with phenyl magnesium bromide in diethyl ether to prepare l-methyl-3-carbomethoxy-4-phenyl piperidine. Thus in the process described in US-A-4007196, arecoline base is liberated from the hydrobromide salt and reacted with the Grignard reagent 4-fluorophenyl magnesium bromide using the procedure of Plati et al to give a piperidine ester of structure (2). This piperidine ester is converted to a piperidine carbinol of structure (3), which is coupled with sesamol, then deprotected. to give paroxetine (4).

Paroxetine is the (-) trans isomer of 4-(4'-fluorophenyl)-3-(3',4'-methylenedioxy- phenoxymethyl)-piperidine. The above described processes produce compounds of structure (2) as a mixture of enantiomers, and conversion of compounds of structure (2) to useful pharmaceuticals will normally require a resolution stage. Particularly useful forms of compounds (2) and (3) are thus compounds (A) and (B) which are in the (-) trans configuration:

(A) (B)

The prior art processes for the_ preparation of paroxetine (4) from arecoline (1) suffer from a number of disadvantages which render them unsuitable for large scale manufacture. In particular, the reaction of arecoline with the Grignard reagent is carried out in diethyl ether, and the resulting piperidine ester is extracted into ether and subsequently distilled under vacuum. These conditions are hazardous and unsuitable for lar^e scale manufacture of compounds of structure (2). We have also have found that the Plati procedure generates a thick unstirrable gel. and that this gel is not broken down by adding further diethyl ether.

Furthermore we have found that other ether solvents conventionally used in Grignard reactions, such as tetrahydrofuran or diisopropyl ether result in little if any of the desired 1 ,4-conjugate addition product, as the major product arises from attack of the Grignard reagent on the ester grouping (so called 1,2- addition).

We have discovered that the Plati et al procedure can be rendered suitable for large scale manufacture by varying the conditions under which the Grignard reagent is used, enabling the stirring problems to be overcome and the use of diethyl ether eliminated or significantly reduced.

In an unpublished patent application we disclose a process for the preparation of a compound of structure (5)

(5)

in which R and R' are independently an alkyl, aryl, or arylalkyl group, most suitably lower alkyl, which comprises reacting a compound of structure (6) where R and R' are as defined for structure (5)

R (6) with a Grignard reagent in a suitable non-ether reaction solvent, optionally in the presence of a proportion of an additional solvent.

The Grignard reagent may either be prepared in the chosen reaction solvent, or prepared in an ether solvent and the ether subsequently removed by distillation and replaced by the chosen solvent. When little or no additional solvent is employed, the Grignard reagent may be partially or completely insoluble, but the resulting reaction suspension is stirrable and compatible with large scale operation. When a significant proportion of suitable additional solvent is employed, a completely clear reaction solution may be obtained, rendering the process particularly suitable for industrial scale operation.

Surprisingly we have found that by using the above-described processes the reaction is more efficient, and the large excess of Grignard reagent specified by Plati (2 molar equivalents) can be significantly reduced without loss in yield. We have also found that the reaction is equally efficient if the order of addition of the reagents is reversed, i.e. the Grignard reagent is added to the tetrahydropyridine ester. A further advantage we have found is that the crude product is sufficiently pure to be carried forward to the next synthetic step without the need for the distillation specified by Plati.

Compounds of formula (6) may be prepared from the natural products guvacine, arecaidine or arecoline, by conventional methods, or by synthesis from other materials. A particularly convenient synthetic procedure involves the esterification, quaternisation and partial reduction of nicotinic acid [see for example Journal of Organic Chemistry (1955), volume 20, pages 1761-1765; Journal of Chemical Research (1983), volume 10, pages 2326 - 2342; Journal of Pharmaceutical Sciences (1992), volume 81, pages 1015 -1019; and references quoted therein].

Other methods for the preparation of compounds of structure (6) are given in Tetrahedron (1989) volume 45 pages 239-258, and Heterocycles ( 1990) volume 30 pages 885 - 896.

In a further unpublished patent application we propose an alternative procedure based on the finding that a mixture of crystalline arecoline hydrobromide in a suitable organic solvent may treated with a suitable anhydrous strongly basic reagent to generate a solution which may be reacted directly with the Grignard reagent. This process is higher yielding than the prior art process, has fewer processing steps, and exposure of operators to the toxic arecoline base is avoided. By comparison with arecoline base, the hazards associated with handling arecoline hydrobromide, which is a non-volatile crystalline solid and freely soluble in water, are greatly reduced. The process of this invention is therefore particularly suitable for large scale manufacture.

Hereinafter we describe processes for the preparation of paroxetine starting from arecoline or an arecoline analogue which are suitable for large scale manufacture. These processes proceed through an intermediate of formula (5) above, which is advantageously made by the above described process rather than the previously known process of Plati.

A procedure describing the conversion of a piperidine ester of structure (2) to paroxetine is described in US-A-4007196 whereby the initially formed piperidine methyl ester prepared by the Plati method is epimerised to the trans form, hydrolysed to the piperidine acid, converted to the acid chloride and reacted with (-) menthol to give the corresponding menthol ester. This menthol ester is distilled, converted to the hydrobromide salt and fractionally crystallised to give a single enantiomer. The resolved menthol ester is liberated from the salt and reduced with lithium aluminium hydride to give the (-) trans carbinol, compound (B), which is coupled with sesamol, then deprotected to give paroxetine. This multi-step process, while sufficient for investigational purposes, is not suitable for large scale manufacture.

A shorter procedure is described in the form of a flow chart in Acta Chemica Scandinavica (1996) volume 50 page 164, but few details of the conditions are supplied. The first part of this procedure is represented in Scheme ( 1), the (-) trans carbinol of structure (B) being converted to paroxetine by the further steps of coupling to sesamol, and deprotecting.

Scheme 1

Q (-) trans carbinol racemic trans carbinol

A procedure for carrying out Step 1 of Scheme 1 is described by J.T. Plati, A.K Ingerman and W Wenner, Journal of Organic Chemistry (1957) Volume 22 pages 261-265.

5 Procedures for carrying out Step 2 of Scheme 1 are described in Example 1 of US-A- 4007196 and Example 2 of EP 0219,934 A procedure for carrying out Step 3 of Scheme 1 is outlined on page 3 of EP 0219,934

Procedures for carrying out Step 4 of Scheme 1 are described in Examples 5 and 8 of EP 0223,334

We have developed an improved overall process for the preparation of paroxetine from arecoline following Scheme 1 which is more efficient, more convenient to operate, and is less hazardous than the prior art processes, and is particularly suitable for large scale manufacture.

Important features of this new, improved process are that it is streamlined, employing a common solvent over a number of chemical steps, and that it enables a solution of an intermediate produced from one step to be carried forward and employed directly in the next step without the need for further manipulation or switching of solvents.

Furthermore, the streamlined nature of the improved process enables one or more steps to be combined in a continuous operation in a single vessel.

