WO2001014335A1

WO2001014335A1 - Process for preparation of paroxetin intermediate

Info

Publication number: WO2001014335A1
Application number: PCT/EP2000/008177
Authority: WO
Inventors: David Crowe; David Alan Jones
Original assignee: SmithKline Beecham Ltd
Current assignee: SmithKline Beecham Ltd
Priority date: 1999-08-25
Filing date: 2000-08-18
Publication date: 2001-03-01
Anticipated expiration: 2002-02-25
Also published as: GB9920147D0; AU7278900A

Abstract

A trans-piperidinedione of formula (1), where R is a benzyl group and R' is an optionally substituted C1-6-alkyl, aryl-C1-6-alkyl, C1-6-allyl or aryl group, which process comprises the reaction of a cinnamate ester of formula (3), where R'' has independently the same meaning as R', with a malonamide (4) in the presence of a strong base. Compound (2) is used in the presentation of paroxetine. The preparation of paroxetine by the route from compounds (3 and 4) avoids the formation of difficult to remove impurities found in other routes.

Description

PROCESS FOR PREPARATION OF PAROXETIN INTERMEDIATE

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 3,912,743 and US 4,007,196. 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.

Various processes have been described for the preparation of paroxetine, for example in US 4,007,196 and US 4,902,801. A particularly efficient process is described in US 4,902,801, whereby paroxetine is prepared from an intermediate imide of formula (1), which is reduced to a piperidine (2) and subsequently converted to paroxetine by known means.

US 4,902,801 defines the group R as hydrogen, a

or phenyl Cι.₆alkyl group, but specifically names and exemplifies the preparation of only those compounds (1) and (2) where R is a hydrogen or a methyl group. There is a mention of R as a benzyl group in a class of compounds which includes formula (1) and in which R' is an ethyl group, but no compounds with an N-benzyl group are mentioned specifically by name nor are their preparations or properties described.

Surprisingly, we have discovered that imides (1) where R is a benzyl group have unexpected advantages as intermediates in the preparation of paroxetine. Accordingly, the present invention provides as novel compounds, trans-piperidinediones of formula (1) above, where R is a benzyl group and R' is an optionally substituted Cj.g-alkyl, aryl-Cj.g-alkyl, Ci .g-allyl or aryl group, and in particular trans- l-benzyl-4-(4'-fluorophenyl)-3-ethoxycarbonylpiperidin-2,6-dione, and trans-l-benzyl-4-(4'-fluorophenyl)-3-methoxycarbonylpiperidin-2,6-dione.

The N-benzyl imides of this invention may be prepared by the reaction of an alkyl N- benzylamidomalonate of structure (4) where R = benzyl, with a cinnamate of structure (3) in the presence of a strong base.

(R' and R" are alkyl groups)

When imides (1) with R = hydrogen or methyl are prepared as described in US 4,902,801, by the reaction of a cinnamate (3) and amidomalonate (4) under strongly basic conditions, substitution of the 4-fluoro group by the alkoxide base occurs and gives rise to impurities which persist through the entire manufacturing process and appear as analogues of paroxetine in the final product.

Hence, the reaction of ethyl 4-fluorocinnamate (3, R" = ethyl) and methyl N- methylamidomalonate (4, R = R' = methyl) in ethyl acetate in the presence of sodium methoxide generates imide impurities which appear in the final paroxetine product as compounds (5) and (6).

(5) (6)

These impurities are generated from 4-methoxy and 4-ethoxy analogues of compound (1) which are formed at a level between 0.2 and 1% in the reaction described above. Surprisingly, when methyl N-methylamidomalonate is replaced in the reaction by methyl N-benzylamidomalonate (4, R = benzyl, R' = methyl), less than 100 parts per million of 1 -benzyl-3-methoxycarbonylpiperidin-4-(4'-methoxyphenyl)-2,6-dione, 1 -benzyl-3- ethoxycarbonylpiperidin-4-(4'-methoxyphenyl)-2,6-dione, l-benzyl-3- methoxycarbonylpiperidin-4-(4'-ethoxyphenyl)-2,6-dione, or 1 -benzyl-3- ethoxycarbonylpiperidin-4-(4'-ethoxyphenyl)-2,6-dione are formed, and compounds (5) and (6) are virtually undetectable in the resulting paroxetine.

