Method for preparing 3(R)/(S)-amidogen-1-butanol

Abstract

The invention provides a method for preparing 3(R) / (S)-amidogen-1-butanol. The method comprises the steps that firstly, benzamide reacts with acetoacetic ester under the catalyzing action of p-toluenesulfonic acid, so that 3-benzamido-2-butene acid ester is generated; secondly, catalytic hydrogenation is conducted by using a chiral rhodium-diphosphine ligand compound as a catalyst for enantioselective hydrogenation, so that 3(R) / (S)-benzamide butyrate is generated highly selectively; thirdly, benzoyl is removed by means of mixed solvent of concentrated hydrochloric acid and alcohol, so that 3(R) / (S)-amino-crotonic acid ester hydrochloride is generated; finally, optically pure 3(R) / (S)-amidogen-1-butanol is obtained after ester carbonyl is reduced by means of hydronoron. According to the method, the raw materials are low in cost and easy to obtain, the technological operation is easy and convenient, resolution is not needed, the yield is high, cost is low, environmental friendliness is achieved, the optical purity of product is high, and the method is more suitable for industrial production.

Description

technical field [0001] The present invention relates to the preparation of chiral drugs. In particular, it relates to a preparation method of a chiral drug intermediate 3(R) / (S)-amino-1-butanol. Background technique [0002] Optically active 3(R) / (S)‐amino‐1‐butanol is a key intermediate of many chiral drugs. Such as J.Org.Chem., 1977, 42:1650, it is reported that it is the key intermediate of the antineoplastic drug 4‐methyl cyclophosphamide; Teter.Lett., 1988, 29:231, it is reported that it can be derived into β‐ Lactam, so it is an important intermediate for the synthesis of penem antibiotics; Drugs.Of the Future 2012,37:697, it is reported that it is also the chirality of the anti-AIDS drug Dolutegravir (listed in the United States in 2013, trade name Tivicay) The key intermediate of the six-membered ring. [0003] The synthetic method of this compound mainly contains following several kinds: [0004] Tetrahedron Lett.1988,29(2), 231 reported the synthetic method sho...

AI Technical Summary

Problems solved by technology

It has two disadvantages: one is that chiral phenylethylamine is more expensive; the other is that solvent recrystallization is required to split a pair of epimers, and in order to achieve a product with optical purity that meets the requirements, repeated crystallization is required. times, leading to a decrease in yield

However, its shortcoming is that the yield of the first step condensation reaction and the last step carboxyl reduction reaction is low, and the yields of these two steps are only 55-61% and 47-54% respectively.

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