Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-04-25
1999-11-30
Rotman, Alan L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D21130
Patent
active
059945486
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to a process for the manufacture of analgesic agents such as levobupivacaine, i.e. as substantially single enantiomers, and also analogues thereof.
BACKGROUND OF THE INVENTION
Levobupivacaine and analogues thereof such as ropivacaine are useful as local anaesthetics. These (S)-enantiomers are of increasing interest as analgesics having a higher therapeutic index than the corresponding racemates. Known syntheses have various disadvantages.
Tullar et al, J. Med. Chem. 14(9):891-2 (1971), and GB-A-1180712, describe the use of natural (R,R)-tartaric acid as the resolving agent for the separation of levobupivacaine and its antipode. 2 Molar equivalents of the base are used per molar equivalent of the acid resolving agent. For the preparation of levobupivacaine on an industrial scale, this is impractical, as the (R)-bupivacaine (R,R)-tartrate salt crystallises first, necessitating additional processing and therefore lowering the overall operating efficiency.
Further, for separation of levobupivacaine from its antipode, the method described in the prior art does not give reproducible yields of the tartrate salt, and the diastereomeric excess is variable.
This prior art does not describe a consistently reproducible process. Experiments sometimes failed, using the known conditions.
Federsel et al, Acta. Chem. Scand. B41:757-761 (1987), disclose the use of 0.52 equivalents of the resolving agent dibenzoyl tartrate, en route to the (S)-enantiomer of formula I when R.dbd.H. Water of crystallisation only is present. The resolving agent is costly.
SUMMARY OF THE INVENTION
The present invention is based on the surprising discoveries that: an alcoholic resolution medium, gives a much more reproducible resolution, allows the process to be run at higher concentrations (typically 20% w/v) and yields levobupivacaine (S,S)-tartrate or its antipode at higher optical purity (typically >98% diastereomeric excess). preferably 0.25 molar equivalents, yields levobupivacaine (S,S)-tartrate or its antipode at higher optical purity (typically >98% diastereomeric excess), and makes more efficient use of the resolving agent.
In addition: (S,S)-tartrate salt first, is a more efficient procedure for the preparation of levobupivacaine. into the hydrochloride salt. This is in contrast to the prior art, which involves the less efficient procedure of forming the desired hydrochloride from free base.
These discoveries can be utilised in connection with all compounds of the formula in claim 1, i.e. pipecolic acid 2,6-dimethylanilide or a N-alkyl derivative. They include optically-enriched bupivacaine, especially levobupivacaine, and ropivacaine.
DESCRIPTION OF THE INVENTION
The novel process is preferably conducted in accordance with all the parameters given above. In other respects, conventional crystallisation technology may be used. The reaction is preferably conducted using a C.sub.1-6 alkanol, such as isopropanol, as the primary reaction solvent, but any suitable water-miscible organic solvent may be used.
This invention is conveniently operated in conjunction with a racemisation process. Levobupivacaine and its antipode, and analogues thereof, in free base form or as its salts, can be racemised, as described in International Patent Application No. PCT/GB95/02247, as part of an efficient recycle procedure.
The following Examples illustrate the invention.
EXAMPLE 1
Bupivacaine hydrochloride monohydrate (1 kg, 2.916 mol) was charged to a separator with water (5 l) and TBME (5 l). Sodium hydroxide solution (10 N, 300 ml, 3 mol) was then added, and the reaction mixture was stirred for 5 min until all the solids had dissolved. The stirrer was stopped and the layers were allowed to separate over 0.5 h. The aqueous layer was separated and the organic layer was washed with water (2 l). The organic layer was charged to a vessel configured for atmospheric distillation. TBME (2.5 l) was distilled. Isopropanol was added and the distillation continued until all the TBME had been removed. T
REFERENCES:
patent: 4695576 (1987-09-01), Ekenstam et al.
Langston Marianne
Skead Benjamin Mark
Covington Raymond
Darwin Discovery Ltd.
Rotman Alan L.
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