Ace Inhibitors - Fosinopril Synthesis Process

The development, action mechanisms, clinic application and market outlook of the angiotensin-converting enzyme inhibitor(ACEI) agents were briefly reviewed in this thesis. We presented fosinopril specially, which is one of the representatives of the third generation ACEI drugs, and studied its synthetic process in detail.Based on the literatures, fosinopril can be disconnected into two distinct fragments: trans-4-cyclohexyl-L-proline(2), and [(R)-[(lS)-2- methyl -1- (1- oxopropoxy)-propoxy] (4-phenylbutyl)phosphinyl]acetic acid(3). We focused on the synthetic process of compound 2 and designed a new synthetic route by referring to the relative literatures. The compound 2 was obtained in an overall yield of 14.5% via nine steps in this new route by using L—glutamic acid as the starting material. The compound 3 was obtained in an overall yield of 2.49% via eight steps by using phenyl chlorine as the starting material according to the literature . Through the condensation of compound 2 and compound 3, fosinopril was synthized successfully in a yield of 43%.This synthetic route of fosinopril comprises eighteen steps in total, including some special reactions, such as the protection and deprotection of the amino and carboxyl, reduction and animation, Aldol condensation, reduction of carbonyl group, chiral synthesis and split and so on. Finally, fosinopril was synthesised successfully in an overall yield of 6.2%.In this thesis, we designed a new synthetic route for fosinopril and study its synthetic process in detail. The structures of most of intermediates and the final product were identified by MS NMR and their physical property. This route improves the purity of final product by avoiding uncomplete Birch reduction, and could be applied to industrial production of fosinopril.