Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-12-18
2002-05-07
Chang, Ceila (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06384227
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the racemisation of optically-enriched piperidine-2-carboxanilides. In particular, the process is suitable for use in the manufacture of levobupivacaine and related piperidinecarboxanilide anaesthetic agents.
BACKGROUND OF THE INVENTION
Compounds of formula 1
wherein R
2
is 2,6-dimethylphenyl and R
1
is methyl (mepivacaine), n-propyl (ropivacaine as S-enantiomer) or n-butyl (bupivacaine) are widely used as local anaesthetics. The corresponding compound when R
1
is H is a useful intermediate.
Biological studies have shown that the (S)-enantiomers of such N-alkyl-piperidine-2-carboxanilides display lower cardiotoxicity than the corresponding racemates, whilst maintaining the same anaesthetic potency, and are therefore 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. For this purpose, conventional resolution approaches invariably afford up to 50% of the unwanted enantiomer. To improve atom utilisation in such processes, it is desirable to recycle the unwanted enantiomer by effecting its racemisation in order to provide material suitable for subsequent resolution.
Friberger et al, Acta. Pharm. Suec. (1971) 8: 361-364, report a study of the solubility and partition coefficients of the racemates and enantiomers of mepivacaine and bupivacaine. It is reported that racemic bupivacaine is more soluble than the isomers at a pH above 6. All of the compounds tested have solubilities decreasing to low levels, especially for bupivacaine, at pH values approaching neutrality.
Fyhr et al, Acta.Pharm.Suec. (1988) 25:121-132, report the racemisation of optically-enriched ropivacaine hydrochloride in dilute aqueous solution at pH 1-6 and 80-130° C. HCl or citric acid was: present, in order to establish the pH. The conclusions of this pre-formulation stability study were that the racemisation involves hydroxyl ion-catalysed racemisation of the N-protonated species. This study provides no useful indication as to how to conduct racemisation as such, and does not suggest any volume-efficient commercial process.
SUMMARY OF THE INVENTION
The present invention is based on the surprising discovery that piperidine-2-carboxanilides, including compounds of formula 1 wherein R
1
is H, methyl, n-propyl or n-butyl and R
2
is 2,6-dimethylphenyl, undergo rapid racemisation when heated in aqueous solution, provided that an organic cosolvent is present when R
1
is not H. The practical nature of this discovery is evident in that much more concentrated systems can be used than in the prior art.
Whereas, at concentrations of 30 mg/ml, at a pH above 5, the use of conditions otherwise specified by Fyhr et al lead to complete inhibition of racemisation of ropivacaine and bupivacaine, the rate of racemisation can be increased, under the conditions used in this invention, with increasing pH of the solution. Racemisation occurs most efficiently at a pH greater than 6, without loss of solubility, which means that no acid need be added.
DESCRIPTION OF THE INVENTION
The reaction can be carried out in water alone, when R
1
is H. In this case, a preferred embodiment of the invention is the racemisation of optically-enriched 2′,6′-dimethylpiperidine-2-carboxanilide (1: R
1
=H, R
2
=2,6-dimethylphenyl).
Alternatively, for N-alkylpiperidine compounds of formula 1, the reaction is carried out in the presence of an organic cosolvent such as an alcohol or polyol, e.g. ethylene glycol thus allowing solutions of higher concentration to be used, than in the prior art. A preferred embodiment of this aspect of the invention is the racemisation of optically-enriched bupivacaine in ethylene glycol containing 10% v/v water. The presence of salt forms of compounds of formula 1 does not impede the efficiency of the racemisation process.
The reaction conditions may comprise heating, as desired. Suitable conditions will depend on the nature of the reactants, but can be readily chosen by those skilled in the art.
In summary, the present invention establishes simple and economical processes for the racemisation of piperidine-2-carboxanilides, in either neat aqueous media or aqueous media combined with inert organic cosolvents. The invention is particularly suited to the optimum utilisation of unwanted enantiomer in the preparation of enantiopure therapeutic agents, and therefore in practice the starting material will usually be richer in the (R)-enantiomer. When R
1
is H, a compound of formula 1 is an intermediate en route to anaesthetic agents. When R
1
is n-butyl, the present invention is of particular utility for preparing (S)-bupivacaine, in conjunction with a resolution process, e.g. that described in PCT/GB95/02513 and South African Application No. 95/8993.
The following Examples illustrate the invention.
REFERENCES:
patent: 2301498 (1976-09-01), None
patent: 9609290 (1996-03-01), None
Scott et al. (1993) “Synthesis of enantiomerically pure drugs” In Drug Stereochemistry, ed. Wainer, Macel Dakker Pub. pp. 183-187.
Pine “Organic Chemistry” CGraw-Hill, Inc. pp. 98-102 (1987).
Fyhr, P., C. Hogstroem (1988) “A Preformulation Study on the Kinetics of the Racemisation of Ropivacaine Hydrochloride”Acta Pharmaceutica Suecica25(3):121-132.
Yadada, S. et al. (1983) “Method for the Racemisation of Optically Active Amino Acids”J. Org. Chem.48:843-846.
Smith, G.G. et al. (1978) “Rate of Racemisation of Amino Acids and Their Significance to Geochronology”J. Org. Chem.43(i), pp. 1-5.
Shiraiwa, T. et al. (1991) “Transformation of Proline and 2-Piperdinecarboxylic Acid via Formation of Salts with Optically Active Tartaric Acid”Bull. Chem. Soc. Jpn.64:3251-3255.
Sato, M. et al. (1970) “Racemisation of Amino Acids and Their Derivatives”Chem. Pharm. Bull.18(9):1794-1798.
Dyer Ulrich Conrad
Langston Marianne
Woods Martin
Chang Ceila
Darwin Discovery Ltd.
Saliwanchik Lloyd & Saliwanchik
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