Accordingly a first aspect of this invention provides a process for the large scale manufacture of paroxetine and pharmaceutically acceptable salts thereof from an arecoline derivative and a 4-fluorophenylmagnesium halide which comprises the steps

a) reacting a salt of an arecoline derivative of formula (6)

R (6) with a 4-fluorophenylmagnesium halide and extracting the racemic cis/trans piperidine ester of formula (5)

(5)

b) converting the cis/trans piperidine ester of formula (5) to the corresponding trans ester by epimerising with a strong base,

c) reducing the trans piperidine ester of formula (5) with a hydride reducing agent to obtain the corresponding (+/-) trans carbinol,

d) resolving the trans carbinol by use of a chiral acid, liberating and extracting the free base of the (-) trans carbinol,

e) forming a sulphonate ester of the (-) trans carbinol then coupling with sesamol to obtain an N-protected paroxetine,

f) deprotecting the N-protected paroxetine via formation of a carbamate, followed by hydrolysis to generate paroxetine base,

g) isolating the paroxetine base or forming a paroxetine salt by contacting the paroxetine base with a source of a preferably pharmaceutically acceptable acid, and isolating the salt.

More specifically, a particular embodiment of this aspect of the invention comprises

a) reacting an arecoline salt with a 4-fluorophenylmagnesium halide, optionally isolating the intermediate arecoline base, extracting and optionally isolating cis/trans l-methyl-3- carbomethoxy-4-(4'-fluorophenyl) piperidine, b) converting cis/trans l-methyl-3-carbomethoxy-4-(4'- fluorophenyl) piperidine to the corresponding trans ester by epimerising with a strong base, with optional isolation of the trans ester,

c) reducing trans l-methyl-3-carbomethoxy-4-(4'- fluorophenyl) piperidine with a hydride reducing agent and optionally isolating the trans carbinol, that is trans-4-(4 - fluorophenyl)-3-hydroxymethyl- 1 -methylpiperidine,

d resolving the trans carbinol by use of a chiral acid, liberating, extracting and optionally isolating the free base of the (-) trans carbinol,

e) forming and optionally isolating a sulphonate ester of the (-) trans carbinol then coupling with sesamol, and optionally isolating the resulting N-protected paroxetine,

f) deprotecting the N-protected paroxetine via formation and optional isolation of a carbamate, followed by a hydrolysis reaction, generating and optionally isolating paroxetine base,

g) forming a paroxetine salt by contacting the paroxetine base with a source of a pharmaceutically acceptable acid, optionally converting to a second paroxetine salt, and isolating drying and optionally recrystallising the final product.

Preferably two or more of the steps are carried out in a common reaction solvent, optionally with one or more additional solvents, and optionally combining one or more of the steps a) to g).

The compound of formula (6) is most conveniently arecoline. Suitable arecoline salts at step a) are the hydrobromide and hydrochloride. A preferred arecoline salt is the hvdrobromide. Suitable 4-fluorophenylmagnesium halides at step a) are 4-fluorophenylmagnesium bromide and 4-fluorophenylmagnesium chloride. A preferred halide is the bromide.

Suitable strong bases at step b) include sodium methoxide, sodium ethoxide and potassium tert-butoxide. A preferred strong base is sodium methoxide.

A preferred hydride reducing agent at step c) is lithium aluminium hydride.

Suitable chiral acids at step d) include dibenzoyl tartaric acid, ditoluoyl tartaric acid and nitrotartranilic acid. A preferred chiral acid is (-) ditoluoyl tartaric acid.

Suitably the resolved product is liberated at step d) using a basic reagent such as aqueous sodium carbonate, aqueous sodium hydroxide, and the corresponding potassium salts.

Suitable sulphonate esters at step e) include those formed from the carbinol by reaction with methane sulphonyl chloride, benzene sulphonyl chloride or 4-toluene sulphonyl chloride.

Suitable carbamates at step f) include those formed by heating the N-protected paroxetine with ethyl chloroformate or phenyl chloroformate A preferred carbamate is the phenyl carbamate. Suitably the carbamate is hydrolysed by heating with potassium hydroxide.

Suitable pharmaceutically acceptable acids at step g) include acetic acid, maleic acid, methane sulphonic acid and hydrochloric acid. Preferred acids are methane sulphonic acid and hydrochloric acid.

Suitable reaction solvents include dichloromethane and toluene. A preferred reaction solvent is toluene.

Suitable additional solvents include those which increase solubility, selectivity or reactivity, such as ether, tetrahydrofuran, acetone, dimethyl formamide, methanol, ethanol or propan-2-ol. A particularly useful feature of an additional solvent is that it may be effectively removed during processing, for example by reason of volatility or aqueous solubility, allowing the reaction stream in the preferred reaction solvent to be carried forward to the next manufacturing step.

The nature of the additional solvent is dependant on the individual chemical step. Thus a preferred additional solvent for the reaction of arecoline with a Grignard reagent is diethyl ether as this solvent selectively promotes the desired 1 ,4 addition reaction of the Grignard reagent to arecoline.

A preferred additional solvent for the reduction of the trans piperidine ester to the trans carbinol is tetrahydrofuran, as this solubilises the hydride reducing agent.

A preferred additional solvent for the resolution step is acetone, as this promotes efficient crystallisation of the desired optical isomer of the salt of the trans carbinol with the chiral acid.

A preferred additional solvent for the reaction of the (-) trans carbinol with sesamol is dimethyl formamide as this promotes the coupling reaction.

Preferred additional solvents for the preparation of paroxetine mesylate or paroxetine hydrochloride hemihydrate are ethanol or propan-2-ol, as these solvent promote an efficient crystallisation.

Preferred additional solvents for the preparation of paroxetine hydrochloride anhydrate Form A are propan-2-ol or acetone, as these solvents promote the formation of paroxetine hydrochloride solvates, which may be de-solvated to give paroxetine hydrochloride anhydrate Form A using procedures described in WO96/24595.

We have also found that (-) trans-4-(4'-fluorophenyl)-3-hydroxymethyl-l- methylpiperidine (B) may be prepared from arecoline by an alternative sequence of steps involving the formation and reduction of (-) trans l-methyl-3-carbomethoxy-4-(4'- fluorophenyl) piperidine (A), and employed in the synthesis of paroxetine. Such a process is outlined in Scheme 2

(-) trans carbinol (-) trans ester

A procedure for carrying out Step 1 of Scheme 2 is described by J.T. Plati, A.K Ingerman and W Wenner, Journal of Organic Chemistry (1957) Volume 22 pages 261-265.

Procedures for carrying out Step 2 of Scheme 2 are described in Example 1 of US-A- 4007196 and Example 2 of EP 0219,934

An outline method for the chemical resolution of trans l-methyl-3-carbomethoxy-4-(4'- fluorophenyl) piperidine (Step 3 of Scheme 2) using unspecified optical forms of mandelic acid or dibenzoyl tartaric acid has been described in the literature in the form of a flowchart [Acta Chemica Scandinavica (1996) volume 50 page 164], but no details of the conditions are given. The same flowchart outlines the reduction of the (-) trans ester (A) to the (-) trans carbinol (B), step 4 of Scheme 2.

We have made numerous attempts carry out this resolution procedure but have been unable to obtain any crystallise salts using either mandelic acid or dibenzoyl tartaric acid in a wide range of organic solvents. In addition, no chemical or physical properties for the individual (+) and (-) optical isomers of trans l-methyl-3-carbomethoxy-4-(4'- fluorophenyl) piperidine or analogous trans compounds of structure (5) have been reported, either as salts or in the free base form.