Further unexpected benefits have been discovered in the manufacture of paroxetine by means of an N-benzyl imide intermediate. We have found that the N-benzyl amidomalonates (4) are more conveniently prepared and do not suffer from the disproportionation problems reported in EP 802185 for N-methylamidomalonates.

N-benzylamidomalonates of structure (4) where R is a benzyl group may be prepared by the reaction of an alkyl malonyl chloride, for example methyl malonylchloride, with benzylamine under basic conditions. Alternatively a dialkylmalonate ester may be reacted with benzylamine, with or without an auxiliary solvent, preferably by heating benzylamine in excess malonate ester as solvent.

When prepared by previously known processes, the imide product (1) in which R is methyl is mainly the trans isomer, but can contain as much as 5% of the cis isomer. By contrast the imide product (1), in which R is benzyl, when prepared by the processes of this invention, contains very much lower levels of cis isomer, for example less than 0.5%, preferably less than 0.1%.

Paroxetine may be prepared from the compounds of structure (1) of this invention by reduction to the carbinol (2) as described in US 4,902,801, followed by activation, reaction with sesamol, and removal of the benzyl group.

For example, the N-benzyl imides of structure (1) may be reduced to N-benzyl piperidine carbinols of structure (2) by means of a hydride reducing reagent, such as lithium aluminiumhydride or sodium borohydride, in a suitable solvent, for example tetrahydrofuran. Activation of the resulting carbinol (2) (R=H) and coupling with sesamol may be carried out according to the procedures outlined in Acta Chemica Scandinavica 1996, volume 50, pages 164-169. The coupling is preferably carried out via formation of a sulphonate such as 4-(4-fluorophenyl)-3-methylsulfonyloxymethyl- 1 - benzylpiperidine and reaction with sesamol under basic conditions.

The trans carbinol of structure (2) where R is a benzyl group, that is 4-(4'-fluorophenyl)- l-benzyl-3-hydroxymethyl-piperidine, exists as (+) and (-) enantiomers. Paroxetine is the (-)-trans isomer of 4-(4'-fluorophenyl)-3-(3",4"-methylenedioxyphenoxymethyl) piperidine, so the preparation of paroxetine from (2) requires a resolution step. Suitably the carbinol (2) is resolved into (+) and (-) enantiomers and the (-) isomer is coupled with sesamol. The resolution of (2) may be carried out using a chiral acid to form diastereomeric salts which are separated by crystallisation. Prefered chiral acids are ditoluoyltartaric acid or dibenzoyltartaric acid. Alternatively the resolution may be achieved at the later stages of the synthesis, for example (±) paroxetine may be resolved using L(-)-di-p-toluoyl tartaric acid.

The preparation of paroxetine via a carbinol of structure (2) requires the removal of the N-benzyl protecting group from N-benzyl paroxetine. We have found that nitrogen deprotection via an intermediate carbamate, as described for demethylation in US 4,902,801 may also be used for N-benzyl deprotection, and that this process can be operated under surprisingly mild conditions. Although elevated temperatures are preferred for the reaction of N-methylparoxetine with phenyl chloro formate, ambient or sub-ambient temperatures are sufficient for the efficient reaction of N-benzyl paroxetine with phenyl chloroformate.

The resultant paroxetine is preferably obtained as or converted to a pharmaceutically acceptable derivative such as a salt, more especially the methanesulphonate salt or the hydrochloride salt and most preferably the hemihydrate of that salt, as described in EP- A-0223403. Paroxetine free base may be converted to paroxetine methanesulphonate by treatment with methansulphonic acid or a labile derivative thereof, for example a soluble salt such as ammonium methanesulphonate. Paroxetine hydrochloride may be prepared by treatment of paroxetine free base with a source of hydrogen chloride, for example gaseous hydrogen chloride, or a solution thereof, or aqueous hydrochloric acid.

The preparation of paroxetine hydrochloride by removal of an N-benzyl group from N- benzyl substituted paroxetine free base by catalytic hydrogenolysis followed by treatment with a source of hydrogen chloride has been described in PCT WO 98/01424 (see Example 22) and PCT WO 98/53424 (see Example 7).

