WO1996011185A1

WO1996011185A1 - Asymmetric transformation of pipecolic acid, a precursor of levobupivacaine and analogues thereof

Info

Publication number: WO1996011185A1
Application number: PCT/GB1995/002384
Authority: WO
Inventors: Christopher James Lock
Original assignee: Chiroscience Ltd
Current assignee: Chirotech Technology Ltd
Priority date: 1994-10-07
Filing date: 1995-10-09
Publication date: 1996-04-18
Anticipated expiration: 1997-04-07
Also published as: ZA958499B; AU3614195A; GB9420246D0

Abstract

A process for the preparation of optically-enriched pipecolic acid as a salt with an optically-active acid, comprises asymmetric transformation of pipecolic acid, as a racemic mixture or a mixture enriched in the opposite enantiomer from that desired, with the optically-active acid in a solvent comprising an acid that causes racemisation, in the absence of aldehyde.

Description

ASYMMETRIC TRANSFORMATION OF PIPECOLIC ACID,

A PRECURSOR OF LEVOBUPIVACAINE

AND ANALOGUES THEREOF

Field of the Invention

This invention relates to the racemisation and crystallisation of (R) - or (S)-pipecolic acid. Background of the Invention

(S)-Pipecolic acid is an amino-acid which can be isolated from a variety of natural sources. Pipecolic acid and derivatives find many uses in the pharmaceutical industry, and the use of optically active (S)-pipecolic acid as an intermediate in the synthesis of the local anaesthetics levobupivacaine and ropivacaine, is just one important example. See US-^: 595576.

Beyerman, Receuil (195& 3:134, and 'Chemistry of the Amino Acids', Greenstein and » litz (eds) Vol.3, John Wiley and Sons, New York (1973) , int r alia , disclose processes for the enantiomeric separat: of (R)- and (S)-pipecolic acid. As in the majority enantiomeric separation techniques, the key to the aconomic viability of the process lies in the ability to recycle the undesired enantiomer. The key to the recycling process step is to identify a procedure which is as simple as possible. A particularly effective resolution and recycle (asymmetric transformation) of amino acids has been described for readily-racemised amino-acids such as phenyl- glycines, by which in situ racemisation is achieved in conjunction with selective crystallisation, to convert racemic amino acids through to single enantiomers, is disclosed by Shiraiwa et al , Bull. Chem. Soc. Japan (1993) 66:1430. However, there has been no simple procedure for the racemisation of pipecolic acid or analogues. The difficulty with h therto-available technology is the use of additional reagents to convert optically-enriched pipecolic acid into more easily racemised derivatives and their subsequent conversion to racemic pipecolic acid. For example, an aldehyde can be used to produce an iminium species which is known to promote the racemisation of amino acids.

Shiraiwa et al , Bull, Chem. Soc. Jpn. (1991) 64:3251, disclose asymmetric transformation of pipecolic acid, with the addition of aldehyde. Other examples describe the derivatisation as an N-alkyl or N-acyl and then subsequent racemisation; see Clark et al , JCS Perkin I (1976) 475, and Grigg et al, Tet. Lett. (1983) 24:4457. In all the above examples, the formation of a derivative, the subsequent degradation back to pipecolic acid, and the use of additional reagents, mean wasteful and inevitably less pure products, since reactions rarely go to completion and usually involve undesired side-reactions. This is clearly a disadvantage, particularly when the ultimate product is to be formulated as a pharmaceutical drug, where ensuring the consistency of the product is essential. Further, the known processes are generally undesirable, from an environmental viewpoint. Summary of the Invention

The present invention is based on the surprising discovery that, when a pipecolic acid salt of a suitable optically-active acid is treated under simple acidic conditions, the less soluble diastereomeric pipecolic acid salt crystallises from the solution. The remaining solution which is transiently enriched in the other enantiomer is concomitantly racemised under the conditions, providing additional quantities of the less soluble salt which again crystallises from solution; this process continues until substantially all the starting pipecolic acid, irrespective of its optical activity, is converted into the salt of the desired enantiomer. This process is known as asymmetric transformation or alternatively as dynamic resolution. This represents an advantageous process over the prior art since the use of aldehyde is not required to racemise pipecolic acid. This advantage renders the process more commercially viable, because aldehyde does not need to be purchased or disposed of, and avoids the disadvantages described above. It is also an advantage because the purity of the product is critical to the successful manufacture of safe pharmaceutical end product, and use of additional reagents can compromise the impurity profile of the product. Conversion to the N- acetyl or alkyl derivative is also not required. Description of the Invention

For use in the racemisation of the invention, acids are preferably selected which can function as solvent or co-solvent and also as facilitator of the racemisation. Preferably, this acid is volatile (bp<250°C) and can therefore be readily removed by distillation. Either as solvent alone or by judicious choice of co-solvent, it facilitates the racemisation, provided that any mixture with co-solvent also facilitates crystallisation of the desired pipecolic acid enantiomer as a diastereomeric salt. The optically-active acid for resolution can be chosen from a number of commercially-available resolving agents. Preferred embodiments are D and L tartaric acid or derivatives thereof. The acid for racemisation is preferably a C^C-, aliphatic carboxylic acid, i.e. including formic acid and any octanoic acid, more particularly a C₂-C₆ n-alkyl carboxylic acid, and most preferably butyric acid. The following Example illustrates the invention. Example

Racemic pipecolic acid was placed in 20 vols of butyric acid with nitrogen and treated with D-tartaric acid

(1 equivalent) and heated to 110°C. On attaining this temperature, the slurry was stirred for 4 hours before being cooled in an ice-bath for half an hour. The solution was then filtered to give the (S)-pipecolic acid (D) - tartrate salt in 76% yield (76.6% (S) ee) . This was then recrystallised from a solution of 10 volumes methanol and 0.7 volumes of water followed by filtration to give 65% recovery of (S)-pipecolic acid (D;-tartrate salt. The free pipecolic acid (>95% ee) was then obtained by dissolving the salt in water and treatment with a basic ion-exchange resin as documented in the literature, see Chemistry of the Amino Acids, supra .

Claims

1. A process for the preparation of optically-enriched pipecolic acid as a salt with an optically-active acid, which comprises asymmetric transformation of pipecolic acid, as a racemic mixture or a mixture enriched in the opposite enantiomer from that desired, with the optically- active acid in a solvent comprising an acid that causes racemisation, in the absence of aldehyde.

2. A process according to claim 1, wherein the optically- active acid is D or L-tartaric acid.

3. A process according to claim 1 or claim 2, wherein the acid that causes racemisation has a boiling point below 250°C.

4. A process according to any preceding claim, wherein the acid that causes racemisation is an alkyl carboxylic acid.

5. A process according to claim 4, wherein the carboxylic acid has 1 to 8 C atoms.

6. A process according to claim 4, wherein the carboxylic acid is (C_J._J n-alkyl) carboxylic acid.

7. A process according to claim 4, wherein the acid is butyric acid.

8. A process according to any preceding claim, wherein the acid is in admixture with a co-solvent.

9. A process according to any preceding claim, which additionally comprises converting the salt to optically- enriched pipecolic acid.

10. A process according to claim 9, which comprises preparing (S)-pipecolic acid and, additionally, converting it to levobupivacine.

11. A process according to claim 9, which comprises preparing (s)-pipecolic acid and, additionally, converting it to ropivacaine.