摘要
目的:改进Janus激酶抑制剂(JAKi)巴瑞替尼(baricitinib,1)的合成工艺.方法:3-(氰基亚甲基)氮杂环丁烷-1-甲酸叔丁酯(2)脱Boc得到中间体 2-(3-氮杂环丁基亚基)乙腈盐酸盐(3),再经磺酰化反应得到 2-[1-(乙基磺酰基)-3-氮杂环丁亚基]乙腈(4),再发生迈克尔加成反应得到1-(乙基磺酰基)-3-[4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基]-3-氮杂环丁烷乙腈(5),最后与 4-氯-7H-吡咯并[2,3-d]嘧啶发生偶联反应得到 1.结果与结论:总收率为 63.6%,纯度为 99.9%(HPLC面积归一化法),目标终产物及关键中间体的结构经MS和1H-NMR确证正确.该方法所使用的起始原料价廉易得.反应后处理简单,总收率较高,适合大量制备,可为巴瑞替尼的生产及其衍生物的合成研究提供参考.
Abstract
Objective:To improve the synthetic route of Janus kinase inhibitor baricinib(1).Methods:3-(cyanomethylene)azocyclobutane-1-carboxylic acid tert-butyl ester(2)was deprotected to obtain the intermediate 2-(3-azocyclobutanylidene)acetonitrile hydrochloride(3),which was then subjected to sulfonation reaction to obtain 2-[1-(ethylsulfonyl)-3-azocyclobutanylidene]acetonitrile(4),followed by Michael addition reaction to obtain 1-(ethylsulfonyl)-3-[4-(4,5,5-tetramethyl-1,3,2-dioxocyclopentane-2-yl)-1H-pyrazole-1-yl]-3-azocyclobutane acetonitrile(5).Finally,a coupling reaction was carried out with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine to obtain 1.Results&Conclusion:The total yield was 63.6%with the purity 99.9%(HPLC area normalization method).The structures of the target end product and key intermediates were confirmed to be correct by MS and 1H-NMR.The starting materials used in this method are inexpensive and readily available and the post-treatment of the reaction is simple.The new route has a high overall yield and is suitable for large-scale preparation,and can provide reference for the production of baricitinib and the synthesis research of its derivatives.
维普
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