度鲁特韦的合成工艺改进  

Improvement of the Synthesis Process of Dolutegravir

作　　者：侍笑娜 刘建武[1,2] 刘涛 严生虎 张跃[1,2] 沈介发 马晓明[1,2] 辜顺林 SHI Xiao-na;LIU Jian-wu;LIU Tao;YAN Sheng-hu;ZHANG Yue;SHEN Jie-fa;MA Xiao-ming;GU Shun-lin(School of Pharmacy,Changzhou University,Changzhou 213164,China;Continuous Flow Engineering Laboratory of National Petroleum and Chemical Industry,Changzhou 213164,China;Zhejiang Wanfeng Chemical Co.,Ltd.,Shaoxing 312073,China)

机构地区：[1]常州大学药学院,江苏常州213164 [2]石油和化工行业连续流技术工程实验室,江苏常州213164 [3]浙江万丰化工股份有限公司,浙江绍兴312073

出　　处：《化学试剂》2022年第4期617-622,共6页Chemical Reagents

基　　金：工信部产业技术基础公共服务平台项目(2020-0107-3-1)。

摘　　要：以4-氯乙酰乙酸甲酯和甲醇钠为原料制备4-甲氧基乙酰乙酸甲酯,再与N,N-二甲基甲酰胺二甲基缩醛缩合,与氨基乙醛缩二甲醇加成、草酸二甲酯环合、氢氧化锂选择性水解得到重要的吡啶酮中间体,然后在酸性条件下脱保护基与(R)-3-氨基-1-丁醇环化,与2,4-二氟苄胺酰胺化,最后经氯化镁脱甲基得到度鲁特韦,目标产物结构经^(1)HNMR、^(13)CNMR以及MS表征。与文献报道的以麦芽酚或4-甲氧基乙酰乙酸甲酯为起始原料合成路线相比,采用“一锅法”合成中间体1-(2,2-二甲氧基乙基)-5-甲氧基-6-(甲氧基羰基)-4-氧代-1,4-二氢吡啶-3-羧酸,该合成方法原料易得,减少分离纯化步骤,具有效率高、成本低、绿色环保等优点。Methyl 4-methoxyacetoacetate was synthesized with methyl 4-chloroacetoacetate and sodium methoxide as raw materials,then it was condensed with N,N-dimethylformamide dimethyl aceta,addition with aminoacetaldehy dedimethyl acetal,and aminoacetaldehyde dimethyl acetal.Important pyridine intermediate compounds were obtained from cyclization of dimethyl oxalate and selective hydrolysis of lithium hydroxide.After removing the aldehyde protecting group,they were cyclized with(R)-3-amino-1-butanol followed by being amidated with(2,4-difluorophenyl)methanamine and then demethylated by magnesium chloride to obtain Dolutegravir.The structure of the product was characterized by ^(1)HNMR,^(13)CNMR and MS.Compared with the synthetic route reported in literatures using maltol or methyl 4-methoxyacetoacetate as starting materials,a “one-pot method” was used to synthesize 1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid by employing methyl 4-chloroacetoacetate as the starting material.The synthesis method has the advantages of easy-to-obtain raw materials,reduced separation and purification steps,high efficiency,low cost,and environmental protection.

关 键 词：度鲁特韦 4-甲氧基乙酰乙酸甲酯 吡啶酮 合成 

分 类 号：TQ460.6[化学工程—制药化工]