Patent ID: 6043365
Filing Date: 2000-03-28
Classification: A61P,C07D,Y02P

Abstract:
A process for the preparation of a compound of the formula ##STR22## or a tautomer thereof, wherein Ar represents biaryl, carbocyclic or heterocyclic aryl, or of a pharmaceutically acceptable salt thereof, as a substantially pure enantiomer thereof which comprises:(a) condensing a compound of the formula ##STR23## as a substantially pure enantiomer, wherein Ar has meaning as defined above and R.sub.6 is an O-protecting group with a lower alkyl ester of formic acid to obtain a compound of the formula ##STR24## as a substantially pure enantiomer; (b) then condensing the compound so obtained with a compound of the formula ##STR25## wherein R.sub.8 is hydrogen or COOR.sub.3 and R.sub.3 is lower alkyl, to obtain a compound of the formula ##STR26## or an enamine tautomer thereof, as a substantially pure enantiomer; (c) then cyclizing the compound so obtained to a compound of the formula ##STR27## as a substantially pure enantiomer; (d) and then condensing the compound so obtained(1) with a carbocyclic aroyl isothiocyanate and treatment of the product so obtained with an alkyl halide followed by anhydrous ammonia; or(2) with cyanamide in acid, optionally followed by treatment with a base;and wherein in the above definitions, carbocyclic and heterocyclic aryl are either monocyclic or bicyclic; monocyclic carbocyclic aryl represents phenyl or phenyl substituted by one to three substituents, such being lower alkyl, hydroxy, lower alkoxy, acyloxy, halogen, cyano, trifluoromethyl, carbocyclic aryloxy or carbocyclic aryl-lower alkoxy; bicyclic carbocyclic aryl represents 1- or 2-naphthyl or 1- or 2-naphthyl substituted by lower alkyl, lower alkoxy or halogen; monocyclic heterocyclic aryl represents thienyl, furanyl, pyridyl, pyrrolyl, thiazolyl, pyrazinyl, pyridazinyl or pyrazolyl, or thienyl, furanyl or thiazolyl substituted by lower alkyl, or pyridyl substituted by lower alkyl, halogen or cyano; bicyclic heterocyclic aryl represents indolyl or benzothiazolyl, or indolyl or benzothiazolyl substituted by hydroxy, lower alkyl, lower alkoxy or halogen; and biaryl represents phenyl substituted by carbocyclic aryl or heterocyclic aryl located ortho, meta or para to the point of attachment of the phenyl ring; and acyloxy is lower alkanoyloxy, lower alkoxycarbonyloxy, monocyclic carbocyclic aroyloxy or monocyclic heterocyclic aroyloxy.