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：

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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。