Synthesis of 4-[3′-bis(2″-chloroethyl) aminophenyl] -4,4-difluorobutanoic acid [4,4-difluoro-meta-chlorambucil]

Article abstract of DOI:10.1016/S0022-1139(97)00070-5

The synthetic sequence to make 4-[4′-bis(2″-chloroethyl)aminophenyl]-4,4-difluorobutanoic acid {4,4-difluorochlorambucil} was not taken beyond the intermediate stage involving methyl 4,4-difluoro-4-(4′-aminophenyl) butanoate, since this amine was hydrolytically unstable. Reaction of methyl 4-(3′-nitrophenyl)-4-oxobutanoate with sulfur tetrafluoride, followed by hydrogenation, afforded the stable isomer, methyl 4,4-difluoro-4-(3′-aminophenyl)butanoate. Bis(hydroxyethylation) by treatment with oxirane, conversion of OH to Cl by Ph₃P/ CCl₄, and then hydrolysis of the ester group, gave 4-[3′-bis(2″-chloroethyl)aminophenyl]-4,4-difluorobutanoic acid {4,4-difluoro-meta-chlorambucil}.