PRACTICAL SYNTHESIS AND REGIOSELECTIVE ALKYLATION OF METHYL NTAFLUOROETHYL)-2-PROPYLIMIDAZOLE-5(4)-CARBOXYLATE TO GIVE DUP-532, A POTENT ANGIOTENSIN-II ANTAGONIST

DuP 532 (2), which is a potent angiotensin II receptor antagonist, has been prepared by two different routes. One route, which is more pract ical for large-scale synthesis, required the preparation of methyl nta fluoroethyl)-2-propylimidazole-5(4)-carboxylate (9). This imidazole wa s synthesized in five steps from commercially available 11 in 32% over all yield. Alternate perfluoroalkylation methods of the iodoimidazole precursor 14 are presented. Imidazole 9 is remarkably stable to basic conditions and is alkylated by thyl)tetrazol-5-yl]-4'-(bromomethyl)-1, 1'-biphenyl (8), giving only the desired regioisomer. A comparison of the alkylation of the trisubstituted precursors and analogues to 9 wit h 8 indicate that even under mildly basic conditions (K2CO3/DMF), the mechanism is S(E)2cB (anionic), except for 2-propyl-4(5)-(hydroxymethy l)imidazole (11) which alkylates as a neutral species (S(E)2').