摘要
乐伐替尼是一种口服的多受体酪氨酸激酶(RTK)抑制剂。以对硝基苯基氯甲酸酯为原料,经两次酰化反应得到关键中间体1-(2-氯-4-羟基苯基)-3-环丙基脲,再在叔丁醇钾和无水碳酸钠作用下与4-氯-7-甲氧基喹啉-6-甲酰胺缩合,得到目标化合物乐伐替尼。通过1 HNMR、FTIR对中间体和目标化合物的结构进行了表征,并对其合成工艺进行了改进,优化了酰化反应的原料投料比和反应温度、缩合反应的碱试剂投料比。通过改进,目标化合物乐伐替尼总产率为51.2%,降低了反应成本,提高了反应产率,符合绿色化学的要求。
Lenvatinib is an oral polyceptor tyrosine kinase（PTK） inhibitor.Using 4-nitrophenyl chloroformate as a raw material,we obtained a key intermediate 1-（2-chloro-4-hydroxyphenyl）-3-cyclopropylurea by two steps of acylation reaction.Then,we obtained the target compound Lenvatinib by the condensation reaction of 1-（2-chloro-4-hydroxyphenyl）-3-cyclopropylurea and 4-chloro-7-methoxy quinoline-6-formamide in the presence of potassium tert -butoxide and anhydrous sodium carbonate.Furthermore,we confirmed the structures of the intermediates and the target compound by 1HNMR and FTIR,and improved the synthetic process.Meanwhile,we optimized the molar ratio of raw materials,the reaction temperature in the acylation reaction,and the molar ratio of two bases in the condensation reaction.The total yield of Lenvatinib is 51.2%,and the improved process has the advantages of low cost and high yield,which meets the requirements of green chemistry.
作者
武磊
冯菊红
胡学雷
王思哲
WU Lei;FENG Ju hong;HU Xue lei;WANG Si zhe(School of Chemical Engineering and Pharmacy,Wuhan Institute of Technology,Wuhan 430074,China;Key Laboratory of Green Chemical Process of Ministry of Education,Wuhan 430074,China)
出处
《化学与生物工程》
CAS
2018年第10期12-15,共4页
Chemistry & Bioengineering
基金
湖北省自然科学基金重点项目(2011CDA048)
关键词
乐伐替尼
对硝基苯基氯甲酸酯
酰化反应
缩合反应
Lenvatinib
4-nitrophenyl chloroformate
acylation reaction
condensation reaction
