SYNTHESIS OF (2''-CHLOROETHYL)AMINOPHENYL]-4,4-DIFLUOROBUTANOIC ACID [4,4-DIFLUORO-META-CHLORAMBUCIL]

The synthetic sequence to make (2''-chloroethyl)aminophenyl]-4,4-diflu orobutanoic acid {4,4-difluorochlorambucil} was not taken beyond the i ntermediate stage involving methyl 4,4-difluoro-4-(4'-aminophenyl) but anoate, since this amine was hydrolytically unstable. Reaction of meth yl 4-(3'-nitrophenyl)-4-oxobutanoate with sulfur tetrafluoride, follow ed by hydrogenation, afforded the stable isomer, methyl 4,4-difluoro-4 -(3'-aminophenyl)butanoate. Bis(hydroxyethylation) by treatment with o xirane, conversion of OH to Cl by Ph3P/ CCl4, and then hydrolysis of t he ester group, gave (2''-chloroethyl)aminophenyl]-4,4-difluorobutanoi c acid {4,4-difluoro-meta-chlorambucil}. (C) 1997 Elsevier Science S.A .