巴瑞替尼的新合成方法  

Synthesis of Baricitinib

作　　者：黄双 杨健 徐强[2] 吴四清 HUANG Shuang;YANG Jian;XU Qiang;WU Siqing(Nanjing Red Sun Pharmaceutical Research Institute Co., Ltd., Nanjing 211300;Jiangsu Zhongbang Pharmaceutical Co., Ltd., Nanjing 211300)

机构地区：[1]南京红太阳医药研究院有限公司,江苏南京211300 [2]江苏中邦制药有限公司,江苏南京211300

出　　处：《中国医药工业杂志》2019年第6期618-622,共5页Chinese Journal of Pharmaceuticals

摘　　要：本研究设计一条新路线合成巴瑞替尼。4-氯吡咯并嘧啶(2)经氨基保护得4-氯-7-叔丁氧羰基-7H-吡咯并[2,3-d]-嘧啶(3),不经纯化,直接与水合肼、丙烯醛"一锅法"反应得4-(1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-7-甲酸叔丁酯(4)。此外,用易得的1,3-二溴丙酮和乙二醇以对甲苯磺酸作催化剂,经缩醛反应得2,2-双(溴甲基)-1,3-二氧戊环(5)。5与乙基磺酰胺缩合得(1-乙基磺酰基)氮杂环丁-3-酮(6),再与氰甲基磷酸二乙酯在氢化钠作用下反应得2-[1-(乙基磺酰基)氮杂环丁烷-3-亚甲基]乙腈(7),3步收率65.8%。然后化合物4和7经加成和氨基脱保护得目标产物,总收率77.8%(以2计)。本法中由1,3-二溴丙酮制备6,及由3制备4的方法未见文献报道。A novel synthetic route for baricitinib was reported. 4-Chloro-7 H-pyrrolo[2,3-d]pyrimidine(2)reacted with di-tert-butyl dicarbonate to give 4-chloro-7-(tert-butyloxycarboryl)-7 H-pyrrolo[2,3-d]pyrimidine(3), which was subjected to substitution and cyclization with hydrazine hydrate and acrolein in "one-pot" method directly to afford tert-butyl 4-(1 H-pyrazol-4-yl)-7 H-pyrrolo[2,3-d]pyrimidin-7-carboxylate(4). Meanwhile, 1,3-dibromopropan-2-one reacted with ethane-1,2-diol with p-toluenesulfonic acid as the catalyst to produce 2,2-bis(bromomethyl)-1,3-dioxolane(5), which was followed by a condensation with ethanesulfonamide to give 1-(ethylsulfonyl)azetidin-3-one(6), and then the latter reacted with diethyl(cyanomethyl)phosphonate to give 2-[1-(ethylsulfonyl)azetidin-3-ylidene]acetonitrile(7)in a yield of 65.8%. Finally, compound 4 and 7 were subjected to addition and deprotection to obtain the target compound with a total yield of 77.8%(based on 2). In this process, the preparation of compound 6 from 1,3-dibromopropan-2-one,and compound 4 from 3 have not yet been reported in literature.

关 键 词：巴瑞替尼 JAK1/JAK2抑制剂 “一锅法” 合成 

分 类 号：R979.5[医药卫生—药品] R914.5[医药卫生—药学]