Synthesizing method using serine to prepare Ramipril key intermediate

Abstract

The invention relates to a synthesizing method using serine to prepare a Ramipril key intermediate. The Ramipril key intermediate is 2-azabicyclo[3.3.0] octane-3-carboxylic acid hydrochloride or benzyl ester hydrochloride. The synthesizing method includes: using the serine as the initial raw material, and sequentially performing esterification, acyl chloride acylation, deacidification, Michael addition, hydrolysis and hydrogenation reduction to obtain the Ramipril key intermediate. The synthesizing method has the advantages that the key intermediate is synthesized by a five-step method, and the synthesizing method is cheap in raw material, environmentally friendly, simple in preparation process, simple to operate, mild in reaction condition, short in reaction cycle, convenient in post-treatment, low in equipment requirement, capable of avoiding heavy metal pollution and the use of expensive catalysts, few in three wastes, high in product yield and purity and suitable for industrial production.

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical and chemical intermediates, especially the preparation of ramipril key intermediate 2-azabicyclo[3.3.0]octane-3-carboxylate hydrochloride or benzyl ester hydrochloride by using serine as raw material synthetic method. Background technique [0002] Ramipril (Ramipril) is a long-acting, potent angiotensin-converting enzyme inhibitor (ACEI), which is one of the global products of Aventis and developed by its predecessor Hoechst (EP0079022). It is the drug of choice for the treatment of mild and essential hypertension and malignant congestive heart failure. This product has the characteristics of quick onset, long duration, high tissue specificity, good tolerance, and low toxicity and side effects. Chemical name: (S)-2-[N-(1-ethoxycarbonyl-3-phenyl-propyl)alanyl]-2-azabicyclo[3.3.0]octane-3-carboxylate Acid, CAS number: 87333-19-5, the structure is as follows: [0003] [0004] In thi...

AI Technical Summary

Problems solved by technology

[0009] In 2011, G.C.M.Kondaiah et al. reported the method for obtaining compound (I) through condensation of cyclopentanone and SAMP, LDA reduction, nucleophilic substitution, acid hydrolysis, cyclization, and hydrogenation reduction. SAMP, LDA, and the third step in this route Iodocarboxylate raw materials are more expensive, and the yield is low, which is not conducive to industrial production (Synthetic Communications, 41:1186–1191, 2011)

However, the amount of concentrated sulfuric acid used is relatively large, and the carbonization of the fifth step reaction is relatively serious. The reaction route is as in Scheme 3:

Images