Alternatively removal of an N-benzyl group can be carried out by hydrogenation of a salt of N-benzyl paroxetine resulting in the preparation of the correspondingparoxetme salt, such as the hydrochloride, whereby a separate salt forming step is avoided. Such a process is described in Examples 18 and 23 of WO 98/01424 in which is disclosed the direct preparation of paroxetine hydrochloride hemihydrate (7) by catalytic hydrogenation of (-)-trans-l-benzyl-4-(4-fluorophenyl)-3-(3 ,4- methylenedioxyphenoxymethyl) piperidine hydrochloride (8) in propan-2-ol.

(8) (7)

We have carried the preparation of paroxetine hydrochloride by the process described in Examples 18 and 23 of WO 98/01424 and found that, contrary to the statements made in the Examples, the isolated yield is low. In addition, we have found that it is extremely difficult to bring the reaction to completion, with the result that the paroxetine hydrochloride (7) is contaminated with significant amounts of compound (8). Contamination with (8) is highly undesirable, as (8) is know to be a potent pharmaceutical agent (EP 0190496 A2 describes N-benzyl paroxetine as having anti- ulcer activity).

We have discovered conditions that result in a faster, more efficient hydrogenation reaction which gives higher yields of paroxetine hydrochloride (7) containing low levels of compound (8)

In this aspect of the invention, paroxetine hydrochloride is prepared from (-)-trans-l- benzyl-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl) piperidine hydrochloride by catalytic hydrogenation in either

a mixture of propan-2-ol and a co-solvent, such as water or acetic acid, optionally in the presence of water, or an alternative solvent, preferably ethanol or methanol, optionally with a co-solvent such as water or acetic acid, or a mixture thereof.

Suitable catalysts for the hydrogenation include palladium on an inert support, preferably carbon. The hydrogenation may be carried out at atmospheric or above atmospheric pressure, preferably at elevated temperature, suitably at 50-80°C.

On completion of the hydrogenation, the reaction mixture is filtered to remove the catalyst, and the paroxetine hydrochloride is recovered from the filtrate by conventional means, such as concentration by evaporation, optionally adding a further solvent to assist crystallisation of the desired product. In both aspects of the formation of the hydrochloride, pre- or post-debenzylation, any of the known crystalline forms of paroxetine hydrochloride may be isolated from the process of this invention, provided suitable conditions are employed at the final isolation step. For example, if water is present during the isolation step, the isolated product is paroxetine hydrochloride hemihydrate. Other anhydrous forms of paroxetine hydrochloride may be isolated using suitable solvent systems, as described in GB 2297550.

The present invention includes within its scope the compound paroxetine, particularly paroxetine hydrochloride, especially as an anhydrate or the hemihydrate, when obtained via any aspect of this invention, and any novel intermediates resulting from the described procedures.

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 salt obtained using the process of this invention and a pharmaceutically acceptable carrier; the use of paroxetine or paroxetine salt 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 salt obtained using the process of this invention to a person suffering from one or more of the Disorders. Pharmaceutical compositions using active compounds 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 utilised in conventional manner, for example in a manner similar to that already used for marketed anti-depressant agents.

This invention is illustrated by the following Examples.

Example 1

Preparation of methyl N-benzylamidomalonate.

A two phase mixture of potassium carbonate (20 g), water (100 ml) and dichloromethane (150 ml) containing methyl malonylchloride (5 ml) and benzylamine (6 ml) was stirred vigorously at ambient temperature for 2 hours. The layers were separated and the organic portion washed in succession with 0.5M hydrochloric acid (100 ml) and water (100 ml). The organic layer was dried with anhydrous magnesium sulphate and evaporated to give methyl N-benzylamidomalonate as a viscous oil that crystallised on standing. Yield 2.79 g

Nuclear magnetic resonance (^H, CDCI3, 400 MHz): δ = 3.30 (2H, s), 3.75 (3H,s), 4.40

(2H, d), 7.2-7.4 (5H, m), 7.5 (IH, broad s).

