Biocatalyzed synthesis of the optically pure (R) and (S) 3-methyl-1,2,3,4-tetrahydroquinoline and their use as chiral synthons for the preparation of the antithrombic (21R)- and (21S)-argatroban

摘要

The present invention relates to the biocatalyzed synthesis of enantiomerically pure (3R) and (3S)-methyl-1,2,3,4-tetrahydroquinoline. Said enantiomerically pure compounds are useful as chiral synthons in organic synthesis and, in particular, for the preparation of diastereomerically pure (21R) and (21S)-agratroban and its analogs. New compounds used as intermediates in the process of the invention are also disclosed.

主权项

1. A process for the preparation of enantiomerically pure (3S)-methyl-1,2,3,4-tetrahydroquinoline comprising the following steps:
a) transforming quinoline-3-carboxylic acid into a C1-C4 linear or branched alkyl or aryl ester, wherein aryl is a phenyl or benzyl moiety, optionally substituted with one or more C1-C4 linear or branched alkyl groups; b) reducing said ester to (R,S)-1,2,3,4-tetrahydroquinoline-3-carboxylate ester; c) reducing said (R,S)-1,2,3,4-tetrahydroquinoline-3-carboxylate ester to obtain (R,S)-3-(1′-hydroxy-methyl)-1,2,3,4-tetrahydroquinoline; d) protecting the amino group of said (R,S)-3-(1′-hydroxy-methyl)-1,2,3,4-tetrahydroquinoline using di-tertbutyl carbonate to obtain (R,S)-3-(1′-hydroxy-methyl)-1-tertbutyloxycarbonyl-1,2,3,4-tetrahydroquinoline; e) reacting the (R,S)-3-(1′-hydroxy-methyl)-1-tertbutyloxycarbonyl-1,2,3,4-tetrahydroquinoline with an ester of vinyl alcohol, the ester comprising a C2-C8, linear or branched alkyl carboxylic acid, in a first transesterification reaction catalyzed by Pseudomonas fluorescens lipase (PFL) in a toluenic solution, wherein the reaction is stopped at a PFL rate of conversion comprised between 30 and 40% to obtain isomer S of (R,S)-3-(1′-carboalkoxy-methyl)-1-tertbutyloxycarbonyl-1,2,3,4-tetrahydroquinoline, which is subsequently hydrolyzed by the PFL at a rate of conversion comprised between 60 and 75% to obtain enantiomerically pure (S)-3-(1′-hydroxy-methyl)-1-tertbutyloxycarbonyl-1,2,3,4-tetrahydroquinoline; f) transforming the enantiomerically pure (S)-3-(1′-hydroxy-methyl)-1-tertbutyloxycarbonyl-1,2,3,4-tetrahydroquinoline with a sulphonyl chloride R″—SO2—Cl, wherein R″ is a C1-C4 linear or branched alkyl, phenyl, optionally substituted by one or more methyl groups thus obtaining a sulphonyl derivative of (S)-3-(1′-hydroxy-methyl)-1-tertbutyloxycarbonyl-1,2,3,4-tetrahydroquinoline; g) reducing said sulphonyl derivative to (S)-3-methyl-1-tertbutyloxycarbonyl-1,2,3,4-tetrahydroquinoline with a hydride; and h) removing the protective group of the amino nitrogen atom to obtain enantiomerically pure synthon (S)-3-methyl-1,2,3,4-tetrahydroquinoline.