Chemistry: molecular biology and microbiology – Process of utilizing an enzyme or micro-organism to destroy... – Resolution of optical isomers or purification of organic...
Patent
1995-12-18
1998-07-07
Higel, Floyd D.
Chemistry: molecular biology and microbiology
Process of utilizing an enzyme or micro-organism to destroy...
Resolution of optical isomers or purification of organic...
435122, 435130, 435822, 435849, 435873, 5462734, 5462737, C12P 1100, C07D40112
Patent
active
057767653
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/SE 95/01416 field Nov. 27, 1995,
The present invention relates to a method of obtaining compounds as defined below, either as a single enantiomer or in an enantiomerically enriched form.
BACKGROUND OF THE INVENTION
The racemic form of the compounds prepared by the method of the present invention are known compounds. Some of the compounds are also known in single enantiomeric form. The compounds are active H.sup.+ K.sup.+ ATPase inhibitors and they, including their pharmaceutically acceptable salts, are effective acid secretion inhibitors, and known for use as anti ulcer agents. The compounds, which include the known compounds omeprazole (compound of formula (IIa) below), Iansoprazole (compound of formula (IIc) below) and pantoprazole (compound of formula (IIb) below), are known for example from European Patent specifications EP 5129 and 124495, EP 174726 and EP 166287.
These compounds, being sulfoxides, have an asymmetric centre in the sulfur atom, i.e. exist as two optical isomers (enantiomers). It is desirable to obtain compounds with improved pharmacokinetic and metabolic properties which will give an improved therapeutic profile such as a lower degree of interindividual variation.
The separation of enantiomers of omeprazole in analytical scale is described in e.g. J. Chromatography, 532 (1990), 305-19. Also the separation of enantiomers of compounds with which the present invention is concerned, including omeprazole and pantoprazole, is described in German Patent Specification DE 4035455.
Recently there has been a great deal of literature published relating to the synthesis of optically active compounds using biocatalysts. The majority of this work has been aimed at finding routes to single enantiomer forms of pharmaceuticals. The reactions receiving most attention have been those involved in the preparation of esters, acids and alcohols due to the general utility of these funtionalities in synthesis and also because the biocatalysts are readily available.
Studies on the synthesis of optically active sulfoxides are relatively rare partly due to the small number of pharmaceuticals containing sulfoxide groups and partly due to the fact that enzymes that react with the sulphur centre are not available commercially. The enantioselective reduction of methylphenylsulfoxide to the sulfide has been discussed by Abo M., Tachibana M., Okubo A. and Yamazaki S. (1994) Biosci. Biotech. Biochem. 596-597.
DESCRIPTION OF THE INVENTION
According to the present invention there is provided a method of obtaining a compound of formula (II) either as a single enantiomer or in an enantiomerically enriched form: ##STR4## wherein: ##STR5## and ##STR6## wherein: N in the benzimidazole moiety of Het.sub.2 means that one of the carbon atoms substituted by any one of R.sub.6 to R.sub.9 optionally may be exchanged for an unsubstituted nitrogen atom; hydrogen, alkyl, alkoxy optionally substituted by fluorine, alkylthio, alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenylalkyl, phenylalkoxy; alkyl, aralkyl; alkyl, alkoxy, halogen, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, oxazolyl, trifluoroalkyl or adjacent groups are attached optionally substituted ring structures; halogen or alkyl; formula (II) in racemic form.
The compounds of formula (II) are active H.sup.+ K.sup.+ APTase inhibitors.
The compounds of formula (II) possess a stereogenic (asymmetric) centre which is the sulphur atom which forms the sulfoxide group between the Het.sub.1 -X-and Het.sub.2 moieties. The compounds of formula (II) generally are a racemic mixture initially.
In the method according to the present invention the starting compound of formula (II) in racemic form is stereoselectively bioreduced to the corresponding sulfide of the formula: obtained compound of formula (II) as a single enantiomer or in enantiomerically enriched form which may be separated from the sulfide produced.
In the above definitions allyl groups or moieties may be branched or straight chained or comprise cyclic alkyl groups, for exam
REFERENCES:
patent: 4873337 (1989-10-01), Sih et al.
patent: 5274099 (1993-12-01), Brandstroom et al.
Abo et al. (1997) "Preparative asymmetric deoxygenation of alkyl aryl sulfoxides . . . " Tetrahedron: Asymmetry 8:345.
Erlandsson (1990) "Resolution of the enantiomers of omeprazole and . . . " Journal of Chromatography 532: 305-319.
Cashman, J.R. et al. 1993 "Chemical, enzymatic and Human enditioselective S-oxygenation" Drug Metabolism and Dispostion 21:587.
Kashiyama et al. 1994 "Chiral inversion of drug: . . . " Biochem. Pharmacology 48:237.
Biosci, Biotech. Biochem., (1994) 58, pp. 596-597, Abo et al.
J. Chromatography, 532 (1990), pp. 305-319, Erlandsson et al.
Graham Daniel
Holt Robert
Lindberg Per
Taylor Stephen
Astra Aktiebolag
Higel Floyd D.
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