Example 2

Preparation of 4-(4'-fluorophenyl)-l-benzyl-2,6-dioxo-piperidine-3-carboxylic acid ethyl ester

A solution of 4-fluorobenzaldehyde (1.30 g) in ethyl acetate (5 ml) was added to a rapidly stirred suspension of sodium methoxide (1.60 g) in ethyl acetate (20 ml) over 20 minutes. The reaction mixture was stirred for a further 20 minutes at room temperature, then a solution of methyl N-benzyl malonamide (2.40 g) in ethyl acetate (10 ml) was added slowly. The reaction was stirred for 1 hour at ambient temperature, then treated with dilute hydrochloric acid (20 ml, 2 molar) and ethyl acetate (50 ml). The layers were separated and the organic portion washed with water (20 ml), dried with anhydrous magnesium sulphate and evaporated to an oil. The oil was triturated with propan-2-ol to give trans 4-(4'-fluorophenyl)-l-benzyl-2,6-dioxo-piperidine-3-carboxylic acid ethyl ester (1.46 g) as a white crystalline solid.

Mass Spectrometry: (M-H)⁺ = 368. Nuclear magnetic resonance (1H, CDCI3, 400 MHz): δ = 1.18 (3H, t), 2.82 (IH, ABX),

3.03 (IH, ABX) 3.7 (lH,ddd), 3.80 (IH, d), 4.08 (2H, q), 5.0 (2H, q), 7.0 (2H, t), 7.17

(2H, m), 7.3-7.4 (5H, m).

Infra red spectrum (nujol mull): υ_max 1736, 1724, 1681, 1602, 1511, 1379, 1350, 1322,

1203, 1178, 1135, 1100, 947, 836 cm"¹.

Example 3

Preparation of (±)-4-(4'-fluorophenyI)-l-benzyl-3-hydroxymethyl-piperidine

A solution of 4-(4'-fluorophenyl)-l-benzyl-2,6-dioxo-piperidine-3-carboxylic acid ethyl ester (0.901g) in tetrahydrofuran (10ml) was treated slowly with a solution of lithium aluminium hydride (10 ml of a 1 Molar solution in tetrahydrofuran) at 0-5°C under nitrogen. The reaction mixture was allowed to warm to 20-21°C and stirred at this temperature for 2.5 hours. Water (6 ml) was carefully added followed by aqueous sodium hydroxide solution (1 Molar, 1ml) and water (3 ml). The suspension was stirred for 30 minutes then filtered through celite. The filter bed was washed with ethyl acetate (50 ml) and the combined organic solution dried over magnesium sulfate and evaporated to give 4-(4'-fluorophenyl)-l-benzyl-3-hydroxymethyl-piperidine as a viscous yellow oil (0.612 g).

Mass Spectrometry: (M-H)⁺ = 300.

Example 4

Resolution of (±)-4-(4'-fluorophenyl)-l-benzyI-3-hydroxymethyI-piperidine. i) A solution of (±)-4-(4'-fluorophenyl)-l-benzyl-3-hydroxymethyl-piperidine (100 mg) in acetone (5ml) was treated with a solution of ditoluyltartaric acid (155mg) in acetone (3ml). The solution was evaporated to give an oil. Toluene (2 ml) was added and the oily residue scratched to induce crystallisation. The resulting suspension was used as seed crystals for the bulk. ii) A solution of (±)-4-(4'-fluorophenyl)-l -benzyl-3 -hydroxymethyl-piperidine (300 mg) and ditoluyltartaric acid (370 mg) in acetone (5ml) was treated with the suspension of seed crystals in toluene. The mixture was evaporated to an oily solid and triturated with acetone to give separation of the enantiomers. Capillary electrophoresis showed a ratio of 67% to 33% in favour of the (+)-enantiomer.

Capillary electrophoresis conditions.

Example 5

Preparation of (-)-trans-l-benzyI-4-(4'-fluorophenyl)-3-methanesulfonyloxymethyl piperidine.

(-) -trans- l-benzyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine (2.13g) was dissolved in dichloromethane (10ml) and triethylamine (0.8 lg) was added at ambient temperature. Methanesulfonyl chloride (0.88g) was added over 10-15 minutes, with stirring under nitrogen, and the mixture was stirred at ambient temperature for 3 hours. After the reaction was complete water (5.7ml) was added and the pH was adjusted to 8 by adding 10%) w/v sodium hydrogen carbonate solution. The phases were separated and the aqueous layer was extracted with dichloromethane (5ml). The combined organic extracts were washed with water (5ml), dried over magnesium sulphate and evaporated to give (-)-trans-l-benzyl-4-(4'-fluorophenyl)-3-methanesulfonyloxymethyl piperidine (2.26 g) as a yellow oil.

