"One-pot" synthesis of irbesartan intermediate

Abstract

The invention relates to an improved synthesis process of an antihypertensive drug irbesartan intermediate 2-butyl-1,3-diazaspiro[4.4]nonane-1-en-4-one. Cyclopentanone undergoes an addition reaction to obtain 1-aminocyclopentyl cyanide. The cyanide is first acylated, then hydrolyzed and cyclized under alkaline conditions to obtain the product. The positive effect of the present invention is that the first hydrolysis, then acylation and cyclization reported in the prior art is improved to first acylation, then hydrolysis and cyclization, each step does not go through the separation process, and the "one pot method" is realized Production. The operation process is simplified, the product yield is improved, the product quality is guaranteed, the production cost is reduced, and it is more conducive to large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and specifically relates to the preparation of an antihypertensive drug irbesartan intermediate 2-butyl-1,3-diazaspiro[4.4]nonane-1-en-4-one method. Background technique [0002] 2-Butyl-1,3-diazaspiro[4.4]nonane-1-en-4-one, commonly known as spiroheterocycle, is mainly used in the synthesis of angiotensin II receptor antagonist irbesartan , is a key intermediate in the synthesis process of irbesartan. [0003] Bernhart. C. A., Perreaut P. M., Ferrari B. P. et al. in J. Med. Chem. [1993, 36(22): 3371-3380], Takenaka H., Hayase Y. in Heterocycles [1989, 29(6) : 1185-1189] and U.S. Patent USP5270317[1993.12.14], USP5559233[1996.7.24] the synthetic route of this spiroheterocyclic ring is mainly to obtain (reaction formula 1) through the following steps with cyclopentanone as starting material: [0004] Reaction 1 [0005] [0006] The starting material cyclopentanone is added...

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Problems solved by technology

[0007] Chinese patent CN1429817[2003.7.16] has reported the production technology that above-mentioned technical process is improved, and cyclopentanone obtains 1-amino cyclopentanecyanide through addition reaction, and this The cyanide is improved to be hydrolyzed under alkaline conditions to obtain the compound amidoamide (II), and the compound amidoamide (II) is not separated and subjected to valerylation to obtain the compound diamide (III), but it needs to be cooled to -12 The low temperature below ℃ is not conducive to industrial production, and the compound diamide (III) needs to be separated and purified, and then cyclized under alkaline conditions to obtain the spiroheterocycle (IV)

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