Process for making paroxetine

• US 6,172,233 B1
• Filed: 01/15/1998
• Issued: 01/09/2001
• Est. Priority Date: 01/15/1997
• Status: Expired due to Fees

• Current Assignee: Smithkline Beecham PLC
• Original Assignee: Smithkline Beecham PLC
• Inventors: Ward, Neal
• Primary Examiner(s): Kight, John
• Assistant Examiner(s): COVINGTON, RAYMOND K
• Application Number:
  US09/007,475
• Time in Patent Office: 1,090 Days
• Field of Search: 546/185, 546/225, 546/227, 546/228
• US Class Current: 546/185
• CPC Class Codes: C07D 211/22 by oxygen atoms
• CPC Class Codes: C07D 211/60 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

Compounds of structure (2) are prepared by reaction of an arecoline analogue of structure(4) with an organometallic compound containing an X-substituted phenyl group, such as a compound of structure (3).

Suitably the compound of structure (3) is a Grignard reagent, where M is magnesium and Y is a halogen atom, or M may be a Group II metal and Y is a halogen atom or a second X-substituted phenyl group. When structure (3) is a Grignard reagent, the reaction is carried out either in a suitable non-ether solvent, typically a hydrocarbon or a non-reactive chlorinated hydrocarbon, or in a mixture of such a solvent with diethyl ether. Compounds of structure (2) are important intermediates in the preparation of inter alia paroxetine.

Claims

1. A process for industrial scale preparation of a compound of structure (2)

in which R and R′

are independently selected from an alkyl, aryl, or arylalkyl group, X is fluorine which comprises reacting a compound of structure (4)

with an organometallic compound having one or more X-substituted phenyl groups, in a suitable organic solvent, provided that the solvent is not wholly an ether solvent when the organometallic compound is a Grignard reagent.

2. A process according to claim 1, in which the organometallic compound is a compound of structure (3)

in which X is as defined in claim 1, M is a Group II metal and Y is a halogen or an X-substituted phenyl group.

3. A process according to claim 2, in which M is Zn and Y is a second X-substituted phenyl group.

4. A process according to claim 2, in which structure (3) is a Grignard reagent and the organic solvent is a non-ether solvent or a mixture of a non-ether solvent with diethyl ether.

5. A process according to claim 4, in which M is Mg and Y is Cl or Br.

6. A process according to claim 1, in which the solvent is a hydrocarbon or a non-reactive chlorinated hydrocarbon.

7. A process for the preparation of a 4-aryl-3-hydroxymethyl-piperidine of structure (1)

comprising converting a compound of structure (2) obtained by the process of claim 1 into a compound of structure (1).

8. A process for preparing paroxetine comprising obtaining a compound of structure (1) in which X is 4-fluoro by a process as claimed in claim 7, replacing the 3-hydroxymethyl group by a 3-(3,4-methylenedioxyphenyloxymethyl) group, and replacing the substituent R with a hydrogen atom.

9. A process according to claim 8, in which paroxetine is obtained as, or converted to, a hydrochloride salt.

10. A process according to claim 9, in which the paroxetine hydrochloride salt is obtained as the hemihydrate.

11. Paroxetine when prepared according to the process of claim 8.

12. Paroxetine hydrochloride when prepared according to the process of claim 9.

13. Paroxetine hydrochloride hemihydrate when prepared according to the process of claim 10.

14. A process according to claim 1, in which the solvent contains toluene.

15. A process according to claim 1, in which the solvent contains dichloromethane.

16. A process according to claim 7, wherein a reducing agent is used to convert the compound of structure (1) into a compound of structure (2).