Process for the optical purification of enantiomerically enriche

Details Process for the optical purification of enantiomerically enriche Process for the optical purification of enantiomerically enriche

1996-07-19

1999-07-27

Fan, Jane

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

546183, 5483071, C07D40112

Patent

active

059292440

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to a process for the optical purification of enantiomerically enriched preparations of some 2-(pyridinylmethylsulphinyl)-1H-benzimidazole derivatives as well as another structurally related sulphoxide.


PRIOR ART

There are a large number of patents and patent applications disclosing different substituted 2-(pyridinylmethylsulphinyl)-1H-benzimidazoles and structurally related sulphoxides. This dass of compounds has properties making the compounds useful as inhibitors of gastric acid secretion. For example the compound enzimidazole), having the generic name omeprazole, and therapeutically acceptable salts thereof are described in EP 5129. Omeprazole and its alkaline salts are effective gastric acid secretion inhibitors, and are useful as antiulcer agents. Other compounds also effective as gastric add secretion inhibitors are the compounds enzimidazole having the generic name lansoprazole, described in EP-A1-174726; dazole having the generic name pariprazole, described in EP 268956; the generic name leminoprazole, described in GB 2163747 and H-benzimidazole which is described in EP 434999.
These compounds omeprazole, lansoprazole, pariprazole and leminoprazole all have a stereogenic centre at the sulphur atom and thus exist as two stereoisomers (enantiomers). The compound H-benzirnidazole has two stereogenic centers, one centre at the methine carbon atom adjacent to the sulphur atom and one at the sulphur atom. Thus, this compound exists as four stereoisomers (two pair of enantiomers). Even though the 2-(pyridinylmethylsulphinyl)-1H-benzimidazole class of chiral sulphoxides, including omeprazole, have been described in the scientific literature since the late seventies, there is not yet any efficient asymmetric process reported for the synthesis of the single enantiomers thereof. The single enantiomers of pharmacologically active compounds have met an increased interest in the last years because of improved pharmacokinetic and biological properties. Therefore, there is a need for a process that can be used in large scale for the preparation of the single enantiomers of omeprazole and of other optical pure omeprazole analogues. Generally, asymmetric processes for obtaining chiral sulphoxides afford optically active sulphoxides in enantiomerically enriched forms rather than in pure single enantiomeric forms unless the processes are enzymatic transformations or resolution methods. Therefore, there is also a need for a method that can be used in large scale for the enhancement of optical purity for enantiomerically enriched preparations of optically active omeprazole and other optically active omeprazole analogues.
Prior art discloses processes for resolution of different substituted 2-(2-pyridinylmethylsulphinyl)-1H-benzimidazoles. For example in DE 4035455 and WO 94/27988 such resolution processes are described. These processes involve reaction steps wherein a diastereomeric mixture is synthesised from the racemate of the corresponding substituted 2-(2-pyridinylmethylsulphinyl)-1H-benzimidazoles. The diastereomers are then separated and finally the separated diastereomer is converted to the optically pure sulphoxide in a hydrolytic step. These resolution methods involving diastereomeric intermediates, suffer from at least three fundamental disadvantages namely: racemic intermediate, has to be further processed in a couple of reaction steps before the single enantiomers can be obtained. stereoisomer, in the form of the opposite diastereomer, is discarded.
Further, prior art disdoses for instance enantioselective synthesis of a 2-(2-pyridinylmethylsulphinyl)-1H-benzimidazole derivative, namely the single enantiomers of the sulphoxide agent -6-(1H)-one) see Euro. J. Biochem. 166 (1987) 453-459. This process is based on an enantioselective oxidation of the corresponding prochiral sulphide to said sulphoxide. The authors state that the crude product of the sulphoxide, showing an enantiomeric excess (e.e.) of about 30%, can be crystallisation. However, the yields and t

REFERENCES:
Eur. J. Biochem, 166 (1987), pp. 453-459--Sigrist-Nelson, et al., Ro 18-5364, a potent new inhibitor of the gastric (H+ + K+)-ATPase.
Chem. Pharm. Bull., vol. 42, No. 3, (1994), pp. 718-720, Synthesis and Antiulcer Activities . . . , Yamada, et al.

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