SYNTHESIS OF LOROETHYL)AMINOPHENYL]-3-(TRIFLUOROMETHYL)BUTANOIC ACID [3-(TRIFLUOROMETHYL)CHLORAMBUCIL]

Benzyl trifluoromethyl ketone and ethyl bromoacetate afforded ethyl 3- hydroxy-4-phenyl-3-(trifluoromethyl) butanoate in a Reformatsky-type r eaction. This hydroxy ester, by successive stages of dehydration to a but-2-enoate, hydrogenation of the double bond, nitration, and convers ion of the nitro group to amino, was converted into ethyl 4-(4'-aminop henyl)-3-(trifluoromethyl) butanoate. Treatment of this with oxirane g ave the bis(2''-hydroxyethyl) amino derivative, from which the bis(chl oroethyl) analogue was made using Ph3P/CCl4. The target chlorambucil b earing a trifluoromethyl group was then obtained after hydrolysis of t he ester. With DAST, the hydroxy ester afforded the same but-2-enoate as that from the dehydration stage. (C) 1997 Elsevier Science S.A.