Development of a New Synthetic Route of the Key Intermediate of Irbesartan,Organic Process Research & Development

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Development of a New Synthetic Route of the Key Intermediate of Irbesartan
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2022-08-04 , DOI: 10.1021/acs.oprd.2c00113
Zhaohang Chen ₁ , Yuanxia Guo ₁ , Huilong Niu ₁ , Jinxin Wang ₁ , Jianming Li ₁ , Chao Li ₁ , Renzhong Qiao ₁

Affiliation

Herein, we describe a new synthetic route to prepare 4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile (5), an intermediate of irbesartan. Compared with leucine or its derivatives as the starting material to synthesize irbesartan in many previous reports, the intermediate 5 could be obtained in four steps from low-cost and commercially available glycine methyl ester as the starting material, which also avoided the use of highly toxic cyanide. The spirocycle structure in the intermediate 5 was constructed with dihaloalkanes via a simple alkylation reaction. The related impurities and process parameters were studied in detail. Finally, the scale-up of this route was successfully performed on a 200 g scale, affording 332 g of the intermediate 5 with 98.4% purity and 54.2% overall yield in four steps. Meanwhile, process mass intensity and yield stability were demonstrated. The current synthetic route provides an alternative strategy for the production of irbesartan.

中文翻译：

厄贝沙坦关键中间体合成新路线的开发

在此，我们描述了一种制备 4'-((2-丁基-4-氧代-1,3-二氮杂螺[4.4]non-1-en-3-yl)methyl)-[1,1'-联苯]-2-甲腈( 5 )，厄贝沙坦的中间体。与以往多篇报道以亮氨酸或其衍生物为起始原料合成厄贝沙坦相比，中间体5可以以低成本、市售的甘氨酸甲酯为起始原料，四步制得，也避免了使用剧毒。氰化物。中间体5中的螺环结构由二卤代烷通过一个简单的烷基化反应。对相关杂质及工艺参数进行了详细研究。最后，该路线的放大在 200 g 规模上成功进行，在四个步骤中提供了 332 g 纯度为 98.4% 和总产率为 54.2%的中间体5 。同时，工艺质量强度和产量稳定性得到了证明。目前的合成路线为厄贝沙坦的生产提供了一种替代策略。

更新日期：2022-08-04

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