WO2001014369A2

WO2001014369A2 - Process for the preparation of paroxetin.hcl

Info

Publication number: WO2001014369A2
Application number: PCT/EP2000/008176
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: AU7510100A; WO2001014369A3; GB9920146D0

Abstract

Paroxetine hydrochloride is prepared by subjecting (-)-trans-1-benzyl-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl) piperidine hydrochloride to catalytic hydrogenation in the presence of a noble metal catalyst in a solvent system consisting of either a mixture of propan-2-o1 and a co-solvent, such as acetic acid, or a solvent other than propan-2-o1, preferably ethanol or methanol, optionally with a co-solvent such as water or acetic acid. Use of this solvent system reduces the amount of residual starting material in the paroxetine hydrochloride product.

Description

NOVEL PROCESS

The present invention relates to a new process for preparing paroxetine hydrochloride.

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'-fiuorophenyl)-3- (3',4'-methylenedioxy-phenoxymethyl)-piperidine. This compound is used in therapy as the hydrochloride salt to treat inter alia depression, obsessive compulsive disorder (OCD) and panic.

A particulary useful process for the preparation on paroxetine hydrochloride employs N-benzyl protection of the piperidine nucleus, followed by removal of the N-benzyl group as the final step. Such a process is described in WO 98/01424 (Gedeon Richter). Examples 18 and 23 of WO 98/01424 disclose the direct preparation of paroxetine hydrochloride hemihydrate (1) by catalytic hydrogenation of (-)-trans-l- benzyl-4-(4-fluorophenyl)-3 -(3 ,4- methylenedioxy-phenoxymethyl) piperidine hydrochloride (2) in propan-2-ol.

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 (1) is contaminated with significant amounts of compound (2). Contamination with (2) is highly undesirable, as (2) is know to be a potent pharmaceutical agent (EP 0190496 A2 describes N-benzyl paroxetine as having anti- ulcer activity).

We have discovered conditions which result in a faster, more efficient hydrogenation reaction which gives higher yields of paroxetine hydrochloride (1) containing low levels of compound (2).

In the process of this 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 acetic acid, or

a solvent other than propan-2-ol, preferably ethanol or methanol, optionally with a co- solvent such as water or acetic acid.

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. 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 from the filtrate using suitable solvent systems, as described in GB 2297550.

The present invention includes within its scope the compound 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.

The (-)-trans- 1 -benzyl-4-(4-fluorophenyl)-3 -(3 ,4-methylenedioxyphenoxymethyl) piperidine hydrochloride starting material may be prepared by the procedures disclosed in WO 98/01424.

Paroxetine hydrochloride obtained using this invention may be formulated for therapy in the dosage forms described in EP-A-0223403 or W096/24595, 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 hydrochloride obtained using the process of this invention and a pharmaceutically acceptable carrier; the use of 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 hydrochloride 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 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% 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 x 5 ml) and dried under vacuum to give paroxetine hydrochloride hemihydrate.

Yield 2.8g (76%). /14369 o r- PCT/EPOO/08176

Example 2

Preparation of paroxetine hydrochloride hemihydrate

A mixture of (-)-trans-l-benzyl-4-(4-fluorophenyl)-3-(3,4- methylenedioxy- phenoxymethyl) 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

Yield 7.03g (95%)

Claims

1. A process for the preparation of paroxetine hydrochloride whereby (-)-trans- 1 - benzyl-4-(4-fluorophenyl)-3 -(3 ,4-methy lenedioxyphenoxymethyl) piperidine hydrochloride is subjected to catalytic hydrogenation in the presence of a nobel metal catalyst in a solvent system consisting of either

a mixture of propan-2-ol and a co-solvent, such as acetic acid

or

2. A process according to claim 1 in which the product is isolated by evaporation, optionally adding a further solvent or solvents to assist in the generation of the desired form.

3. A process according to Claim 1 or 2 in which the catalyst is palladium on carbon.

4. A process according to Claim 1, 2 or 3 in which the solvent system for the hydrogenation is a mixture of propan-2-ol, acetic acid and water.

5. Paroxetine hydrochloride whenever prepared according to any one of Claims 1 to 4.

6. Paroxetine hydrochloride of Claim 5, as the hemihydrate or an anhydrate.

7. A method of treating the Disorders which comprises administering an effective or prophylactic amount of paroxetine hydrochloride of Claim 5 or 6 to a person suffering from one or more of the Disorders.