Trans-4-dimethylamino crotonic acid hydrochloride preparation method

Abstract

A trans-4-dimethylamino crotonic acid hydrochloride preparation method is as follows: trans-4-dimethylamino crotonic acid hydrochloride is obtained by HWE reaction of N, N-dimethylamino acetaldehyde hydrosulphite as a substrate and triethyl phosphonoacetate. By optimization of reaction conditions, the trans-4-dimethylamino crotonic acid hydrochloride can be obtained by the HWE reaction.

Description

Technical field: [0001] The invention relates to the preparation of a crotonic acid derivative. Background technique: [0002] Trans-4-dimethylaminocrotonate hydrochloride (CAS: 848133-35-7) is a key intermediate for the synthesis of afatinib. Chinese patent document 200480007723.9 discloses a method using 4-bromocrotonate methyl 4-Dimethylaminocrotonate methyl ester is obtained by reacting the ester with dimethylamine tetrahydrofuran solution, and then the 4-dimethylaminocrotonate methyl ester is hydrolyzed with sodium hydroxide. A method for obtaining trans-4-dimethylaminocroton hydrochloride by crystallization extraction. The process of this method is cumbersome to operate, and the final product is very likely to contain salt, requiring multiple washings and recrystallization. The Horner-Wadsworth-Emmons reaction (HWE reaction for short), also known as the Wittig-Horner reaction, is an improved Wittig reaction in which phosphoric acid esters are used instead of phosphor...

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Problems solved by technology

However, the literature also pointed out that under normal conditions without substituents, the reaction product should be mainly in the trans structure, indicating that whether it is a charge-absorbing or a supply-donating group, it will affect the stereoselectivity of the reaction, resulting in the inability to obtain the desired product. The product

And also pointed out in this document, when adopting methyl alcohol, acetonitrile to carry out the HWE reaction of acetaldehyde and diformonitrile phosphate as solvent, it is easier to react than in common tetrahydrofuran solvent, and when reacting in methanol, the trans structure in the product More (about 65:35), but in this reaction, a strong charge-absorbing group was adopted in the phosphoric acid ester, and there was triethyl phosphonoacetate used in the preparation of trans-4-dimethylamino croton markedly different

And through our experiments, it was found that the reaction yield of trans-4-dimethylaminocroton hydrochloride was not ideal when purely using methanol as a solvent and adopting HWE reaction

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