Pl. Coe et al., SYNTHESIS OF HLOROETHYL)AMINOPHENYL]-3-(DIFLUOROMETHYL)BUTANOIC ACID [3-(DIFLUOROMETHYL)CHLORAMBUCIL], Journal of fluorine chemistry, 89(2), 1998, pp. 183-188
Benzyl chlorodifluoromethyl ketone, ethyl bromoacetate and zinc afford
ed ethyl (chlorodifluoromethyl)-3-hydroxy-4-phenylbutanoate in a Refor
matsky-type reaction. By successive stages of dehydration to a mixture
of but-2- and -3-enoates; simultaneous hydrogenation of the double bo
nd and replacement of Cl by H nitration; and conversion of the nitro-g
roup to amino; this hydroxy-ester was converted into ethyl 4-(4'-amino
phenyl)-3-(difluoromethyl)butanoate. Treatment of this with oxirane ga
ve the bis(2 ''-hydroxyethyl)-amino-derivative, from which the bis(chl
oroethyl)-analogue was made using Ph3P/CCl4. The target chlorambucil,
bearing a difluoromethyl group at position 3, was then obtained after
hydrolysis of the ester. (C) 1998 Elsevier Science S.A. All rights res
erved.