We therefore conclude that no workable process for obtaining (-) trans l-methyl-3- carbomethoxy-4-(4'-fluorophenyl) piperidine (A) or analogous resolved trans compounds of structure (5) is available in the prior art.

We have surprisingly found that the desired (-) form of a trans ester of structure (5) can be prepared by enzymatic resolution of a racemic trans ester of structure (5), enabling paroxetine to be manufactured from arecoline by the steps outlined in Scheme 2.

Accordingly in a second aspect of this invention we provide a process for the large scale manufacture of paroxetine and pharmaceutically acceptable salts thereof from an arecoline derivative and a 4-fluorophenylmagnesium halide which comprises the steps

a) reacting a salt of an arecoline derivative of formula (6)

R (6) with a 4-fluorophenylmagnesium halide and extracting the cis/trans piperidine ester of formula (5)

(5)

b) converting cis/trans piperidine ester of formula (5) to the corresponding trans ester by epimerising with a strong base,

c) enzymatic resolution of the trans piperidine ester to give the (-) trans piperidine ester,

d) reducing the (-) trans piperidine ester with a hydride reducing agent to obtain the corresponding (-) trans carbinol,

e) forming a sulphonate ester of the (-) trans carbinol then coupling with sesamol, to obtain an N-protected paroxetine,

More specifically, a particular embodiment of this aspect of the invention comprises a) reacting an arecoline salt with a 4-fluorophenylmagnesium halide, optionally isolating the intermediate arecoline base, extracting and optionally isolating cis/trans l-methyl-3- carbomethoxy-4-(4 -fluorophenyl) piperidine,

b) epimerising the cis/trans l-methyl-3-carbomethoxy-4-(4 '-fluorophenyl) piperidine to the corresponding trans ester with a strong base, with optional isolation of the trans ester.

c) enzymatic resolution of the trans ester to give the (-) trans ester, liberating, extracting and optionally isolating the (-) trans ester,

d) reducing (-) trans l-methyl-3-carbomethoxy-4-(4 -fluorophenyl) piperidine with a hydride reducing agent and optionally isolating the (-) trans carbinol, that is (-) trans-4- (4'-fluorophenyl)-3-hydroxymethyl- 1 -methylpiperidine,

The compound of formula (6)js most conveniently arecoline. Suitable arecoline salts at step a) are the hydrobromide and hydrochloride. A preferred arecoline salt is the hydrobromide.

Suitable 4-fluorophenylmagnesium halides at step a) are 4-fluorophenylmagnesium bromide and 4-fluorophenylmagnesium chloride. A preferred halide is the bromide. Suitable strong bases at step b) include sodium methoxide, sodium ethoxide and potassium tert-butoxide. A preferred strong base is sodium methoxide.

At step c), the chosen enzyme may selectively hydrolyse the unwanted (+) trans isomer to the corresponding acid, which may be removed by a conventional extraction, for example with an aqueous base, leaving the desired (-) trans isomer as the ester for further processing.

Alternatively, the chosen enzyme may selectively hydrolyse the desired (-) trans isomer of the ester to the corresponding (-) trans acid, compound (C)

ns

(C) which is recovered by extraction with an aqueous base, and re-esterified to give the (-) trans ester. The (+) trans ester is unaffected by the enzyme treatment and may be recovered from the organic phase of this extraction.

In a particularly useful alternative aspect, the (-) trans acid of formula (C) is reduced directly to the desired (-) trans carbinol, for example with a borohydride reducing agent, thus avoiding the re-esterification step.

Suitable enzymes for selective hydrolysis at step c) include Porcine liver esterase (PLE), Subtilisin Carlsberg, Subtilisin BPN, Pig liver acetone powder, Bovine liver acetone powder and Horse liver acetone powder.

Suitable solvents for the enzymatic resolution include aqueous N,N'-dimethyl formamide and aqueous dimethyl sulphoxide. A preferred hydride reducing agent at step d) is lithium aluminium hydride.

Suitable additional solvents include those which increase solubility, selectivity or reactivity, such as ether, tetrahydrofuran, acetone, dimethyl formamide, methanol. ethanol or propan-2-ol. A particularly useful feature of an additional solvent is that it may be effectively removed during processing, for example by reason of volatility or aqueous solubility, allowing the reaction stream in the preferred reaction solvent to be carried forward to the next manufacturing step.

A preferred additional solvent for the reduction of the trans piperidine ester to the trans carbinol is tetrahydrofuran, as this solubilises the hydride reducing agent. A preferred additional solvent for the reaction of the (-) trans carbinol with sesamol is dimethyl formamide as this promotes the coupling reaction.

We have also surprisingly found that the desired (-) trans ester of structure (A) can be obtained from a racemic cis ester of structure (5) by a novel procedure which comprises resolution of the racemic cis ester to give the (+) cis form, followed by reaction with a strong base. In this process inversion of configuration occurs, providing, for example, the (-) trans ester (A) in good yield in high optical purity, suitable for reduction to the (-) trans form of the carbinol, compound (B). The resolution may be carried out, for example, via the formation of a salt with a chiral acid.

This enables paroxetine to be manufactured from arecoline by the steps outlined in Scheme 3.

(-) trans carbinol (-) trans ester

A procedure for carrying out Step 1 of Scheme 3 is described by J.T. Plati. A.K Ingerman and W Wenner, Journal of Organic Chemistry (1957) Volume 22 pages 261-265.

An outline method for the reduction of the (-) trans ester (A) to the (-) trans carbinol (B), step 4 of Scheme 3, has been described in the literature in the form of a flowchart [Acta Chemica Scandinavica (1996) volume 50 page 164], but no details of the conditions are given.

Steps 2 and 3 of Scheme 3 have not previously been described.

We have surprisingly found that the cis/trans mixture of esters of structure (5) which are produced by the reaction of a Grignard reagent with a compound of structure (6) can be used directly in these resolution procedures. Accordingly in a third aspect of this invention we provide a process for the large scale manufacture of paroxetine and pharmaceutically acceptable salts thereof from an arecoline derivative and a 4-fluorophenylmagnesium halide which comprises the steps

a) reacting a salt of an arecoline derivative of formula (6)

with a 4-fluorophenylmagnesium halide and extracting the racemic cis/trans piperidine ester of formula (5)

(5)

b) converting the cis/trans piperidine ester to the (+) cis ester, and liberating the (+) cis ester,

c) epimerising the (+) cis piperidine ester with a strong base to form the corresponding (-) trans piperidine ester,

d) reducing (-) trans piperidine ester with a hydride reducing agent and to obtain the corresponding (-) trans carbinol,

e) forming a sulphonate ester of the (-) trans carbinol then coupling with sesamol, to obtain an N-protected paroxetine, f) deprotecting the N-protected paroxetine via formation of a carbamate, followed by hydrolysis to generate paroxetine base,

a) reacting an arecoline salt with a 4-fluorophenylmagnesium halide, optionally isolating the intermediate arecoline base, extracting and optionally isolating cis/trans l-methyl-3- carbomethoxy-4-(4 -fluorophenyl) piperidine,

b) converting cis/trans l-methyl-3-carbomethoxy-4-(4 '-fluorophenyl) piperidine to the (+) cis ester, liberating and optionally isolating the (+) cis ester as a crystalline solid,

c) epimerising the (+) cis ester with a strong base to form the corresponding (-) trans ester, with optional isolation of the (-) trans ester,

d) reducing (-) trans l-methyl-3-carbomethoxy-4-(4 -fluorophenyl) piperidine with a hydride reducing agent and optionally isolating the (-) trans carbinol, that is (-) trans-4- (4'-fluorophenyl)-3-hydroxymethyl-l -methylpiperidine,

f) deprotecting the N-protected paroxetine via formation and optional isolation of a carbamate. followed by a hydrolysis reaction, generating and optionally isolating paroxetine base, g) forming a paroxetine salt by contacting the paroxetine base with a source of a pharmaceutically acceptable acid, optionally converting to a second paroxetine salt, and isolating drying and optionally recrystallising the final product.

