β-地西他滨合成工艺改进  

Improved synthesis of β-decitabine

作　　者：季春伟 姚彤 毛联岗 李林哲 李润莱 李树安 JI Chunwei;YAO Tong;MAO Liangang;LI Linzhe;LI Runlai;LI Shu'an(School of Environment and Chemical Engineering,Jiangsu Ocean University,Lianyungang 222005,Jiangsu,China;College of Polymer Science and Engineering,Sichuan University,Chengdu 610065,Sichuan,China;JARI Pharmaceutical Co.,Ltd.,Lianyungang 222006,Jiangsu,China;School of Marine Science and Fisheries,Jiangsu Ocean University,Lianyungang 222005,Jiangsu,China)

机构地区：[1]江苏海洋大学环境与化学工程学院,江苏连云港222005 [2]四川大学高分子科学与工程学院,四川成都610065 [3]连云港杰瑞药业有限公司,江苏连云港222006 [4]江苏海洋大学海洋科学与水产学院,江苏连云港222005

出　　处：《精细化工》2021年第9期1867-1874,1887,共9页Fine Chemicals

基　　金：江苏省苏北科技专项(SZ-LYG202017);江苏省优势学科建设工程资助项目(5511201901X);江苏海洋大学博士启动基金(KQ16001);江苏省研究生科研与实践创新计划项目(KYCX_192292,KYCX19_2269,KYCX19_2273);江苏省大学生创新项目(SD201911641104003,X201911641319001)。

摘　　要：以2-脱氧-D-核糖为起始原料,用乙醇/乙酰氯替代甲醇/HCl,进行缩醛反应得到1-乙氧基-2-脱氧核糖;以二氯甲烷作为溶剂,用对氯苯甲酰氯代替对甲基苯甲酰氯保护1-乙氧基-2-脱氧核糖的3,5-二羟基得到1-乙氧基-2-脱氧-3,5-二对氯苯甲酰氧基-D-呋喃核糖,1-乙氧基-2-脱氧核糖转化率为100.00%,并用低温析晶方法除去过量对氯苯甲酰氯;再经5′-氮杂胞嘧啶与糖苷缩合反应,氨甲醇脱保护反应,分离异构体得到β-地西他滨。采用^(1)HNMR、^(13)CNMR、MS、FTIR和X单晶衍射仪对产物及中间体的结构进行了表征。小试总收率达到30.62%,经千克级放大实验,β-地西他滨的总收率为30%以上。Methanol/hydrogen chloride was replaced by ethanol/acetyl chloride to obtain 1-ethoxy-2-deoxyribose by acetalization from 2-deoxy-D-ribose. Subsequently, 1-ethoxy-2-deoxy-3,5-di-p-chlorobenzoyloxyD-ribofuran was obtained using p-chlorobenzoyl chloride instead of p-methyl benzoyl chloride to protect the 3,5-dihydroxyl of 1-ethoxy-2-deoxy-ribose, and the conversion rate of 1-ethoxy-2-deoxy-ribose was 100%. Extra p-chlorobenzoyl chloride was removed by low-temperature crystallization. β-Decitabine was synthesized by condensation reaction of 5′-azacytosine with glycoside, deprotection by ammonia methanol, and isomer isolation. The structures of the product and intermediates were characterized by ^(1)HNMR, ^(13)CNMR, MS, FTIR and X-ray single crystal diffractometer. The yields of trial batch and kilogram-level scale-up batch were 30.62% and 30%, respectively.

关 键 词：β-地西他滨 乙缩醛化 对氯苯甲酰氯 改进工艺 医药原料 

分 类 号：TQ460.6[化学工程—制药化工]