Process

Details Process Process

1999-11-30

2001-11-27

Geist, Gary (Department: 1623)

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

Organic compounds

Amino nitrogen containing

C564S304000, C564S305000, C564S308000

Reexamination Certificate

active

06323368

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process for the manufacture of single enantiomers of tramadol.
BACKGROUND TO THE INVENTION
Tramadol (cis-2-dimethylaminomethyl-1-(3-methoxy-phenyl)-1-cyclohexanol) is a chiral drug substance which is used as a high-potency analgesic agent. Although tramadol is currently marketed as the racemate only, there has been considerable interest in the physiological properties associated with its individual enantiomers, namely 1S, 2S-(−)-tramadol and 1R, 2R-(+)-tramadol, the latter shown below as (1). For example, lead references to literature on this topic are highlighted in WO-A-9840053. It is possible that further investigations in this field will lead to a better understanding of the pharmacology of tramadol enantiomers, which could in turn allow for improved pharmaceutical compositions to be identified.
In connection with our own interest in this area, we required an efficient and reliable method for the preparation of individual enantiomers of tramadol. Due to the ready availability of racemic tramadol a classical resolution process, involving separation of diastereomeric salts by selective crystallisation, appeared ideal for this purpose.
Initially, literature procedures for the resolution of tramadol were investigated. In U.S. Pat. No. 5,723,668, it is reported that use of L-(+)-tartaric acid as resolving agent facilitates a highly efficient resolution whereby 49% yield (with respect to racemic base) of a diastereomerically-pure salt of 1S, 2S-(−)-tramadol is obtained after a single crystallisation from ethanol solution, by filtration and washing with solvent. However, in our hands, these results could not be reproduced. Typically, following dissolution of racemic tramadol and L-(+)-tartaric acid, we observed crystallisation, but analysis of the isolated salt showed little or no diastereomeric enrichment.
Another resolution process is described in U.S. Pat. No. 3,830,934, in which O,O-dibenzoyl-D-tartaric acid is used as resolving agent. Our own investigation of this process indicated that at least three cycles of dissolution-crystallisation-filtration are required in order to obtain salt of >98% de (diastereomeric excess), corresponding to >98% ee (enantiomeric excess) tramadol free base after cracking. Thus the process may be suitable as a small-scale preparative method. However, the need for multiple crystallisation cycles with cumulative lowering of yields may render the process unsuitable and economic for operation on a larger scale, e.g. for manufacturing processes.
SUMMARY OF THE INVENTION
This invention is based on the discovery that racemic tramadol can be resolved efficiently using the substantially single enantiomers of O,O-di-p-toluoyltartaric acid (DTTA) as a revolving agent. This resolving agent may also be used to increase the optical purity of enantiomerically-enriched tramadol, i.e. tramadol which is already enriched in one of its two enantiomers.
DESCRIPTION OF THE INVENTION
The process of this invention may be carried out under conditions that are generally known to those skilled in the art of classical resolution methods. The resolution process is extremely simple. In a typical example, dissolution of tramadol free base and O,O-di-p-toluoyl-L-tartaric acid (1 molar equivalent) by warming in ethanol, followed by cooling, gave crystallisation in 47% yield (based on racemic tramadol) of a diastereomeric salt enriched in (−)-tramadol, with a de of 97%, corresponding to 97% ee tramadol. This salt was reslurried in ethanol, and then filtered, washed and dried, which resulted in an enhanced de of 99.5%. Thus, in contrast to the multiple cystallisation cycles required when O,O-dibenzoyltartaric acid is used as the resolving agent, the present process allows diastereomericallly pure salts to be isolated in high yield after a single cystallisation from solution. It is surprising that what may be regarded as a small structural difference between O,O-dibenzoyltartaric acid and O,O-di-p-toluoyltartaric acid, i.e. aromatic hydrogen atoms, remote at positions from the chiral centres, replaced by methyl groups, results in such a dramatic improvement in the efficiency of the resolution process.
Any suitable solvent may be used to effect the process of the present invention. Preferred solvents are C
1-4
alkanols, of which ethanol is especially preferred.
Since both enantiomers of the resolving agent are readily available in quantity, either can be used to effect resolution, depending on the which enantiomer of tramadol is required. For example O,O-di-p-toluoyl-L-tartaric acid gives initial crystallisation of a diastereomeric salt enriched in (−)-tramadol, whereas with O,O-di-p-toluoyl-D-tartaric acid a diastereomeric salt enriched in (+)-tramadol is obtained. When both enantiomers of tramadol are required, these processes can be combined in a so-called “mirror image” resolution whereby after crystallisation of, say, a diastereomeric salt of (−)-tramadol and O,O-di-p-toluoyl-L-tartaric acid, mother liquors remaining are processed to isolate residual tramadol free base enriched in the (+)-enantiomer, which is then purified further by treatment with O,O-di-p-toluoyl-D-tartaric acid and crystallisation of the resultant salt.
Other beneficial aspects of the process of the present invention have been identified and these can be summarised as follows:
1. The O,O-di-p-toluoyltartaric acid resolving agent can be easily recovered in a state of high purity, such that it can be re-used in one or more subsequent resolution processes.
2. Typically, 1 molar equivalent of the O,O-di-p-toluoyltartaric acid is used relative to racemic tramadol free base. However, if desired, less than 1 molar equivalent may be used, e.g. as little as 0.50 molar equivalent, preferably around 0.5-0.6 molar equivalents, such that the yield of diastereomeric salt obtained on initial crystallisation is comparable to that achieved with 1 equivalent of resolving agent, leaving an excess of tramadol free base in solution. Isolated diastereomeric salts obtained by either method have a 1:1 stoichiometry of resolving agent:tramadol.
3. Efficient resolution can be achieved when the feedstock of racemic tramadol is contaminated with isomeric trans-2-dimethylaminomethyl-1-(3-methoxyphenyl)-1-cyclo-hexanol, which may be formed in levels of up to 10-20% during the manufacture of the former.
In the context of this Application, by a substantially single enantiomer typically we mean that one of the enantiomers is present in an excess of at least 70%, preferably at least 90%, and more preferably at least 95%, with respect to its opposite enantiomer, including an optically-pure enantiomer.
The present invention is further illustrated by the following examples.


REFERENCES:
patent: 3830934 (1974-08-01), Flick et al.
patent: 5723668 (1998-03-01), Buschmann et al.
Frankus, Von E. et al. (1978) “Über die Isomerentrennung, Strukturaufklärung und pharmakologische Charakterisierung von 1-(m-Methoxyphenyl)-2-(dimethylaminomethyl)cyclohexan-1-ol”Drug Res.28(1):114-121.

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