The compound of formula (6) is most conveniently arecoline. Suitable arecoline salts at step a) are the hydrobromide and hydrochloride. A preferred arecoline salt is the hydrobromide.

Suitable 4-fluorophenylmagnesium halides at step a) are 4-fluorophenylmagnesium bromide and 4-fluorophenylmagnesium chloride. A preferred halide is the bromide.

Suitable chiral acids at step b) are dibenzoyl tartaric acid, ditoluoyl tartaric acid and nitrotartranilic acid. However, we have found that crystallisation of chiral acid salts of the cis-ester at Step 2 gives unpredictable results, so the chiral acid must be selected with care. For example, when crystallised from methanol, the salt generated from (-) dibenzoyl tartaric acid produces the desired (+) cis ester, whereas the corresponding (-) ditoluoyl tartaric acid gives the unwanted (-) cis isomer. Preferred chiral acids are (-) dibenzoyl tartaric acid and (+) ditoluoyl tartaric acid.

Suitable strong bases at step c) include sodium methoxide, sodium ethoxide and potassium tert-butoxide. A preferred strong base is sodium methoxide.

A preferred hydride reducing agent at step d) is lithium aluminium hydride.

Suitable sulphonate esters at step e) include those formed from the carbinol by reaction with methane sulphonyl chloride, benzene sulphonyl chloride or 4-toluene sulphonyl chloride. Suitable carbamates at step f) include those formed by heating the N-protected paroxetine with ethyl chloroformate or phenyl chloroformate A preferred carbamate is the phenyl carbamate. Suitably the carbamate is hydrolysed by heating with potassium hydroxide.

A suitable additional solvent for the resolution with a chiral acid is methanol.

A preferred additional solvent for the reduction of the (-) trans piperidine ester to the (-) trans carbinol is tetrahydrofuran, as this solubilises the hydride reducing agent.

A preferred additional solvent for the reaction of the (-) trans carbinol with sesamol is dimethyl formamide as this promotes the coupling reaction. Preferred additional solvents for the preparation of paroxetine mesylate or paroxetine hydrochloride hemihydrate are ethanol or propan-2-ol, as these solvent promote an efficient crystallisation.

Preferred additional solvents for the preparation of paroxetine hydrochloride anhydrate Form A are propan-2-ol or acetone, as these solvents promote the formation of paroxetine hydrochloride solvates. which may be de-solvated to give paroxetine hydrochloride anhydrate Form A using procedures described in WO96/24595.

The processes which proceed via Schemes 2 and 3 share the same advantageous features as those outlined for the process which proceeds via Scheme 1, with an additional advantage of significance in the cost of manufacture. As the resolution step is carried out before the hydride reduction step in Schemes 2 and 3. only half the hydride reducing agent is required, compared with operating via Scheme 1

The present invention includes within its scope the compound paroxetine as the base, and also particularly as paroxetine mesylate or paroxetine hydrochloride, especially paroxetine hydrochloride anhydrate or paroxetine hydrochloride hemihydrate, when obtained via any aspect of this invention.

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 mesylate or 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". Most suitably the paroxetine products obtainable by the present invention is applied to the treatment of depression, OCD and panic.

Compositions containing paroxetine products prepared in accordance with this invention are usually adapted for oral administration, but formulations for dissolution for parental administration are also within the scope of this invention.

The composition is usually presented as a unit dose composition containing from 1 to 200mg of active ingredient calculated on a free base basis, more usually from 5 to 100 mg, for example 10 to 50 mg such as 10, 12.5, 15, 20, 25, 30 or 40 mg by a human patient. Most preferably unit doses contain 20 mg of active ingredient calculated on a free base basis. Such a composition is normally taken from 1 to 6 times daily, for example 2, 3 or 4 times daily so that the total amount of active agent administered is within the range 5 to 400 mg of active ingredient calculated on a free base basis. Most preferably the unit dose is taken once a day.

Preferred unit dosage forms include tablets or capsules, including formulations adapted for controlled or delayed release.

The compositions of this invention may be formulated by conventional methods of admixture such as blending, filling and compressing. Suitable carriers for use in this invention include a diluent, a binder, a disintegrant, a colouring agent, a flavouring agent and/or preservative. These agents may be utilized in conventional manner, for example in a manner similar to that already used for marketed anti-depressant agents.

Specific examples of pharmaceutical compositions include those described EP-B- 0223403, and US 4,007, 196 in which the anhydrate product of the present invention may be used as the active ingredient.

Accordingly, the present invention also provides: a pharmaceutical composition for treatment or prophylaxis of the Disorders comprising paroxetine or paroxetine mesylate 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 mesylate 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.

Analytical Procedures

The cis and trans piperidine compounds of this invention can be readily distiguished by conventional analytical techniques such as HPLC and NMR.

The optical activity of the piperidine compounds of this invention may be determined in a suitable solvent, such as methanol, using a conventional polarimeter. The ratio of (+) and (-) isomers may be determined by chiral HPLC, or preferably by chiral capillary electrophoresis (CCE). A review entitled "Separation of optically active pharmaceuticals using capillary electrophoresis" by TJ. Ward, and K. D. Ward has been published in Chem. Anal. (N. Y.) (1997), volume 142 pages 317-344.

Example 1

Use of arecoline hydrobromide and sodium hydride in the preparation of cis/trans 1- methyl-3-carbomethoxy-4-(4'-fluorophenyl)-piperidine

A 60% dispersion of sodium hydride in mineral oil (2.0 g) is added carefully to a suspension of arecoline hydrobromide (1 1.8 g) in toluene and the mixture cooled to about -10°C. A solution of 4-fluorophenylmagnesium bromide in diethyl ether (2.0M, 50 ml) is added slowly with stirring under argon, maintaining the temperature at about - 10°C, and the mixture is stirred at this temperature for 3 hours

The reaction is quenched by adding 2M hydrochloric acid (250 ml). The aqueous layer is washed with toluene (100 ml) then covered with fresh toluene (100 ml) and ad_justed to pH 9-10 by the cautious addition of anhydrous potassium carbonate. The precipitated solids are removed by filtration, the phases are separated and the aqueous phase is extracted twice more with toluene (100 ml). The combined toluene layers are washed with saturated aqueous sodium chloride (100 ml) and partially evaporated at atmospheπc or reduced pressure to give an anhydrous toluene solution of cis/trans l-methyl-3- carbomethoxy-4-(4'-fluorophenyl) piperidine.

If a solvent-free product is desired, the toluene solution may be further distilled at atmospheric or reduced pressure until no more solvent can be removed, to give cis/trans l-methyl-3-carbomethoxy-4-(4'-fluorophenyl) piperidine as an oily solid.

