WO1996028426A1

WO1996028426A1 - N-alkylpipecolic acid compounds, their preparation and use in the synthesis of levobupivacaine and analogues

Info

Publication number: WO1996028426A1
Application number: PCT/GB1996/000505
Authority: WO
Inventors: Ulrich Conrad Dyer; Hooshang Shahriari Zavareh
Original assignee: Chiroscience Limited
Priority date: 1995-03-10
Filing date: 1996-03-05
Publication date: 1996-09-19
Also published as: AU4886296A; GB9504876D0; ZA961911B

Abstract

Optically-enriched N,O-dialkyl pipecolates are useful in the preparation of levobupivacaine and related analgesics. They may be prepared simply by dialkylating optically-enriched pipecolic acid by reaction with an alkylating agent, in the presence of base and a polar aprotic solvent.

Description

N-ALKYLPIPECOLIC ACID COMPOUNDS. THEIR PREPARATION AND USE IN THE SYNTHESIS OF LEVOBUPIVACAINE AND ANALOGUES

Field of the Invention

This invention relates to the synthesis of (S)- or (-R) -N-alkyl pipecolic acids and esters thereof which can be used in the preparation of optically-active piperidine-2-carboxanilides of formula 1, especially levobupivacaine. Background of the Invention

Compounds of formula 1 (see formulae, below) wherein R is methyl, n-propyl, n-butyl or cyclopropyl and R² is 2 , 6-dimethylphenyl are widely used as local anaesthetics. Biological studies have shown that (S)-enantiomers of such compounds display lower cardiotoxicity than the corresponding racemates whilst maintaining the same anaesthetic potency, and are therefore potentially more beneficial for clinical uses. Thus there is a requirement for efficient processes to manufacture compounds of formula 1 in the form of single enantiomers.

PL-A-0118594, PL-A-0118595, PL-A-0148960, Xue et al, Zhongguo Yiyao Gongye Zazhi 21:250 (1990), and WO-A-8500599 disclose the synthesis of bupivacaine (1: R¹ = n-butyl, R² = 2,6-dimethylphenyl) and ropivacaine (1: R¹ = n-propyl, R² = 2,6-dimethylphenyl, absolute configuration = S) via the intermediate pipecolic acid, and also racemic N-alkyl pipecolic acids. PL-A-0118594 describes alkylation of racemic pipecolic acid, in boiling toluene.

Patrick et al, Chirality 3 (3) : 208-211 (1991), disclose alkylation of (S)-pipecolic acid, en route to thioridazine. The conditions involve heating to reflux, and are suitable for methylation at the N-atom only.

Cervinka et al, Chem. Abs. 111(19):166785v (1989), disclose two-step butylation of enantiomeric 6-methylpipecolic acid. The dibutyl product is then converted to a methyl-substituted analogue of bupivacaine.

Summary of the Invention

Novel compounds according to the present invention are optically-enriched N-alkyl pipecolic acid esters of formula 2, wherein R is C_3-10 alkyl, e.g. C_3-6 alkyl. They are synthesised by alkylation of pipecolic acid. The novel compounds preferably exist with an optical purity of at least 50%, more preferably at least 70%, and most preferably at least 90% ee. A preferred embodiment of the present invention is a compound of formula 2 of (S) -configuration wherein R is n-butyl; this is a useful precursor to levobupivacaine.

We have discovered that conditions used to alkylate (S)-pipecolic acid do not adversely affect the optical activity of the product. This observation is surprising, in that racemisation of structurally-related piperidine-2-carboxanilides has been observed under both acid and basic conditions (see International Patent Applications Nos. PCT/GB95/02247 and PCT/GB96/00067).

Synthesis of the key intermediates of formula 2 is of particular importance because access to such compounds makes the synthesis of optically-active piperidine-2-carboxanilides of formula 1 particularly effective, in that the synthesis is made more convergent. In comparing a convergent synthesis to a linear synthesis, a greater percentage of starting material is converted to product in the former case.

Description of the Invention

According to this invention, (S)-pipecolic acid is conveniently reacted with an alkyl halide such as n-butyl bromide and base in a suitable polar, e.g. dipolar, aprotic solvent, thereby effecting alkylation at two sites, to generate an (S)-N-alkylpipecolate ester in one step. Surprisingly, this novel process permits the synthesis of these derivatives to occur under mild conditions and with high yields. Suitable solvents for this procedure include hexamethylphosphoramide and, preferably, acetonitrile, dimethylformamide, dimethylacetamide, dimethyl sulphoxide or 1-methyl-2-pyrrolidinone. Suitable bases for this reaction include sodium hydroxide and carbonates such as sodium carbonate or, most preferably, potassium carbonate. Upon completion of the reaction, the salts are removed by filtration and the N-alkylpipecolate ester is isolated by direct distillation. Alternatively, the reaction mixture may be diluted with water and the product isolated by extraction.

Conversion of the optically-enriched N-alkylpipecolate ester to optically-enriched N-alkylpipecolic acid may be achieved by saponification with a suitable base such as sodium hydroxide. Alternatively, the optically-enriched N-alkylpipecolic acid may be prepared by enantioselective biocatalytic resolution of a racemic compound of formula 2.

The butyl ester of (S)-N-butylpipecolic acid may be used for the preparation of levobupivacaine (1: R = n-butyl, R² = 2,6-dimethylphenyl, absolute configuration = S), using a process similar to that described in

International Patent Application No. PCT/GB95/02514.

The following Example illustrates the invention.

Example

A round-bottom flask was charged with (S) -pipecolic acid (26 g, 0.2 mol), potassium carbonate (41 g, 0.3 mol), and dimethylformamide (60 ml). Butyl bromide (55 g, 0.4 mol) was then added and the mixture was stirred at 45°C for 18 hours. The suspension was filtered off and the filtrate was evaporated under vacuum to give (S)-butyl N-butylpipecolate (41 g) as a colourless oil.

Claims

1. An optically-enriched compound of formula 2

substantially free of its optical antipode, wherein R is

C_3-10 alkyl.

2. A compound according to claim 1, wherein R is C_3-6 alkyl.

3. A compound according to claim 1, wherein R is n-propyl.

4. A compound according to claim 1, wherein R is n-butyl.

5. A compound according to any preceding claim, wherein the absolute configuration is (S).

6. A process for preparing a compound according to any of claims 1 to 5, which comprises dialkylating optically-enriched pipecolic acid by reaction with an alkylating agent, in the presence of base and a polar aprotic solvent.

7. A process for preparing a compound according to any of claims 1 to 5, which comprises dialkylating pipecolic acid by reaction with an alkylating agent, in the presence of base and a polar aprotic solvent, followed by resolution.

8. A process according to claim 7, wherein the resolution is effected by enantioselective biocatalysis.

9. A process according to any of claims 6 to 8, wherein the alkylating agent is an alkyl halide.

10. A process according to claim 6, wherein (S)-pipecolic acid is reacted with n-butyl bromide.

11. A process according to any of claims 6 to 10, wherein the solvent is acetonitrile, dimethylformamide, dimethylacetamide, dimethyl sulphoxide or 1-methyl-2- pyrrolidinone.

12. A process according to any of claims 6 to 11, wherein the base is potassium carbonate.

13. Use of a compound according to any of claims 1 to 5, or the product of a process according to any of claims 6 to 12, for the preparation of a corresponding optically-enriched analgesic agent in which the ester group is converted to 2,6-dimethylphenylamino.

14. Use according to claim 13, wherein the compound is according to claim 5 and the agent is levobupivacaine.