多韦替尼乳酸盐的合成 |
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引用本文: | 陈金芳,朱冬斌,王 亚,徐启明. 多韦替尼乳酸盐的合成[J]. 武汉工程大学学报, 2014, 0(5): 1-4 |
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作者姓名: | 陈金芳 朱冬斌 王 亚 徐启明 |
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作者单位: | [1]绿色化工过程教育部重点实验室(武汉工程大学),湖北武汉430074; [2]武汉工程大学化工与制药学院,湖北武汉430074; [3]新型反应器与绿色化学工艺湖北省重点实验室(武汉工程大学),湖北武汉430074 |
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摘 要: | 为了解决多韦替尼乳酸盐合成工艺中操作比较繁琐的问题,以5-氯-2-硝基苯胺和N-甲基哌嗪为原料,经取代、还原、在酸性条件下与3-乙氧基-3-亚胺基丙酸乙酯盐酸盐回流成环,最后在碱性条件下与2-氨基-6-氟苯腈进行环合得到多韦替尼,与乳酸成盐,得到终产品多韦替尼乳酸盐.通过对反应过程中的每步反应工艺条件研究,得到各步工艺条件:取代反应不采用溶剂,n(5-氯-2-硝基苯胺)∶n(N-甲基哌嗪)=1∶2.5,产率可达97.8%;在氨取代反应中2-氟-6-胺基苯腈的产率为85%;在还原的过程中,选择在80℃时钯碳催化加氢;在40℃下采用六甲基硅胺钾作为碱合成多韦替尼,最终产率达到44.5%.
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关 键 词: | 多韦替尼 抗肿瘤 合成 |
Synthesis of dovtinib lactic acid salt |
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Affiliation: | CHEN Jin-fang,ZHU Dong-bin,WANG Ya,XU Qi-ming(1.Key Laboratory of Green Chemical Process(Wuhan Institute of Technology), Ministry of Education,Wuhan 430074,China;2.Schoool of Chemical Engineeing and Pharmacy, Wuhan Institute of Technology,Wuhan 430074,China;3.Hubei Key Laboratory of Novel Chemical Reactor & Green Chemical Technology(Wuhan Institute of Technology),Wuhan 430074 ,China) |
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Abstract: | To solve the problem of complicated production process conditions of synthizing dovtinib lactic acid salt,5-chloro-2nitroaniline and 2-amino-6-fluorobenzonitrile were applied as starting materials to prepare dovtinib lactic acid salt.via substitution,cyclization with ethyl-β-ethoxy-β-imino propanoate hydrochloride was refluxed under acidic conditions,cyclization with 2-amino-6-fluorobenzonitrile under base conditions,and then lactic acid was carried out.The results show that the yield is 97.8% when the molar of (5-chloro-2nitroaniline) ∶ (1-methylpiperazine) is 1 ∶ 2.5 in substitution;the yield of 2-amino6-fluorobenzonitrile is 85 % when the temperature is 90 ℃ in substitution of NH3 ;the optimum conditions of the reduction reaction are demonstrated at 80 ℃ for 6 h through catalytic hydrogenation of Pd/C;the total yield is 44.5% after using the base of lithium bis-trimethylsililyl)amide at 40 ℃ to synthize the dovtinib. |
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Keywords: | dovitinib antitumor synthesis |
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