多韦替尼乳酸盐的合成

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%.

Synthesis of dovtinib lactic acid salt

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.