反应详情

U.S. Pat. No. 4,808,605 (to Hoffinann-La Roche) discloses various calcium antagonists including mibefradil, (1S,2S)-2-[2-{[3-(1H-benzimidazol-2-yl)propyl]-methylamino }ethyl]-6-fluoro- 1-isopropyl- 1,2,3,4-tetrahydronaphthalen-2-yl methoxyacetate, the dihydrochloride salt of which is the active ingredient of the antihypertensive POSICOR®. The synthesis of mibefradil, as described in that patent, involves the reaction of (1S,2S)-6-fluoro-1-isopropyl-2-[2-(4-toluenesulfonyloxy) ethyl]-1,2,3,4-tetrahydronaphthalene-2-ol with [3-(1H-benzimidazol-2-yl)propyl]methylamine in the presence of Hunig base (ethyldiisopropylamine) to form ( 1S,2S)-2-[2-{[3-( 1H-benzimidazol-2-yl)propyl]methylamino}ethyl]-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol, which is then acylated with methoxyacetyl chloride in chloroform in the presence of ethyldiisopropylamine to form mibefradil.