Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-11-21
1999-09-28
Kight, John
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D21130
Patent
active
059591129
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a new process for the preparation of ropivacaine hydrochloride monohydrate.
BACKGROUND AND PRIOR ART
The problem underlying the present invention was to provide a new process adapted for production in the plant, giving a reproducible high enantiomeric yield and a high optical purity.
Ropivacaine hydrochloride monohydrate is the generic name for the compound (S)-(-)-1-propyl-2',6'-pipecoloxylidide hydrochloride monohydrate, which compound is a local anesthetic described in EP 0 239 710. It is prepared by adding water and hot acetone to ropivacaine hydrochloride whereafter the desired product is crystallized. The process for the preparation of the starting material ropivacaine hydrochloride, is described in EP 0 151 110.
GB patent no. 1,180,712 discloses a process for the preparation of levo-1-n-butyl-2',6'-pipecoloxylidide. Said process includes a first step of resolving dl-2',6'-pipecoloxylidide, whereby dl-2',6'-pipecoloxylidide is reacted with 0,0-dibenzoyl-d-tartaric acid and thereafter the resulting mixture of diastereoisomeric 0,0-dibenzoyl-d-tartrates is reacted with boiling acetone, the acetone-insoluble dextro-2',6'-pipecoloxylidide salt is separated and the levo-2',6'-pipecoloxylidide salt is isolated from the acetone solution. However, the described process is intricate and includes isolating the product from hot acetone, i.e. it is a plain method for laboratories which could not be used for production in the plant.
The idea of using a resolution method to obtain the longer acting single enantiomers of the local anesthetics mepivacaine and bupivacaine was published in J Med Chem 14:891-892, 1971. A mixture of 2',6'-pipecoloxylidide was treated with dibenzoyl-L-tartaric acid monohydrate whereby isopropanol was added separating the isopropanol-insoluble enantiomer whereafter the desired enantiomer was isolated. Using isopropanol does not give a crystallisation system which is stable during the time required for production in the plant. This is because the solution is supersaturated with the undesired enantiomer, and thus a crystallization of the wrong shape could easily be started by small disturbances which means that isopropanol is not suitable to use for production in large scale.
In Acta Chem Scand B41: 757-761, 1987 it is described to use isopropanol in combination with various water-contents for the resolution step. These combinations gave varying yield and quality. Also the combination of isopropanol and water gave a crystallisation system not enough stable for production in the plant.
OUTLINE OF THE INVENTION
The present invention is directed to a process suitable for the large scale preparation of ropivacaine hydrochloride monohydrate, which is a compound of the formula (I) ##STR1## This new process comprises three steps, the first step being a resolution step.
It has been found that by using a resolving agent forming a stable crystallization system with water, preferably a combination of a ketone and water, it is possible to separate the undesired (R)-pipecoloxylidide and isolate the (S)-pipecoloxylidide in this first step. Thus, a crystallisation system which is stable for up to 24 hours is achieved, which is sufficient for production in the plant.
It is not possible to increase the enantiomeric yield in any of the two subsequent steps, which means that this first step is of major importance. Thus, a further aspect of the present invention was to obtain a reproducable high enantiomeric yield and a high optical purity in the first step. This was achieved by using the combination of a ketone, which together with water forms a stable crystallization system, and water.
The new process according to the present invention for the preparation of the compound (I) comprises the following steps:
Step 1 (i) The racemic starting material pipecoloxylidide hydrochloride of the formula (II) ##STR2## is liberated from its HCl salt, by extraction to an organic solvent with diluted base;
(ii) pipecoloxylidide is resolved by crystallization with
REFERENCES:
Acta Chemica Scandinavica B 41 (1987), pp. 757-761, Federsel, et al., An Efficient Synthesis of a New, Chiral 2',6'-Pipe-cologylidide.
Journal of Medicinal Chemistry, vol. 14, No. 9, (1971), pp. 891-892.
Astra Aktiebolag
Covington Raymond
Kight John
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