氯法拉滨的合成工艺改进及其有关物质的制备  

Improved Synthetic Process of Clofarabine and Synthesis of Its Related Substances

作　　者：代旭勇 王志华 项润华 于剑飞 陈亮 DAI Xuyong;WANG Zhihua;XIANG Runhua;YU Jianfei;CHEN Liang(Wuhan Biocause Pharmaceutical Development Co.,Ltd.,Wuhan 430056)

机构地区：[1]武汉百科药物开发有限公司,湖北武汉430056

出　　处：《中国医药工业杂志》2021年第3期347-351,共5页Chinese Journal of Pharmaceuticals

摘　　要：本研究改进了氯法拉滨(1)的合成工艺。以2-脱氧-2-氟-1,3,5-三苯甲酰基-α-D-阿拉伯呋喃糖(2)为起始原料,经溴代,再与2,6-二氯嘌呤在氢化钙和氢化钠存在下偶联;氨化过程以乙腈为溶剂,仅6-位氯发生氨基取代反应;甲醇醇解后,采用二甲亚砜和水进行精制,产品纯度达到99.67%,最大单杂小于0.1%。同时为了控制1的质量、建立1原料药的质量标准,根据改进的工艺合成路线,制备了3个有关物质:2-氯-9-(5-O-苯甲酰基-2-脱氧-2-氟-β-D-阿拉伯呋喃糖基)-6-氨基-9H-嘌呤(有关物质A)、2-氯-9-(2-脱氧-2-氟-β-D-阿拉伯呋喃糖基)-6-甲氧基-9H-嘌呤(有关物质B)和2-氯-9-(2-脱氧-2-氟-α-D-阿拉伯呋喃糖基)-6-氨基-9H-嘌呤(有关物质C),并经MS和NMR确认结构。The synthetic process of clofarabine(1) was mproved in this report.2-Deoxy-2-fluoro-1,3,5-tribenzoyl-α-D-arabinofuranose(2) was brominated,and coupled with 2,6-dichloropurine in the presence of sodium hydride and calcium hydride.Acetonitrile was used as solvent in the ammoniation,and only 6-chlorine was replaced by amino.After alcoholysis,dimethyl sulfoxide and water were used to purify the crude product.The purity of final product was 99.67% with maximum single impurity less than 0.1%.In order to perform the quality control of 1 according to this improved synthetic process,three related substances,2-chloro-9-(5-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)-6-amino-9H-purine(the related substance A),2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-6-methoxy-9H-purine(the related substance B),2-chloro-9-(2-deoxy-2-fluoro-α-D-arabinofuranosyl)6-amino-9H-purine(the related substance C),were prepared and their structures were confirmed by MS and NMR.

关 键 词：氯法拉滨 工艺改进 有关物质 合成 

分 类 号：R914.5[医药卫生—药物化学]