Practical Synthesis and Regioselective Alkylation of Methyl 4(5)-(Pentafluoroethyl)-2-propylimidazole-5(4)-carboxylate To Give DuP 532, a Potent Angiotensin II Antagonist

Article abstract of DOI:10.1021/jo00069a029

DuP 532 (2), which is a potent angiotensin II receptor antagonist, has been prepared by two different routes.One route, which is more practical for large-scale synthesis, required the preparation of methyl 4(5)-(pentafluoroethyl)-2-propylimidazole-5(4)-carboxylate (9).This imidazole was synthesized in five steps from commercially available 11 in 32percent overall yield.Alternate perfluoroalkylation methods of the iodoimidazole precursor 14 are presented.Imidazole 9 is remarkably stable to basic conditions and is alkylated by 2--4'-(bromomethyl) -1,1'-biphenyl (8), giving only the desired regioisomer.A comparison of the alkylation of the trisubstituted precursors and analogues to 9 with 8 indicate that even under mildly basic conditions (K2CO3/DMF), the mechanism is S_E2cB (anionic), except for 2-propyl-4(5)-(hydroxymethyl)imidazole (11) which alkylates as a neutral species (S_E2')