A yield of about 10 g is obtained.

Example 2 Preparation of cis/trans l-methyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine in toluene (Step 1 Schemes 1, 2, and 3)

A 2 molar solution of 4-fluorophenylmagnesium bromide in diethyl ether (5 ml, 2 molar equivalents) is diluted with toluene (5 ml) and heated under nitrogen until the ether has been removed. The resulting suspension is cooled to ca -5 °C and treated with a solution of arecoline (0 78 g) in toluene (4 5 ml) over 15 minutes The mixture is stirred at -5 °C for 1 hour, then quenched by the addition of a mixture of water (25 ml) and concentrated hydrochloric acid (3 ml) Analysis of the aqueous phase by HPLC shows that yield of cis/trans l-methyl-3-carbomethoxy-4-(4-fluorophenyl)-pιpeπdιne is about 880 mg (70 %) Example 3

Preparation of trans l-rnethyI-3-carbomethoxy-4-⁽4'-fluorophenyl)-piperidine

(Steps 1 and 2, Schemes 1 and 2)

i) A solution of arecoline base (25.0 g) in dichloromethane (160 ml) is added to a stirred solution of 4-fluorophenylmagnesium bromide in diethyl ether (97 ml, 2.0 molar, 1.2 equivalents) over 45 minutes at -5 to -10 °C under nitrogen. After completion of the addition, the mixture is stirred at -5 °C for 1 to 2 hours, then quenched by the addition of saturated aqueous ammonium chloride (300 ml).

Further dichloromethane (100 ml) is added, the phases are separated, and the aqueous phase further extracted with dichloromethane (2 x 250 ml). The organic solutions are combined, washed with saturated sodium chloride (50 ml) and partially evaporated at atmospheric or reduced pressure to give an anhydrous dichloromethane solution of cis/trans 1 -methyl-3-carbomethoxy-4-(4'-fluorophenyl) piperidine.

If a solvent-free product is desired, the dichloromethane solution may be further distilled at atmospheric or reduced pressure until no more solvent can be removed, to give cis/trans l-methyl-3-carbomethoxy-4-(4'-fluorophenyl) piperidine as an oily solid.

A yield of about 32 g is obtained.

Piperidine ester made in this way has a cis/trans ratio, measured by HPLC or NMR analysis, of about 2.2: 1

ii) A solution of arecoline base (15.54 g) in toluene (82 ml) is added to a stirred solution of 4-fluorophenylmagnesium bromide in diethyl ether (60 ml, 2.0 molar, 1.2 equivalents) over 35 minutes at -5°C under nitrogen. After completion of the addition, the mixture is stirred at -5 °C for 1 to 2 hours, then quenched by the addition of saturated aqueous ammonium chloride (200 ml) The phases are separated, and the aqueous phase further extracted with toluene (2 x 100 ml). The organic solutions are combined, washed with saturated sodium chloride (50 ml) and partially evaporated at atmospheric or reduced pressure to give an anhydrous toluene solution of cis/trans l-methyl-3-carbomethoxy-4-(4 '-fluorophenyl) piperidine.

A yield of about 22 g is obtained.

Piperidine ester made in this way has a cis/trans ratio, measured by HPLC or NMR analysis, of about 2.9: 1

in) A nitrogen purged vessel is charged with a solution of cis/trans l-methyl-3- carbomethoxy-4-(4'- fluorophenyl) piperidine (115 g) in toluene (1000 ml) and sodium methoxide (8.0 g) is added. The mixture is stirred and heated to the reflux temperature and the progress of the reaction is monitored by HPLC analysis. When the epimerisation is complete (about 3 hours) the vessel is cooled to 20°C, water (200 ml) is added, the mixture stirred thoroughly, then the lower aqueous phase is separated and discarded. This step is repeated, then 100 ml of toluene is removed by distillation of the organic phase at atmospheric or reduced pressure to give an anhydrous toluene solution of trans 1-methyl- 3-carbomethoxy-4-(4'-fluorophenyl) piperidine.

If a solvent-free product is desired, the toluene solution may be further distilled under reduced pressure until no more solvent can be removed, to give trans l-methyl-3- carbomethoxy-4-(4'-fluorophenyl) piperidine as an oil

A yield of about 107 g is obtained Example 4

Preparation of trans-4-(4'-fluorophenyl)-3-hydroxymethyl-l-methylpiperidine

(Step 3 Scheme 1)

A solution of trans- l-methyl-3-carbomethoxy-4-(4 '-fluorophenyl) piperidine (47.3g) in toluene (400 ml) is added dropwise over about 20 minutes to a nitrogen purged vessel containing lithium aluminium hydride in tetrahydrofuran (1.0 molar, 200 ml) maintaining a temperature of less than 10°C throughout the addition. The mixture is stirred at ambient temperature for about 2 hours, then quenched by the cautious addition of water (35 ml) followed by 10% aqueous sodium hydroxide solution ( 10 ml). The precipitated solids are removed by filtration through celite and washed with toluene (2 x 100 ml). The toluene solutions are combined, washed with saturated sodium chloride (50 ml) and partially evaporated at atmospheric or reduced pressure to give an anhydrous toluene solution of trans-4-(4'-fluorophenyl)-3-hydroxymethyl-l -methylpiperidine.

If a solvent-free product is desired, the toluene solution may be further distilled at atmospheric or reduced pressure until no more solvent can be removed, to give trans-4- (4'-fluorophenyl)-3-hydroxymethyl-l -methylpiperidine as a crystalline solid.

A yield of about 39 g is obtained.

Example 5

Preparation of (-) trans 4-(4'-fluorophenyl)-3-hydroxymethyl-l-methylpiperidine

(Step 4 Scheme 1)

i) A warm solution of trans-4-(4'-fluorophenyl)-3-hydroxymethyl- 1 - methylpiperidine (10.0 g) in toluene (75 ml) is added to a solution of L(-)-di-p-toluoyl tartaric acid (22.5g) in acetone (75 ml), and the stirred mixture allowed to cool slowly to ambient temperature then held at 0°C for 1 hour. The crystals of (-) trans 4-(4'- fluorophenyl)-3-hydroxymethyl- 1 -methylpiperidine L(-)-di-p-toluoyl tartrate are collected by filtration, washed with acetone and dried. A yield of about 12.5 g is obtained.

ii) (-) trans 4-(4'-fluorophenyl)-3-hydroxymethyl-l -methylpiperidine L(-)-di-p-toluyl tartrate (12.0 g) is stirred in toluene (240 ml) and water (120 g) and 10% aqueous sodium hydroxide (25 ml) is added to dissolve the salt. The phases are separated, the toluene solution optionally washed with saturated sodium chloride solution (50 ml) and partially evaporated at atmospheric or reduced pressure to give an anhydrous toluene solution of (- ) trans 4-(4'-fluorophenyl)-3-hydroxymethyl-l -methylpiperidine.

If a solvent-free product is desired, the toluene solution may be further distilled at atmospheric or reduced pressure until no more solvent can be removed, to give (-) trans-4-(4'-fluorophenyl)-3-hydroxymethyl- l -methylpiperidine as a crystalline solid, which may be further purified by recrystallisation

A yield of about 4 g is obtained.

