Moexipril Synthetic Intermediates N-[(s) -1 - (ethoxycarbonyl) -3 - Phenylpropyl]-l-alanine Synthesis Process

With the continuous increase of the morbidity and mortality caused by cardiovascular disease, especially by hypertension, search for antihypertensive drugs have become very important.In the last century, angiotension converting enzyme (ACE) inhibitors have received much attention as a new type of antihypertensive drugs and their clinical efficacy has been well established. In Europe, US and Japan, several new antihypertensive drugs have been successfully developed, such as Ramiro developed by Hotchsh company of Germen in 1989 and launched in France, Benazeprl developed and launched by Swish Ciba-Geigy company in denmark in 1990, Delapril developed in Japan in 1989, Moexpril and Quinpril developed by Swish Warner-Lambert company which were launched in US and England in 1995 and 1989 respectively.This new type of ACEI, which possesses advantages including high and rapid efficacy, longlasting and high selectivity of organs etc, takes all over the world markets very quickly.In this paper, we present a convenient procedure for the synthesis of N-[[(S)-l-(Ethoxycarbonyl)]-3-phenylpropyl]amino]-L-alanine, a key intermediate in the synthesis of Moexpril, starting from a readily available benzene and cis-butylene dianhydride, through the F-C reaction, esterification, Michael addition and hydrogenation. The synthesis of target compound Moexpril was also successfully carried out in the author's research workDue to the requirement of the related experimental data of N-[(R)-1-Ethoxycarbonyl -3-phenylpropyl]-L-alanine, a diastereoisomer of N-[(S)-l-Ethoxycarbonyl-3-phenylpropyl]-L-alanine, which were needed in the declaring of Moexpril as a new medicine, we studied the synthesis of N-[(R)-l-Ethoxycarbonyl-3-phenylpropyl]-L-alanine in this work. Thus, N-[(R)-l-ethoxycarbonyl-3-phenylpropyl-L-alanine was obtained via F-C reaction, reduction, esterification, SN₂ substitution reaction, and then reaction with L-alanine benzyl ester using S-malic acid as the starting material. The structures of the synthesized compounds were confirmed by, ¹H-NMR, ¹3C-NMR, IR, MS, HPLC and elemental analysis.