Process for synthesis of substituted sulphoxides

A process for enantioselective synthesis of a sulfoxide compound of formula I or an alkaline salt thereof in the form of a single enantiomer or in an enantiomerically enriched form ##STR12## wherein Het.sub.1 is ##STR13## Het.sub.2 is ##STR14## and X is ##STR15## wherein N inside the benzene ring of the benzimidazole moiety means that one of the ring carbon atoms substituted by R.sub.6 -R.sub.9 may be exchanged by a nitrogen atom without the substituents;

• R.sub.1, R.sub.2 and R.sub.3 are the same or different and selected from the group consisting of hydrogen alkyl, alkylthio and alkoxy, wherein the alkyl, alkylthio and alkoxy are unsubstituted or substituted by fluorine, alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenylalkyl and phenylalkoxy;
• R.sub.4 and R.sub.5 are the same or different and selected from the group consisting of hydrogen, alkyl and aralkyl;
• R.sub.6 ' is hydrogen, halogen, trifluoromethyl, alkyl and alkoxy;
• R.sub.6 -R.sub.9 are the same or different and selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, halo-alkoxy, alkyl-carbonyl, alkoxy carbonyl, oxazolyl and trifluoroalkyl, or adjacent R.sub.6 -R.sub.9 groups form ring structures which are unsubstituted or substituted;
• R.sub.10 is hydrogen or forms an alkylene chain together with R.sub.3 ;
• R.sub.11 and R.sub.12 are the same or different and selected from the group consisting of hydrogen, halogen, alkyl and alkoxy, wherein the alkyl and alkoxy are independently branched or a straight C.sub.1 -C.sub.9 chain or a cyclic alkyl,
• which process comprises oxidizing a pro-chiral sulfide of the formula II
• Het.sub.1 --X--S--Het.sub.2 II
• wherein Het.sub.1 and Het.sub.2 are as defined above, in an organic solvent with an oxidizing agent and in the presence of a chiral titanium complex, wherein the titanium complex has been prepared in the presence of the pro-chiral sulfide, and optionally converting the obtained sulfoxide into a pharmaceutically acceptable salt by a conventional process.

A process for enantioselective synthesis of a sulfoxide compound of formula I or an alkaline salt thereof in the form of a single enantiomer or in an enantiomerically enriched form ##STR16## wherein Het.sub.1 is ##STR17## Het.sub.2 is ##STR18## and X is ##STR19## wherein N inside the benzene ring of the benzimidazole moiety means that one of the ring carbon atoms substituted by R.sub.6 -R.sub.9 may be exchanged by a nitrogen atom without the substituents:

• R.sub.1, R.sub.2 and R.sub.3 are the same or different and selected from the group consisting of hydrogen, alkyl, alkylthio and alkoxy, wherein the alkyl, alkythio and alkoxy are unsubstituted or substituted by fluorine, alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenylalkyl and phenylakoxy;
• R.sub.4 and R.sub.5 are the same or different and selected from the group consisting of hydrogen, alkyl and aralkyl;
• R.sub.6 ' is hydrogen, halogen, trifluoromethyl, alkyl and alkoxy;
• R.sub.6 -R.sub.9 are the same or different and selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, halo-alkoxy, alkylcarbonyl, alkoxycarbonyl, oxazolyl and trifluoroalkyl, or adjacent R.sub.6 -R.sub.9 groups form ring structures which are unsubstituted or substituted;
• R.sub.10 is hydrogen or form an alkylene chain together with R.sub.3 ;
• R.sub.11 and R.sub.12 are the same or different and selected from the group consisting of hydrogen, halogen, alkyl and alkoxy, wherein the alkyl and alkoxy are independently branched or a straight C.sub.1 -C.sub.9 chain or a cyclic alkyl,
• which process comprises oxidizing a pro-chiral sulfide of the formula II
• Het.sub.1 --X--S--Het.sub.2 II
• wherein Het.sub.1 and Het.sub.2 are as defined above, in an organic solvent with an oxidizing agent and in the presence of a chiral titanium complex, wherein the titanium complex has been prepared during an elevated temperature or a prolonged preparation time or both, and optionally converting the obtained sulfoxide into a pharmaceutically acceptable salt by a conventional process.

A process for enantioselective synthesis of a sulfoxide compound of formula I or an alkaline salt thereof in the form of a single enantiomer or in an enantiomerically enriched form ##STR20## wherein Het.sub.1 is ##STR21## Het.sub.2 is ##STR22## and X is ##STR23## wherein N inside the benzene ring of the benzimidazole moiety means that one of the ring carbon atoms substituted by R.sub.6 -R.sub.9 may be exchanged by a nitrogen atom without the substituents;

• R.sub.1, R.sub.2 and R.sub.3 are the same or different and selected from the group consisting of hydrogen, alkyl, alkylthio and alkoxy, wherein the alkyl, alkylthio and alkoxy are unsubstituted or substituted by fluorine, alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenylalkyl and phenylalkoxy;
• R.sub.4 and R.sub.5 are the same or different and selected from the group consisting of hydrogen, alkyl and aralkyl;
• R.sub.6 ' is hydrogen, halogen, trifluoromethyl, alkyl and alkoxy;
• R.sub.6 -R.sub.9 are the same or different and selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, halo-alkoxy, alkylcarbonyl, alkoxycarbonyl, oxazolyl and trifluoroalkyl, or adjacent R.sub.6 -R.sub.9 groups form ring structures which are unsubstituted or substituted;
• R.sub.10 is hydrogen or form an alkylene chain together with R.sub.3 ;
• R.sub.11 and R.sub.12 are the same or different and selected from the group consisting of hydrogen, halogen, alkyl and alkoxy, wherein the alkyl and alkoxy are independently branched or a straight C.sub.1 -C.sub.9 chain or a cyclic alkyl,
• which process comprises oxidizing a pro-chiral sulfide of the formula II
• Het.sub.1 --X--S--Het.sub.2 II
• wherein Het.sub.1 and Het.sub.2 are as defined above, in an organic solvent with an oxidizing agent and in the presence of a chiral titanium complex, wherein the titanium complex is prepared in the presence of the pro-chiral sulfide and during an elevated temperature or during a prolonged preparation time, or both, and optionally converting the obtained sulfoxide into a pharmaceutically acceptable salt by a conventional process.