摘要
以丙二腈为起始原料,与溴代乙醛缩二乙醇(2)发生α-烷基化反应,后经硫脲环合、脱保护、环合、酸化、脱除巯基、Sandmeyer氯代等反应,得到托法替尼中间体,4-氯-7H-吡咯并[2,3-d]嘧啶(1),总收率49%(以2计),纯度99.10%。该工艺有3点创新:(1)将巯基化合物成盐,直接从反应溶剂乙醇中析出,克服了巯基化合物难以纯化的技术难点,以较高收率(85%)制得4,6-二氨基-5-(2,2-二乙氧基乙基)嘧啶-2-硫醇钾盐(4);(2)一锅三步实现盐酸存在下的脱保护、环合、酸化反应,得到4-氨基-7H-吡咯[2,3-d]嘧啶-2-硫醇(5),简化了工序;(3)成功革除了三氯氧磷、2-甲基-3,3-二氯丙烯腈、2-氯乙醛等有毒试剂的使用,工艺更安全,尤其是三氯氧磷的革除大幅减少了三废,绿色环保。优化后的工艺原料经济易得、反应条件温和、操作简便、收率提高,适合工业化生产。
An improved synthetic process of the intermediate of tofacitinib,4-chloro-7H-pyrrolo[2,3-d]-pyrimidine(1),was described in this paper.Started from malononitrile,the desired product 1 was synthesized viaα-alkylation with bromoacetaldehyde diethyl acetal(2),cyclization with thiourea,deprotection,cyclization,acidification,removal of the thiol group,as well as Sandmeyer chlorination,with an overall yield of 49%(based on 2)and a purity of 99.10%.The improved process had three apparent advantages compared with previously reported procedures,including:direct precipitation of the potassium 4,6-diamino-5-(2,2-diethoxyethyl)pyrimidine-2-thiolate(4),from the reaction solvent ethanol as a salt with a high yield of 85%,overcoming the technical dificulties in purifying the thiol compound;②preparation of the 4-amino-7H-pyrrolo[2,3-d]pyrimidine-2-thiol(5)via a one-pot sequential three-step reaction of deprotection,cyclization,and acidification in the presence of hydrochloric acid,simplifying the process;③elimination toxic reagents such as phosphorus oxychloride,2-methyl-3,3-dichloroacrylonitrile,and 2-chloroacetaldehyde,which ensured process safety and improved environmental friendliness,especially the elimination of phosphorus oxychloride.All the raw materials and reagents used in the improved syntheses are inexpensive and readily available,and the operation is simple with mild conditions and high yield,which is suitable for industrial production.
作者
朱俊
孙缜
张耀华
喻婕
赵建宏
ZHU Jun;SUN Zhen;ZHANG Yaohua;YU Jie;ZHAO Jianhong(School of Pharmacy,East China University of Science and Technology,Shanghai 200237;Shanghai Pharmaceuticals Holding Co.,Ltd.,Shanghai 200020)
出处
《中国医药工业杂志》
EI
CAS
CSCD
2024年第1期53-57,共5页
Chinese Journal of Pharmaceuticals