Example 6

Preparation of (-)-trans)-l-benzyl-4-(4'-fluorophenyl)-3-(3',4'-methylenedioxy phenoxymethyl) piperidine hydrochloride

(-) -trans- l-benzyl-4-(4-fluorophenyl)-3-methanesulfonyloxymethyl piperidine (2.14g) was suspended in a mixture of toluene (6ml) and isopropanol (6ml). Sesamol (1.18g) and 50%) aqueous sodium hydroxide were added and the mixture refluxed under nitrogen for 16 hours with vigorous stirring. Toluene (5.7ml) and water (22.8ml) were added. The layers were separated at ambient temperature and the organic layer was washed with water (2 x 10ml), dried over sodium sulphate, evaporated and the residue dissolved in isopropanol (25ml). Concentrated hydrochloric acid was added dropwise to a pH of about 2. A crystalline precipitate formed within a few minutes and the suspension was stirred for 30 minutes at ambient temperature then for 30 minutes at 0°C. The white crystals were then filtered, washed with cold acetone (2 x 2ml) and dried under vacuum to give (-)-trans- 1 -benzyl-4-(4'-fluorophenyl)-3 -(3 ',4'-methylenedioxy phenoxymethyl) piperidine hydrochloride.

Example 7 Preparation of (-)-trans-4-(4'-fluorophenyl)-3-(3', 4'-methylenedioxy phenoxymethyl)-N-phenoxycarbonyl piperidine.

A suspension of (-)-trans-l-benzyl-4-(4'-fluorophenyl)-3-(3',4'- methylenedioxy- phenoxymethyl)piperidine (2.0 g) in 1,2-dichloroethane (40 ml) was treated with triethylamine (1.20 ml). The mixture was stirred at ambient temperature for 30 minutes, then phenyl chloro formate (0.91 ml) was added, and the mixture stirred vigorously at ambient temperature for 30 hours. Water (20 ml), 2 molar hydrochloric acid (10 ml) and dichloromethane (30 ml) were added, and the mixture was stirred, then allowed to settle. The organic portion was separated, washed with water (20 ml), dried with anhydrous magnesium sulphate and evaporated to an oil. The oil was triturated with propan-2-ol (20 ml) to give (-)-trans-4-(4'-fluorophenyl)-3-(3',4'-methylenedioxy-phenoxymethyl)-N- phenoxycarbonyl piperidine (0.997 g) as a white crystalline solid.

Example 8

Preparation of paroxetine hydrochloride hemihydrate

Potassium hydroxide (1.6 g) was added to a solution of (-)-trans-4-(4-fluorophenyl)-3- (3',4'-methylenedioxyphenoxymethyl)-N-phenoxycarbonyl piperidine (1.85 g) in toluene (28 ml) and the mixture heated to reflux for 3 hours with stirring. The mixture was cooled to room temperature and water (28 ml) was added. The phases were separated and the toluene phase was stirred with concentrated hydrochloric acid (1.0 ml) for 2 hours. The crystals were collected, washed with a mixture of toluene and water (5 ml, 1 : 1 mixture) and dried under vacuum to give paroxetine hydrochloride hemihydrate.

Example 9 Preparation of paroxetine hydrochloride hemihydrate

A mixture of (-)-trans-l-benzyl-4-(4'-fluorophenyl)-3-(3',4'- methylenedioxy- phenoxymethyl) piperidine hydrochloride (4.50 g), propan-2-ol (75 ml), glacial acetic acid (7.5 ml) and water (1 ml) was hydrogenated in the presence of 0.2 g of 10%ι palladium on charcoal catalyst at 60°C and 20-25 p.s.i pressure for 4 hours. The warm mixture was filtered through celite and the filter cake washed with propan-2-ol. The volume of the filtrate was reduced to 25 ml by evaporation under reduced pressure and the solution was stored in the refrigerator for 24 hours. The product was collected by filtration, washed with cold propan-2-ol (2 5 ml) and dried under vacuum to give paroxetine hydrochloride hemihydrate (2.8g).

