Patent ID: 6093812
Filing Date: 2000-07-25
Classification: A61P,C07D,C07F

Abstract:
A process for producing a chiral compound of the formula ##STR34## wherein R is phenyl, W-substituted phenyl, naphthyl, W-substituted naphthyl, benzodioxolyl, heteroaryl, W-substituted heteroaryl, benzofused heteroaryl and W-substituted benzofused heteroaryl, wherein heteroaryl is selected from the group consisting of pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolyl, thiazolyl, pyrazolyl, thienyl, oxazolyl and furanyl, and for nitrogen-containing heteroaryls, the N-oxides thereof;R.sup.1 and R.sup.2 are independently selected from H or R;W is 1 to 3 substituents independently selected from the group consisting of lower alkyl, hydroxy lower alkyl, lower alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkoxy, (lower alkoxyimino)-lower alkyl, lower alkanedioyl, lower alkyl lower alkanedioyl, allyloxy,--CF.sub.3, --OCF.sub.3, benzyl, R.sup.3 -benzyl, benzyloxy, R.sup.3 -benzyloxy, phenoxy, R.sup.3 -phenoxy, dioxolanyl, NO.sub.2, --NR.sup.4 R.sup.5, NR.sup.4 R.sup.5 (lower alkyl)-, NR.sup.4 R.sup.5 (lower alkoxy)-, OH, halogeno, --NHC(O)OR.sup.6, --NHC(O)R.sup.6, R.sup.7 O.sub.2 SNH--, (R.sup.7 O.sub.2 S).sub.2 N--, --S(O).sub.2 NH.sub.2, --S(O).sub.0-2 R.sup.4, tert-butyidimethyl-silyloxymethyl, ##STR35## A and D are independently a bond; C.sub.3 -C.sub.6 cycloalkylene; C.sub.1 -C.sub.10 alkylene; C.sub.1 -C.sub.10 alkenylene; C.sub.1 -C.sub.10 alkynylene; an alkylene, alkenylene or alkynylene chain as defined substituted by one or more substituents independently selected from the group consisting of phenyl, W-substituted phenyl, heteroaryl and W-substituted heteroaryl, wherein heteroaryl is as defined above; an alkylene, alkenylene or alkynylene chain as defined interrupted by one or more groups independently selected from the group consisting of --O--, --S--, --SO--, --SO.sub.2 --, --NR.sub.8, --C(O)--, C.sub.3 -C.sub.6 cycloalkylene, phenylene, W-substituted phenylene, heteroarylene and W-substituted heteroarylene; or an interrupted alkylene, alkenylene or alkynylene chain as defined substituted by one or more substituents independently selected from the group consisting of phenyl, W-substituted phenyl, heteroaryl and W-substituted heteroaryl; or R.sup.2 --D is selected from the group consisting of halogeno, OH, lower alkoxy, --OC(O)R.sup.6, --NR.sup.4 R.sup.5, --SH and --S(lower alkyl);R.sup.3 is 1-3 groups independently selected from the group consisting of lower alkyl, lower alkoxy, --COOH, NO.sub.2, --NR.sup.4 R.sup.5, OH or halogeno;R.sup.4 and R.sup.5 are independently selected from H and lower alkyl;R.sup.6 is lower alkyl, phenyl, R.sup.3 -phenyl, benzyl or R.sup.3 -benzyl;R.sup.7 is OH, lower alkyl, phenyl, benzyl, R.sup.3 -phenyl or R.sup.3 -benzyl;R.sup.8 is H, OH, alkoxy, phenoxy, benzyloxy, ##STR36## --NR.sup.4 R.sup.5, lower alkyl, phenyl or R.sup.3 -phenyl; R.sup.9 is --O--, --CH.sub.2 --, --NH-- or --N(lower alkyl)--;R.sup.10 is H, lower alkyl, phenyl lower alkyl or --C(O)R.sup.11 ;R.sup.11 is H, lower alkyl, phenyl or phenyl lower alkyl;provided that when A is a bond, R.sup.1 is not H, and provided that when R.sup.1 is W-substituted phenyl, W is not p-halogeno;comprising cyclizing a hydroxyamide of the formula ##STR37## wherein D, A, R.sup.1, R.sup.2 and R are as defined above, by treating with:(ii) a di- or tri-chlorobenzoyl chloride, an aqueous solution of a base and a phase transfer catalyst; or(iii) a di- or tri-chlorobenzoyl chloride, an aqueous solution of a base and a phase transfer catalyst, isolating the resulting di- or tri-chlorobenzoate intermediate, then treating the intermediate with an aqueous solution of a base and a phase transfer catalyst; or(v) a di- or tri-chlorobenzoyl chloride and a metal hydride.