抗癌药乐伐替尼的合成工艺改进
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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 potassiumtert-butoxide and anhydrous sodium carbonate.Furthermore,we confirmed the structures of the intermediates and the target compound by 1 HNMR 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.
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 potassiumtert-butoxide and anhydrous sodium carbonate.Furthermore,we confirmed the structures of the intermediates and the target compound by 1 HNMR 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.
引文
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[10]李莉,黄伟,岑均达.Lenvatinib的合成[J].中国药物化学杂志,2015,25(4):285-288.LI L,HUANG W,CEN J D.Synthesis of Lenvatinib[J].Chinese Journal of Medicinal Chemistry,2015,25(4):285-288.
[11]刘彦东,郑志兵,李松.受体酪氨酸激酶抑制剂乐伐替尼的合成工艺改进[J].中国药物化学杂志,2016,26(1):29-32.LIU Y D,ZHENG Z B,LI S.Improved synthesis of receptor tyrosine kinase inhibitor Lenvatinib[J].Chinese Journal of Medicinal Chemistry,2016,26(1):29-32.
[2]江刘平.VEGFR酪氨酸激酶抑制剂的临床应用与研究进展[J].安徽医药,2014,18(11):2032-2035.JIANG L P.Clinical use and research of VEGFR inhibitor[J].Anhui Medical and Pharmaceutical Journal,2014,18(11):2032-2035.
[3]张碧燕,谷建钟,郭勇.乐伐替尼治疗中晚期肿瘤的临床研究进展[J].中国新药杂志,2018,27(5):521-526.ZHANG B Y,GU J Z,GUO Y.Progress in the treatment of advanced cancer with Lenvatinib[J].Chinese Journal of New Drugs,2018,27(5):521-526.
[4]王凌霄,肖典,周辛波.口服多靶点酪氨酸激酶抑制剂——乐伐替尼[J].临床药物治疗杂志,2015,13(5):11-14.WANG L X,XIAO D,ZHOU X B.An oral multiple receptor tyrosine kinase inhibitor—Lenvatinib[J].Clinical Medication Journal,2015,13(5):11-14.
[5] US FDA.FDA approves Lenvima for a type of thyroid cancer[OL].[2015-02-13].http://www.fda.gov/news-events/newsroom/pressannouncements/ucm434288.htm.
[6] NAITO T,YOSHIZAWA K.Urea derivative and process for preparing the same:US 7683172[P].2010-03-23.
[7]李兴民.一种乐伐替尼的制备方法:CN 105801481A[P].2016-07-27.
[8]内藤俊彦,吉泽一洋.脲衍生物的制备方法:CN 101337930[P].2004-11-08.
[9]孙欢,李林,何瑞红,等.Lenvatinib的合成[J].中国医药工业杂志,2014,45(6):507-510.SUN H,LI L,HE R H,et al.Synthesis of Lenvatinib[J].Chinese Journal of Pharmaceuticals,2014,45(6):507-510.
[10]李莉,黄伟,岑均达.Lenvatinib的合成[J].中国药物化学杂志,2015,25(4):285-288.LI L,HUANG W,CEN J D.Synthesis of Lenvatinib[J].Chinese Journal of Medicinal Chemistry,2015,25(4):285-288.
[11]刘彦东,郑志兵,李松.受体酪氨酸激酶抑制剂乐伐替尼的合成工艺改进[J].中国药物化学杂志,2016,26(1):29-32.LIU Y D,ZHENG Z B,LI S.Improved synthesis of receptor tyrosine kinase inhibitor Lenvatinib[J].Chinese Journal of Medicinal Chemistry,2016,26(1):29-32.