Example 10 Preparation of paroxetine hydrochloride hemihydrate.

A mixture of (-)-trans-l-benzyl-4-(4'-fluorophenyl)-3-(3',4'- methylenedioxy- phenoxymefhyl) piperidine hydrochloride (9 g), methanol (150 ml), and water (3 ml) was hydrogenated in the presence of 0.3 g of 10%> palladium on carbon catalyst at 60°C and under 20-25 p.s.i. pressure for 3 hours. The warm mixture was filtered through celite, and the filter cake washed with methanol. The filtrate was evaporated under reduced pressure and the crystalline residue dried under vacuum to give paroxetine hydrochloride hemihydrate (7.03g).

Claims

1. A process for the preparation of a trans-piperidinedione of formula (1), where R is a benzyl group and R' is an optionally substituted Cj.g-alkyl, aryl-Cι_6-alkyl, Ci .g-allyl or aryl group, which process comprises the reaction of a cinnamate ester of formula (3), where R" has independently the same meaning as R', with a malonamide (4) in the presence of a strong base.

2. A process as claimed in claim 1 in which a crystalline product is isolated from the reaction mixture.

3. A process for preparing a carbinol of formula (2) by reduction of the compound of formula (1).

4. A process as claimed in claim 3 in which the reducing agent is a hydride.

5. A process as claimed in claim 3 or 4 in which the reducing agent is lithium aluminium hydride or sodium borohydride.

6. A process according to claim 3, 4 or 5 in which the carbinol is resolved to separate the (-) enantiomer

7. A process according to any one of claims 3 to 6 in which carbinol (2) is reacted with sesamol to prepare N-benzyl paroxetine.

8. A process according to claim 7 which comprises the reaction of an aryl, Cι_6alkylaryl or C^alkyl chloro formate with N-benzyl-paroxetine in a solvent, and the hydrolysis of the resultant carbamate for the removal of the N-benzyl protecting group.

9. A process as claimed in claim 8 in which the chloro formate is phenyl chloro formate.

10. A process as claimed in either claim 8 or 9 in which the solvent is 1,2- dichloroethane or toluene.

11. A process as claimed in any one of claims 8 to 10 which is carried out below 35°C.

12. A process as claimed in claim 7 in which the N-benzyl group is removed by catalytic hydrogenation.

13. A process according to any one of claims 7 to 10 in which the resultant paroxetine is contacted with a pharmaceutically acceptable acid to form the acid salt.

14. A process according to claim 12 in which the N-benzyl paroxetine is contacted with a pharmaceutically acceptable acid to form the acid salt prior to hydrogenation.

15. A process according to claim 13 or 14 in which the acid is hydrochloric acid or methanesulphonic acid.

16. A trans-piperidinedione of formula (1) in claim 1, where R is a benzyl group and R' is an optionally substituted C^.g-alkyl, aryl-C^.g-alkyl, Ci _6-allyl or aryl group.

17. Crystalline trans- 1 -benzyl-3-ethoxycarbonylpiperidin-4-(4'-fluorophenyl)-2,6- dione.

18. Crystalline trans- l-benzyl-3-methoxycarbonylpiperidin-4-(4'-fluorophenyl)-2,6- dione.

19. A process for preparation of (-)-trα«5-4-(4'-fluorophenyl)-3-(3',4'- methylenedioxyphenoxymethyl)piperidine that incorporates the process of any one of claims 1 to 15.

20. (-)-tr «5-4-(4'-fluorophenyl)-3-(3",4"-methylenedioxyphenoxymethyl)piperidine whenever obtained by a process including the process of any one of claims 1 to 15.

21. (-)-trα«5-4-(4'-fluorophenyl)-3-(3",4"-methylenedioxyphenoxymethyl)piperidine as claimed in claim 20 in the form of a pharmaceutically acceptable salt such as the hydrochloride or methanesulphonate salt.

22. (-)-tr «5-4-(4'-fluorophenyl)-3-(3',4'-methylenedioxyphenoxymethyl)piperidine hydrochloride as claimed in claim 20 in the form an anhydrate or hemihydrate.

23. A method of treating the Disorders which comprises administering an effective or prophylactic amount of paroxetine or a salt thereof obtained using the process of this invention to a person suffering from one or more of the Disorders.