Synthetic method of trandolapril key intermediate (2S,3aR,7as)-octahydro-1H-indole-2-carboxylic acid

Abstract

The invention relates to a synthetic method for trandolapril key intermediate (2S, 3aR and 7as)-octahydro-1H-indole-2-carboxylic acid. The method comprises the following steps: obtaining a pair of cis 1, 2-cyclohexane dimethyl acid mono-methyl ester after refluxing hexahydrophthalic anhydride by methanol, splitting the cis 1, 2-cyclohexane dimethyl acid mono-methyl ester by (-) N, N-dimethyl amino diol to obtain 1, 2-cyclohexane dimethyl acid mono-methyl ester of (1R, cis) and (1S, cis) respectively; refluxing (1R, cis)-1, 2-cyclohexane dimethyl acid mono-methyl ester obtained by reclaiming mother liquor in hydrochloric acid to obtain cyclohexane o-dioctyl phthalate, and cyclizing the cyclohexane o-dioctyl phthalate to obtain an initial raw material of the hexahydrophthalic anhydride; and circulating the processes unceasingly to improve the impurity of the (1R, cis)-1, 2-cyclohexane dimethyl acid mono-methyl ester, and then directly entering a follow-up synthesizing process. The process effectively solves the problems of treatment of (1S, cis) 1, 2-cyclohexane dimethyl acid mono-methyl ester after racemization of (d1)1, 2-cyclohexane dimethyl acid mono-methyl ester and yield of (1R, cis)-1, 2-cyclohexane dimethyl acid mono-methyl ester, improves utilization efficiency of raw materials, reduces cost of products, is more suitable for industrialized production, can effectively improve follow-up reaction efficiency, and saves energy of a system.

Description

Technical field: [0001] The present invention relates to the synthesis and preparation route of (2s, 3aR, 7as)-octahydro-1H-indole-2-carboxylic acid, especially its use as a key intermediate in the process of synthesizing the angiotensin inhibitor trandolapril time preparation method. Background technique: [0002] Hypertension is one of the most common cardiovascular diseases affecting human health today, and it is also a common disease in our country, which is extremely harmful. The World Health Organization estimates that there are nearly 690 million hypertensive patients in the world, and nearly 3 million people die of hypertension and its complications every year. The number of hypertensive patients in my country is estimated to have exceeded 110 million. Statistics show that controlling blood pressure can reduce stroke by 39% to 42%, myocardial infarction by 8% to 14%, and vascular death by 11% to 12%. At the same time, the awareness rate, medication rate, and contr...

AI Technical Summary

Problems solved by technology

[0012] Comprehensive analysis of the above two routes shows that the total yields are comparable. Route (1) is split by biological enzymes, which is inconvenient for our production operations. In addition, the step of removing isomers in this route is later, resulting in increased synthesis costs; route (2) Using cheap hexahydrophthalic anhydride as a raw material, although the synthetic route is relatively long, most of them are common reactions, and in the second step, the isomers are removed by chemical resolution, which is relatively convenient and feasible route

However, there are also many deficiencies in the synthesis according to route 2 according to the existing route of literature, such as low utilization rate of raw materials, low final product yield, large energy consumption, high cost, etc.

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