Example 6

Enzymatic resolution of trans-l-methyI-3-carbomethoxy-4-(4'-fluorophenyl)- piperidine (Step 3 of Scheme 2)

i) Racemic trans- l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)-piperidine (1.0 g) is dissolved in N,N'-dimethylformamide (3 ml), then added to water (30 ml) and the pH adjusted to 7.00 with 1.0 molar hydrochloric acid. Commercial Porcine Liver Esterase suspension (0.3 ml) is added and the mixture stirred at 25 C, maintaining the pH at 7.00 by the addition of dilute aqueous ammonia. After 6 hours, dichloromethane (60 ml) is added and the mixture is filtered through celite. The aqueous phase is adjusted to pH 8.0 with aqueous ammonia and the dichloromethane layer is separated and evaporated under reduced pressure to give (+) trans- l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)- piperidine as an oil. A yield of about 0.5 g is obtained.

Optical rotation [α]_D ca. +36 ° (c =1, methanol)

ii) The aqueous phase is evaporated under reduced pressure to give (-) trans- 1- methyl-4-(4'-fluorophenyl)piperidine-carboxylic acid as a white solid. (Chiral capillary electrophoresis shows the trans acid to have a ratio of (-) trans to (+) trans of about 96:4) This is stirred in a mixture of methanol (15 ml) and tetrahydrofuran (15 ml) then trimethylsilyldiazomethane (1.6 ml of a 2 molar solution in hexane) is added. The reaction is stirred for 2 hours at room temperature then quenched with a few drops of acetic acid. The solvents are removed by evaporation under reduced pressure and the resulting oil is dissolved in a mixture of dichloromethane (30 ml) and water (30 ml). The pH is adjusted to 8.5 with dilute aqueous ammonia, the dichloromethane layer is separated, washed with water (30 ml), dried over sodium sulphate, and the solvent evaporated to leave the (-) trans- l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)-piperidine as an oil.

A yield of about 0.35g is obtained

Chiral capillary electrophoresis shows the trans ester to have a ratio of (-) trans to (+) trans of about 95:5

Example 7

Resolution of cis-l-methyl-3-carbomethoxy-4-(4'-fluorophenyI)-piperidine (Step 2 of Scheme 3)

i) A solution of cis/trans- 1 -methyl-3-carbomethoxy-4-(4 '-fluorophenyl) piperidine

(20 g) in acetone (100 ml) is mixed with a solution of (-)-dibenzoyl-L-tartaric acid monohydrate (30 g) in acetone (50 ml). The clear solution is stored at 5"C for 24 hours, then diluted with acetone (50 ml). The crystals of cis -l-methyl-3-carbomethoxy-4-(4'- fluorophenyl) piperidine (-)-dibenzoyl-L-tartrate are collected by filtration, washed with acetone (2 x 25ml) and dried under vacuum. NMR analysis confirms that only the salt of the cis-form has crystallised. Analysis by chiral capillary electrophoresis shows that ratio of (+) cis to (-) cis is approximately 1: 1.

ii) Cis- 1 -methyl-3-carbomethoxy-4-(4'-fluorophenyl)piperidine (-)-dibenzoyl-L- tartrate ( 15.0g) is dissolved in hot methanol (100 ml) the solution allowed to cool to room temperature, then stored at 5°C for 3 days. The crystals of (+) cis -l-methyl-3- carbomethoxy-4-(4 -fluorophenyl) piperidine (-)-dibenzoyl-L-tartrate are collected by filtration, washed with acetone (10 ml) and dried under vacuum.

Chiral capillary electrophoresis shows the salt to have a ratio of (+) cis to (-) cis of about 96:4

iii) (+) cis-l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)piperidine (-)-dibenzoyl-L- tartrate (1.5g) is suspended in a mixture of ethyl acetate (30 ml) and water (15 ml), and 10%w/w aqueous sodium hydroxide (5 ml) is added. The layers are separated and the aqueous layer extracted again with ethyl acetate (50 ml). The combined organic layers are dried over magnesium sulphate, filtered, and the ethyl acetate removed by evaporation under reduced pressure to give (+) cis- l-methyl-3-carbomethoxy-4-(4'- fluorophenyl) piperidine as a white solid.

A yield of about 0.6 g is obtained, having the following properties:

N.M.R δ (CDC13) - 7.25 (m, 2H), 6.95 (m, 2H), 3.51 (s, 3H, methyl ester), 3.15 (m, IH), 2.96 (m, 2H), 2.80 (m, IH), 2.65 (m, IH), 2.35 (m, IH), 2.28 (s, 3H), 2.10 (m, IH), 1.80 (m, IH)

Optical rotation [α]²⁶ _D ca. +36 ° (c = 1 , methanol)

Example 8 Conversion of (+)cis-l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)-piperidine. to (-) trans -l-methyI-3-carbomethoxy-4-(4'-fluorophenyl)-piperidine (Step 3 of Scheme 3)

(+)-cis-l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)piperidine (0.35g) is dissolved in dry toluene (10 ml) and treated with sodium methoxide (0.15g). The mixture is heated to reflux under nitrogen for 2 hours, then allowed to cool to ambient temperature. The solution is washed with water (10 ml) followed by saturated aqueous sodium chloride (10 ml) and the toluene is evaporated under reduced pressure to give (-)-trans-l-methyl-3- carbomethoxy-4-(4'-fluorophenyl)piperidine as an oil.

A yield of about 0.30g is obtained, having the following properties:

N.M.R. 5 (CDC13) - 7.15 (m, 2H), 6.95 (q, 2H), 3.44 (s, 3H, methyl ester), 3.10 (m, IH), 2.88 (m, 2H), 2.75 (m, IH), 2.18 (m, 2H), 1.80 (m, 2H).

Optical rotation [α]²⁶ _D ca. - 44 ° (c =1, methanol)

Example 9 Preparation of (-)-trans-4-(4'-fluorophenyl)-3-hydroxymethyI-l-methylpiperidine (Step 4 of Schemes 2 and 3)

A solution of (-) trans- l-methyl-3-carbomethoxy-4-(4'- fluorophenyl) piperidine (47.3g) in toluene (400 ml) is added dropwise over about 20 minutes to a nitrogen purged vessel containing lithium aluminium hydride in tetrahydrofuran ( 1.0 molar, 200 ml) maintaining a temperature of less than 10°C throughout the addition. The mixture is stirred at ambient temperature for about 2 hours, then quenched by the cautious addition of water (35 ml) followed by 10% aqueous sodium hydroxide solution ( 10 ml). The precipitated solids are removed by filtration through celite and washed with toluene (2 x 100 ml). The toluene solutions are combined, washed with saturated sodium chloride (50 ml) and partially evaporated at atmospheric or reduced pressure to give an anhydrous toluene solution of (- ) trans-4-(4'-fluorophenyl)-3-hydroxymethyl-l -methylpiperidine.

If a solvent-free product is desired, the toluene solution may be further distilled at atmospheric or reduced pressure until no more solvent can be removed, to give (-) trans- 4-(4'-fluorophenyl)-3-hydroxymethyl-l -methylpiperidine as a crystalline solid.

A yield of about 39 g is obtained.

Example 10

Preparation of (-) trans 4-(4'-fluorophenyl)-3-(3',4'-methylenedioxy- phenoxymethyl)-l-methyIpiperidine.

