Baricitinib, with a 2-(1-(ethylsulfonyl)azetidin-3-yl)acetonitrile moiety at N-2 position of the pyrazol skeleton, is an oral and selective reversible inhibitor of the JAK1 and JAK2 and displays potent anti-inflammatory activity. Several research-scale synthetic methods have been reported for the preparation of key quaternary heterocyclic intermediates of baricitinib. However, they were all associated with several drawbacks, such as the expensive materials, usage of pollutional reagents, and poor yields. In this manuscript, we established a green and cost-effective synthesis of 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile and tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate for further scale-up production of baricitinib. This synthetic method employs commercially available and low-cost starting material benzylamine and an industry-oriented reaction of green oxidation reaction in microchannel reactor to yield important quaternary heterocyclic intermediates. Generally, this procedure is reasonable, green and suitable for industrial production.

中文翻译：

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一种工业上重要的四元杂环中间体的绿色、简便合成巴瑞替尼

Baricitinib 在吡唑骨架的 N-2 位具有 2-(1-(ethylsulfonyl)azetidin-3-yl)acetonitrile 部分，是一种口服和选择性的 JAK1 和 JAK2 可逆抑制剂，并显示出有效的抗炎活性。已经报道了几种用于制备巴瑞替尼关键季杂环中间体的研究规模合成方法。然而，它们都存在一些缺点，例如材料昂贵、使用污染试剂和产率低。在这份手稿中，我们建立了 2-(1-(乙基磺酰基)azetidin-3-ylidene) 乙腈和 3-(氰基亚甲基)氮杂环丁烷-1-羧酸叔丁酯的绿色且具有成本效益的合成方法，用于进一步扩大生产巴瑞替尼。该合成方法采用市售低成本起始原料苄胺和微通道反应器中绿色氧化反应的工业化反应，生成重要的季杂环中间体。总体而言，该工艺合理、绿色，适合工业化生产。