Preparation of pharmaceutically active compounds by biooxidation

Details Preparation of pharmaceutically active compounds by biooxidation Preparation of pharmaceutically active compounds by biooxidation

1996-11-21

1998-11-24

Fan, Jane

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Preparing heterocyclic carbon compound having only o, n, s,...

5462733, C12P 1716

Patent

active

058405526

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a method of preparing compounds as defined below, either as a single enantiomer or in an enantiomerically enriched form, by biooxidation of their sulphide equivalents.


BACKGROUND TO 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 antiulcer agents. The compounds, which include the known compounds omeprazole (compound of formula (IIa) below), lansoprazole (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, 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 functionalities 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 synthesis of optically active sulfoxides has been described in Holland, H. L. (1988) Chem. Rev. 88, 473-483 and Phillips, R. S. and Sheldon W. M., Enzyme Microb. Technol., 1981, Vol. 3, January, 9-18.


DESCRIPTION OF THE INVENTION

According to the present invention there is provided a method of preparing a compound of formula (II) either as a single enantiomer or in an enantiomerically enriched form: ##STR1## wherein Het.sub.1 is ##STR2## and Het.sub.2 is ##STR3## and X is ##STR4## wherein: N in the benzimidazole moiety means that one of the carbon atoms substituted by R.sub.6 -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 R.sub.6 -R.sub.9 may complete together with the carbon atoms to which they are attached optionally substituted ring structures; halogen or alkyl, which method comprises stereoselective biooxidation of the pro-chiral sulfide counterpart compound.
The compounds of formula (II) are active H.sup.+ K.sup.+ ATPase inhibitors. By the method of the invention these compounds, which are sulfoxides, are obtained in single enantiomer form or such that one enantiomeric form is present in excess leading to an optically active product, by stereoselective biooxidation of the pro-chiral starting sulfide counterpart compound.
In the above definitions alkyl groups or moieties may be branched or straight chained or comprise cyclic alkyl groups, for example cycloalkylalkyl.
Preferably: ##STR5## and Het.sub.2 is ##STR6## and ##STR7## (wherein R.sub.1, R.sub.2, R.sub.3, R.sub.6 to R.sub.9, R.sub.10 and R.sub.11 are

REFERENCES:
patent: 5049674 (1991-09-01), Brandstrom et al.
patent: 5430042 (1995-07-01), Lindberg et al.
Cashman, J.R. et al. 1993 "Chemical, enzymatic and Human enditioselective S-oxygenation" Durg Metabolism and Disposition vol. 21.

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