Studies on Angiotensin Converting Enzyme Inhibitors. V. The Diastereoselective Syntheis of 2-Oxomidazolidine Derivatives
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A diastereoselective syntesis of imidapril (1), which is under clinical study as an antihypertensive drug based on its angiotensin converting enzyme (ACE)-inhibitory activity, was established. N-Alkylation of (2S)-2-amino-4-phenylbutyric acid ester (12) with 3-((2R)-2-methane or toluenesulfonyloxypropionyl)-2-oxoimidazolidine derivative (11) diastereoselectively proceeded in an SN2 fashion to afford tert-butyl (4S)-3-[(2S)-2-[N-[(1S)-1-ethoxycarbonyl)-3-phenylpropyl]amino]propionyl]-1-methyl-2-oxoimidazolidine-4-carboxylate (13), a precursor of 1. Alternatively, benzyl (2S)-2-[N-(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]propionate (15), which is the key building block of 13,was synthesized by teh same strategy. This procedure was also applied to the synthesis of enalapril.