The present invention relates to a novel process for preparing aiyl-piperidine carbinols.

US Patent 4,007,196 describes certain compounds which are described as possessing anti-depressant activity.

An intermediate in the preparation of the above mentioned compounds is a compound of formula (A):

wherein R* represents hydrogen, trifluoro (Cι_4) alkyl, alkyl or alkynyl, and X represents hydrogen, alkyl having 1-4 carbon atoms, alkoxy, trifluoroalkyl, hycu ray, halogen, methylthio, or aralkyloxy.

The compounds of formula (A) are disclosed as having pharmacological properties that make them useful as anti-depressants.

One particular compound of formula (A) has been found to be especially effective as an anti-depressant. This compound is known as paroxetine and has the following formula:

paroxetine

US Patent 4,902,801 describes the preparation of compounds of formula (B):

wherein Ar represents an aryl or substituted aryl group and R represents hydrogen, an alkyl or aralkyl group; by reduction of a compound of formula (C):

Ar

wherein Ar and R are as defined for formula (B), and R ^a is an alkyl group.

Such a process is described as being suitable for preparing the precursor compounds of formula (B) to paroxetine.

The only specially disclosed reducing agents for carrying out the process described in US 4,902,801 are lithium aluminium hydride or aluminium hydride. These reducing agents are expensive, difficult to handle and are associated with a large exotherm which creates process control problems when carrying out the reaction on a large scale.

The present invention surprisingly overcomes or alleviates the above problems by the use of diborane as the reducing agent. It also gives a better yield and is more economical.

Accordingly, the present invention provides a process for the preparation of compound of formula (I):

in which R3 is hydrogen, C\_ alkyl or Cj.β alkylaryl, by reduction using diborane, of a compound of formula (II):

in which R3 is as defined in relation to formula (I) and R4 is C\. alkyl. Preferably R3 is methyl.

Preferably R4 is ethyl or methyl or a mixture of ethyl/methyl. The reaction is suitably carried out in an inert solvent such as tetrahydrofuran or dimethoxyethane (DME).

The diborane is suitably generated in situ by the addition of boron trifluoride etherate to sodium borohydride in the presence of the compound of formula (II), at reduced temperature such as -10 to 20°C, preferably at 0 to 5°G Alternatively, and more preferably for safety and handling reasons diborane is generated by the addition of hydrogen chloride gas (which can suitably be dissolved in an inert solvent such as DME) to sodium borohydride in the presence of the compound of formula (II), at reduced temperature such as -10°C to 20°C, preferably at 0 to 5°C.

Once the addition of the boron trifluoride etherate or the hydrogen chloride gas is complete, the reaction is suitably allowed to warm to ambient or elevated temperature for example 20 to 60°C more preferably 20 to 40°C.

The reaction may then be terminated or "quenched" by the addition of the reaction mixture to a mineral acid such as aqueous hydrochloric acid or by the addition of a mineral acid such as aqueous hydrochloric acid to the reaction mixture. Any resulting solid may then be filtered off and the product compound of formula (I) may be isolated by distilling off the reaction solvent, replacing it with a suitable solvent from which the product may be precipitated from, such as toluene, and precipitating the product by the addition of a suitable precipitating solvent such as n- heptane suitably after concentration of the solution of the product. The present invention also provides a process for the preparation of paroxetine or a pharmaceutically acceptable salt thereof, especially the hydrochloride hemi- hydrate, which comprises forming a compound of formula (I) as described above and thereafter subsequently converting it to paroxetine or a pharmaceutically acceptable salt thereof using conventional techniques especially those described in US Patent 4,902,801 and 4,721,723.

The following examples illustrate the present invention.

