Synthesis method for trans N-ethyl-N-(2'-alkyl phenyl)-2-butenamide

Abstract

The invention relates to a synthesis method for trans N-ethyl-N-(2'-alkyl phenyl)-2-butenamide. The method comprises the steps of: 1) adding trans 2- butenoic acid into a reaction bottle, conducting dilution with an alkane solvent, performing cooling to 0-10DEG C, adding thionyl chloride dropwise, and then carrying out reaction at 10-50DEG C for 3-4h for standby use; 2) adding N-ethyl-2-alkyl aniline into the reaction bottle, conducting dilution with an alkane solvent, adding an alkaline aqueous solution, subjecting the mixed solution to stirring reaction at room temperature, adding the mixed solution obtained in step 1) slowly in a dropwise manner, and then carrying out reaction at 60-90DEG C for 5-6h at the end of dropwise adding; and 3) at the end of the reaction, separating out the organic phase, and washing the organic phase to neutral by water, conducting room temperature distillation to remove the solvent, and then performing pressure reduced distillation to separate the product. The method is simple, has high product yield, and can produce the high purity trans-structure product.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and in particular relates to a synthetic method of trans N-ethyl-N-(2'-alkylphenyl)-2-butenamide. Background technique [0002] N-ethyl-N-(2'-alkylphenyl)-2-butenamide, the structure of the following formula 1 (wherein R=C1-C3 straight-chain alkane) has strong antipruritic, scabicidal, Bactericidal effect, where N-ethyl-N-(2'-methylphenyl)-2-butenamide (R=-CH 3 ) The trade name is crotamiton, which is a drug widely used in medicine at present. [0003] [0004] The preparation of N-ethyl-N-(2'-alkylphenyl)-2-butenamide usually takes o-alkylaniline as starting material with the following two methods for synthesis (as following reaction formula (1) and (2), with R=CH 3 example): [0005] [0006] Method 1: "Journal of China Pharmaceutical University" reported on page 56 of the first phase in 1991 that triethyl orthoformate was reacted with o-toluidine to obtain the interme...

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Problems solved by technology

There are also reports of other technical methods for the second-step reaction. British Patent GB615137A reports direct heating reaction without solvent, but this method is not easy to operate, and produces HCl gas to corrode equipment simultaneously; Ethylbenzyl ammonium chloride was used to separate and purify the product. Repeating the operation of this technology, we found that the reaction could not obtain a product with satisfactory purity and yield.

[0008] In the above two methods, 2-butenoyl chloride is used as the crotonyl acylation reagent in the last step. Due to the existence of cis-trans structure, different reaction conditions have different results on the yield and the cis-trans structure ratio of the product. According to the above-mentioned The method of preparation, because the reaction process causes cis-trans conversion, the cis-trans ratio of the product in the result is generally 5-20:95-80, it is difficult to obtain high-purity trans structure

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