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

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.