Example 1

(±)-/ra/i5-4-(4'-nuorophenyl)-3-hydroxymethyl-N-methyl-p iperidine

Input

* (±) tm/w-3-Ethoxy/methoxycarbonyI-4-(4 ^, -fluorophenyI)-N-methyl piperidine-2,6-dione 15.3g assay 93.7%

Sodium Borohydride 6.3g

Boron Trifluoride etherate 18ml

Tetrahydrofuran (THF) 75 ml

Toluene 200 ml 3N HCL 40ml

Heptane 70ml

40% sodium hydroxide solution 25ml

Method - The following methodology was carried out 1) To 50ml THF add 6.3g sodium borohydride

2) Cool solution to 0-5°C

3) Dissolve 15.3g (±) rrans-3-Ethoxy/methoxycarbonyl-4-(4'- fluorophenyl)-N-methyl piperidine-2,6-dione 1 in 25ml THF. Add over cϋ 5 minutes to borohydride solution keeping temperature at 0-5°C 4) Add slowly to solution 18ml etherate over £a 15 minutes keeping temperature at 0 to 5°C

5) Allow temperature to rise to 20°C over ca 1 hour

6) Warm solution to 35-40°C for 2 hours

7) Cool solution to 0-5°C 8) Inversely add solution slowly to 40ml 3N HCL allowing temperature to rise to 20-25°C

9) Cool solution to 5°C and filter off boric acid solid

10) Wash filter with 20ml water.

11 ) Reflux solution at 65°C to collect THF 12) Allow temperature of solution to rise to 100°C

13) Add 50ml water\75ml toluene to cool solution to 60°C

14) Separate lower aqueous layer

15) Add fuπher 50ml water to toluene keeping the temperature at 60°C

16) Separate and collect aqueous fractions

17) Add 75ml toluene to the aqueous fraction. Take pH to 12-12.5 and separate the layers.

18) Add further 50ml toluene to aqueous and separate 19) Combine toluene phases and evaporate to £a 20g

20) Add 50ml heptane, cool to 5°C and filter

21) Wash filter with 20ml heptane

22) Dry in vac oven overnight 40°C.

Wt isolated 9.6g

Assay 97% Yield 85%.

Assays were performed using high performance liquid chromatography.

H Prepared according to the procedures outlined in US Patent No. 4,902,801.

Example 2

Synthesis of (±)-/rαπs-4-(4'-fluorophenyl)-3-hydroxymethyl-N-methyl piperidine

Input

* (+,-)-trα/ιy-3-Ethoxy/methoxycarbonyl-4-(4'-fluorophenyl)- N-methyl- piperidine - 15.3 g as is

Sodium Borohydride - 8.0g

Hydrogen chloride gas - 6.5g

Dimethoxyethane (DME) - 150ml

Toluene - 50ml 3N Hydrochloric acid solution - 60ml

Heptane - 20ml

40% sodium hydroxide solution - 25ml

Method - The following methodology was carried out

1. Add sodium borohydride (8.0g) to DME (75ml).

2. Cool the solution to 0-5°C.

3. Dissolve (+,-)-trα/ιy-3-ethoxy/methoxycarbonyl-4-(4'-fluorophenyl)- N-methyl

piperidine (15.3g) in DME (25ml) and add to the sodium borohydride slurry maintaining the temperature at 0-5°C.

4. Dissolve hydrogen chloride gas (6.5g) in DME (50ml).

5. Add the hydrogen chloride/DME solution to the borohydride slurry maintaining the temperature at 0-5°C. During this period the reaction is nitrogen blanketed and hydrogen is liberated.

6. Stir the reaction mixture at 0-5°C for 30 mins.

7. Warm the mixture to 35-40°C and stir for 2 hours.

8. Cool the reaction mixture to 0-5°C. 9. Quench the reaction by adding 3N hydrochloric acid solution (60ml) maintaing the temperature below 20°C.

10. Charge water (50ml) to the reaction mixture maintaining the temperature below 20°C.

11. Distil the solution up to 95°C and collect the wet DME solution (ca. 150ml). 12. Add toluene (50ml) and allow the temperature to fall to 80°C.

13. Separate the phases.

14. Cool the aqueous phase to 50-55°C and charge heptane (20ml).

15. Charge sodium hydroxide solution to pH the solution to 11.0-11.5 whilst maintaining the temperature at 50-55°C. 16. Cool the mixture to 5-10°C over at least 30 mins.

17. Filter off the product.

18. Wash the product with water (2x20ml).

19. Dry the product at ca. 40°C.

Typical isolated weight - 9. lg Typical purity 90-95% Typical yield 78-80%

* Prepared according to the procedures outlined in US Patent No. 4,902,801.