Process for preparing levobupivacaine and analogues thereof

Details Process for preparing levobupivacaine and analogues thereof Process for preparing levobupivacaine and analogues thereof

1997-04-25

1998-07-07

Davis, Zinna Northington

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D21160

Patent

active

057771243

DESCRIPTION:

BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATION

This application is a 371 of International Application No. PCT/GB95/02514 filed Oct. 23, 1995.


FIELD OF THE INVENTION

This invention relates to a novel process for the manufacture of racemic bupivacaine or levobupivacaine, and analogues thereof, from pipecolic acid.


BACKGROUND TO THE INVENTION

Bupivacaine (formula I in Scheme 1) and ropivacaine are well-known local anaesthetics. They are described in U.S. Pat. No. 4,695,576, GB-A-1166802, and PCT/NO83/00029. The corresponding N-methyl and N-cyclopropyl compounds also have such activity. However, the production of such material on a large scale, from pipecolic acid, suffers from various difficulties.
Phosphorus pentachloride has been used as a chlorinating agent. On a large scale, its use is problematic, in that. PCl.sub.5 is liable to react with atmospheric moisture, and to generate waste whose separation from the acid chloride intermediate (II) is difficult. Furthermore, the phosphate waste streams which are generated are difficult to treat or otherwise discard.
The use of acetyl chloride as the process solvent for the production of the acid chloride (II) poses similar difficulties.
Whereas isolation of the intermediate acid chloride (II) as described in the art can be carried out on a laboratory scale, its isolation on the larger scale is impractical. This is due to the fact that the intermediate (II) is a very labile substance and may decompose upon exposure to atmospheric moisture.
Washing of the isolated acid chloride (II) with commercial grade acetone, as described in the art, will lead to its decomposition, as commercial acetone usually contains some water.
Reaction of the acid chloride (II) with 2,6-dimethylaniline in a mixture of acetone and N-methylpyrrolidone (NMP), as advocated in the art, leads to the formation of pipecolic acid 2,6-xylidide (III) which is difficult to isolate from the reaction medium.
Alkylation of the intermediate (III) with 1-bromobutane and potassium carbonate in n-butanol affords comparatively poor yield of the desired bupivacaine, since the reaction proceeds very slowly and usually does not go to completion.


SUMMARY OF THE INVENTION

The present invention describes a practical and streamlined one-pot process which is both economical and viable for scale-up. Furthermore, this invention may be used to manufacture racemic bupivacaine, levobupivacaine, or any corresponding N-alkylated material such as ropivacaine (Pr rather than Bu) in racemic or enantiomeric form.
According to this invention, pipecolic acid is initially reacted with hydrogen chloride in a suitable solvent, furnishing pipecolic acid hydrochloride salt.
This compound is not isolated from the reaction medium but is directly treated with thionyl chloride, whereupon pipecolic acid chloride hydrochloride (II) is produced. Other chlorinating agents may be used, provided that they do not contain phosphorus, e.g. oxalyl chloride.
Again, this intermediate is not isolated and is conveniently treated with (2 equivalents of) 2,6-dimethylaniline. This operation generates the HCl salt of the intermediate (III) which is later isolated, after work-up. By controlling the pH, the free base can be obtained, essentially uncontaminated with 2,6-dimethylaniline (which is released as the pH is increased).
Alkylation of the free base of intermediate (III) is carried out with an alkylating agent such as 1-bromobutane in a suitable solvent such as acetonitrile (ACN) or advantageously in dimethylformamide (DMF) in the presence of a suitable base such as potassium carbonate. The reaction proceeds rapidly, and the resulting free base of, say, bupivacaine is isolated after removal of the solvent.
The free base may then be dissolved in a suitable solvent such as isopropanol and treated with hydrogen chloride, affording the HCl salt of, say, bupivacaine which is recovered by filtration (see Scheme 1).
It appears that no significant racemisation occurs during this novel process. Therefore, for example, by using enantiomerically pure (S)-pipeco

REFERENCES:
patent: 4695576 (1987-09-01), af Ekenstam et al.
Vecchietti et al, J. Med. Chem., vol. 34, No. 1, pp. 397-403, 1991.
Pizey et al, Synthetic Reagents, vol. I, Chapter 4, pp. 333-336, 1974.
March, J., Advanced Organic Chemistry, third edition, p. 388.

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