Toluene (210 ml) is charged to a clean, dry 500 ml jacketed vessel fitted with an overhead stirrer and a glycol circulator, and trans-(-)-4-(4'-fluorophenyl)-3- hydroxymethyl-1 -methylpiperidine (35.10 g) is added with stirring to ensure dissolution. The vessel contents are cooled to 5 °C and dimethylethylamine (25.5 ml) is added, and then a nitrogen purge is attached and the vessel contents further cooled to 0^UC. A mixture of benzenesulphonyl chloride and toluene (25 ml + 25 ml) is added slowly from a headflask over 70 minutes, maintaining the temperature between -2 °C and +2°C. On completion of the addition, the mixture is stirred for 20 minutes, allowing the temperature to rise to 10°C.

A mixture of saturated sodium chloride (105 ml) and sodium hydroxide (3.5 g) dissolved in water (105 ml) is charged to the vessel over 10 minutes and stirring continued for 15 minutes at 10^ϋC. The mixture is left to settle for 15 minutes and the aqueous phase is separated. The aqueous phase is extracted with toluene (15 ml) and the combined toluene phases dried over anhydrous magnesium sulphate (5.1 g) for 10 minutes. The solution is then filtered and the magnesium sulphate washed with toluene ( 10 ml). Approximately 100 ml of toluene is then removed by low pressure distillation, to leave about 200 ml of a dry solution of the intermediate sulphonate ester in toluene.

This solution is transferred to a clean, dry vessel, and N,N'-dimethylformamide (100 ml) is added. This mixture is stirred, warmed to 50°C, and a solution of sesamol (22.8g) and sodium methoxide (9.33 g) in N,N'-dimethylformamide (50 ml) is added over 20 minutes. Water (0.85 ml) is added and the mixture heated to 70°C, and stirred at that temperature for 1 hour. After cooling to 50^ϋC. water (250 ml) is added, and the mixture stirred for 15 minutes, allowed to settle, and the aqueous phase removed. The aqueous phase is extracted with toluene (50 ml) and the combined toluene phases washed with 2.5 molar aqueous sodium hydroxide solution (2 x 100 ml) and water (100 ml). The resulting toluene phase is then dried over anhydrous magnesium sulphate ( 10.4 g), filtered, and the magnesium sulphate washed with toluene (25 ml). The combined toluene solutions are partially evaporated at atmospheric or reduced pressure to give an anhydrous toluene solution of (-) trans 4-(4'-fluorophenyl)-3-(3',4'-methylenedioxyphenoxymethyl)-l- methylpiperidine.

If a solvent-free product is desired, the toluene solution may be further distilled at atmospheric or reduced pressure until no more solvent can be removed, and the residue dried in a vacuum oven at 40 °C to give (-) trans 4-(4'-fluorophenyl)-3-(3',4'- methylenedioxyphenoxymethyl)- 1 -methylpiperidine as a pale yellow solid.

A yield of about 47 g is obtained

Example 11

Preparation of (-) trans-4-(4^?-fluorophenyl)-3-(3',4'-methylenedioxyphenoxymethyl)- 1-phenoxycarbonylpiperidine.

(-) trans 4-(4'-fluorophenyl)-3-(3',4'-methylenedioxyphenoxymethyl)-l -methyl piperidine is (3.43g) dissolved in toluene (100 ml) and about half the toluene is removed by distillation to remove any traces of water. The solution is then held at 60 °C and a solution of phenyl chloroformate ( 1.40 ml) in toluene (10 ml) is added dropwise with stirring under nitrogen, over 25 to 30 minutes. The mixture is then stirred at 60°C for 1 hour and cooled to ambient temperature. 5% sulphuric acid ( 10 ml) is added, the mixture was stirred well and the phases separated. The toluene phase is washed with water (10 ml) and the combined aqueous phases further are extracted with toluene (10 ml). The combined toluene phases are washed with water (10 ml) and partially evaporated at atmospheric or reduced pressure to give an anhydrous toluene solution of (-) trans 4-(4'-fluorophenyl)-3-(3',4'-methylenedioxy phenoxymethyl)-l- phenoxycarbonyl piperidine.

If a solvent-free product is desired, the toluene solution may be further distilled at atmospheric or reduced pressure until no more solvent can be removed, to give (-) trans 4-(4'-fluorophenyl)-3-(3',4'-methylenedioxy phenoxymethyl)-l-ρhenoxycarbonyl piperidine as a crystalline solid, which may be further purified by recrystallisation, for example from propan-2-ol.

A yield of about 4 g is obtained

Example 12 Preparation of (-) trans 4-(4'-f_uorophenyl)-3-(3',4'-methylenedioxy - phenoxymethyl) piperidine (paroxetine free base).

Powdered potassium hydroxide (3.0 g) is added to a solution of (-) trans 4-(4'- fluorophenyl)-3-(3',4'-methylenedioxyphenoxymethyl)- 1 -phenoxycarbonyl piperidine (3.6g) in toluene (100 ml) and the well stirred mixture is refluxed for 2 hours. The mixture is cooled to ambient temperature, treated with water (100 ml), stirred well and the phases separated. The toluene phase is washed with water (50 ml), and partially evaporated at atmospheric or reduced pressure to give an anhydrous toluene solution of paroxetine free base. If a solvent-free product is desired, the toluene solution may be further distilled at atmospheric or reduced pressure until no more solvent can be removed, to give paroxetine free base as an oil.

A yield of about 2.5 g is obtained

Example 13

Preparation of paroxetine methane sulphonate

A toluene solution ( 1.0 L) containing unpurified paroxetine base (approximately 225 g) is charged to a nitrogen purged reactor and stirred at 20°C. The vessel is seeded with paroxetine methanesulfonate, then a solution of methane sulfonic acid (70 g) in propan-2- ol (0.4L) is added slowly over a period of 50 minutes. Paroxetine methansulfonate is precipitated as a white crystalline solid during the addition, and the temperature at the end of the addition rises to about 30°C. The suspension is stirred for a further 1 hour, during which time the temperature is reduced to 22°C. The product is collected by filtration, washed on the filter with propan-2-ol (2 x 0.4 L) and dried in a vacuum oven at 40°C for 24 hours.

A yield of about 230 g is obtained

Example 14

Preparation of paroxetine hydrochloride hemihydrate.

A solution of paroxetine free base ( 13.5 g) in toluene (300 ml) is stirred at room temperature and concentrated hydrochloric acid (5.2 ml) is added. The mixture is stirred for 2 hours, then the product is collected, washed with a 1: 1 mixture of toluene and water (25 ml) and dried at 50 °C to give paroxetine hydrochloride hemihydrate.

The product may be recrystallised from aqueous propan-2-ol. Example 15

Preparation of paroxetine hydrochloride anhydrate Form A

i) Trans (-)-4-(4'-fluorophenyl)-3-(3 ',4'-methylenedioxyphenoxymethyl)-N- phenoxycarbonyl piperidine (25 g) and potassium hydroxide flake (22.5 g) are suspended in toluene (375 ml) and the reaction mixture heated to reflux under nitrogen with vigorous stirring for 3 hours. The suspension is cooled to room temperature, washed with water (250 ml), and the layers separated. The organic layer is warmed to 50°C, then concentrated hydrochloric acid (6 ml) is added and the reaction mixture heated to reflux. Approximately half the toluene is removed by distillation to give an anhydrous toluene solution of paroxetine hydrochloride.

The cooled toluene solution is diluted with acetone (300 ml), and the crystalline paroxetine hydrochloride acetone solvate is collected, washed with acetone and dried in vacuum.

The paroxetine hydrochloride acetone solvate is desolvated to paroxetine hydrochloride anhydrate Form A as described in WO96/24595.

ii) (-)-Trans-4-(4'-fluorophenyl)-3-(3',4'-methylenedioxyphenoxymethyl)- 1 - phenoxycarbonylpiperidine (90 g) is heated with potassium hydroxide (8.5 g) in toluene (1500 ml) at reflux for 3 hours, cooled, washed with hot water, acidified with hydrochloric acid, and distilled to approximately one quarter volume under vacuum. Hot propan-2-ol (2000 ml) is added and the mixture cooled slowly with vigorous stirring until the temperature reaches 20°C. After stirring for a further 2 hours, the product is filtered, washed with propan-2-ol, and^{^}dried under vacuum, to give paroxetine hydrochloride propan-2-ol solvate.

The paroxetine hydrochloride propan-2-ol solvate is desolvated to paroxetine hydrochloride anhydrate Form A as described in WO96/24595.

Claims

1. A process for the manufacture of paroxetine and pharmaceutically acceptable salts thereof which comprises the steps

a) reacting a salt of an arecoline derivative of formula (6)

(5)

c) reducing the trans piperidine ester of formula (5) with a hydride reducing agent to obtain the corresponding (+ -) trans carbinol,

d) resolving the trans carbinol by use of a chiral acid, liberating and extracting the free base of the (-) trans carbinol, e) forming a sulphonate ester of the (-) trans carbinol then coupling with sesamol to obtain an N-protected paroxetine,

2. A process according top claim 1 , which comprises

a) reacting an arecoline salt with a 4-fluorophenylmagnesium halide, optionally isolating the intermediate arecoline base, extracting and optionally isolating cis/trans l-methyl-3- carbomethoxy-4-(4'-fluoropheny 1) piperidine ,

b) converting cis/trans l-methyl-3-carbomethoxy-4-(4 -fluorophenyl) piperidine to the corresponding trans ester by epimerising with a strong base, with optional isolation of the trans ester,

c) reducing trans l-methyl-3-carbomethoxy-4-(4 '-fluorophenyl) piperidine with a hydride reducing agent and optionally isolating the trans carbinol, that is trans-4-(4'- fluorophenyl)-3-hydroxymethy 1-1 -methylpiperidine,

d) resolving the trans carbinol by use of a chiral acid, liberating, extracting and optionally isolating the free base of the (-) trans carbinol,

f) deprotecting the N-protected paroxetine via formation and optional isolation of a carbamate, followed by a hydrolysis reaction, generating and optionally isolating paroxetine base, g) forming a paroxetine salt by contacting the paroxetine base with a source of a pharmaceutically acceptable acid, optionally converting to a second paroxetine salt, and isolating drying and optionally recrystallising the final product.

3. A process for the manufacture of paroxetine and pharmaceutically acceptable salts thereof which comprises the steps

a) reacting a salt of an arecoline derivative of formula (6)

with a 4-fluorophenylmagnesium halide and extracting the cis/trans piperidine ester of formula (5)

(5)

d) reducing the (-) trans piperidine ester with a hydride reducing agent to obtain the corresponding (-) trans carbinol, e) forming a sulphonate ester of the (-) trans carbinol then coupling with sesamol, to obtain an N-protected paroxetine,

4. A process according to claim 3, which comprises

a) reacting an arecoline salt with a 4-fluorophenylmagnesium halide, optionally isolating the intermediate arecoline base, extracting and optionally isolating cis/trans l-methyl-3- carbomethoxy-4-(4'-fluorophenyl) piperidine,

b) epimerising the cis/trans l-methyl-3-carbomethoxy-4-(4'-fluorophenyl) piperidine to the corresponding trans ester with a strong base, with optional isolation of the trans ester,

d) reducing (-) trans l-methyl-3-carbomethoxy-4-(4'-fluorophenyl) piperidine with a hydride reducing agent and optionally isolating the (-) trans carbinol, that is (-) trans-4- (4'-fluorophenyl)-3-hydroxymethyl- 1 -methylpiperidine,

5. A process for the large scale manufacture of paroxetine and pharmaceutically acceptable salts thereof from an arecoline derivative and a 4-fluorophenylmagnesium halide which comprises the steps

a) reacting a salt of an arecoline derivative of formula (6)

(5)

b) converting the cis/trans piperidine ester to the (+) cis ester and liberating the (+) cis ester,

c) epimerising the (+) cis piperidine ester with a strong base to form the corresponding (-) trans piperidine ester, d) reducing (-) trans piperidine ester with a hydride reducing agent and to obtain the corresponding (-) trans carbinol,

6. A process according to claim 5, which comprises

b) converting cis/trans l-methyl-3-carbomethoxy-4-(4 -fluorophenyl) piperidine to the (+) cis ester, liberating and optionally isolating the (+) cis ester as a crystalline solid,

d) reducing (-) trans l-methyl_3-carbomethoxy-4-(4 '-fluorophenyl) piperidine with a hydride reducing agent and optionally isolating the (-) trans carbinol, that is (-) trans-4- (4'-fluorophenyl)-3-hydroxymethyl- 1 -methylpiperidine,

e) forming and optionally isolating a sulphonate ester of the (-) trans carbinol then coupling with sesamol, and optionally isolating the resulting N-protected paroxetine, f) deprotecting the N-protected paroxetine via formation and optional isolation of a carbamate, followed by a hydrolysis reaction, generating and optionally isolating paroxetine base,

7. A process according to any preceding claim in which two or more of the steps are carried out in a common reaction solvent, optionally with one or more additional solvents.

8. A process according to any preceding claim which comprises combining one or more of the steps a) to g).

9. A paroxetine product selected from the free base or a salt thereof, especially mesylate and hydrochloride, obtained by a process as claimed in any one of claims 1 to 8.

10. A method of treating the Disorders which comprises administering an effective or prophylactic amount of paroxetine or a salt thereof such as paroxetine mesylate or paroxetine hydrochloride obtained using the process claimed in any one of claims 1 to 8 to a person suffering from one or more of the Disorders.

11. A process for preparing the (-) trans piperidine ester of formula (A) which comprises treating a solution of the trans ester in racemic form with an effective amount of an enzyme to hydrolyse selectively either the (+) trans ester or the (-) trans ester to the corresponding acid, extracting the acid into an aqueous phase and the ester into an organic phase, and recovering the desired (-) trans compound from the appropriate phase.

12. A process according to claim 1 1 in which the (-) trans ester is converted to the acid, which is recovered from the aqueous phase and re-esterified.

13. A process according to claim 12 or 13 in which the enzyme is selected from Porcine liver esterase (PLE), Subtilisin Carlsberg , Subtilisin BPN, Pig liver acetone powder. Bovine liver acetone powder and Horse liver acetone powder

14. A process according to claim 11, 12 or 13 which further comprises reducing the (- ) trans ester to the (-) trans piperidine carbinol of formula (3).

15. A process according to claim 12 in which the (-) trans acid recovered from the aqueous phase is reduced to the (-) trans piperidine carbinol of formula (3).