2-氨基苯腈合成拉帕替尼药物中间体工艺

Synthesis of Rapatinib Drug Intermediate by 2-amino Benzonitrile

以2-氨基苯腈为起始原料,制备靶向抗肿瘤药物拉帕替尼重要中间体N-(3-氯-4-(3-氟苄氧基)苯基)-6-溴喹唑啉-4-胺。2-氯-4硝基苯酚和间氟苄氯通过Williamson缩合在Zn/NH 4Cl还原体系下制备3-氯-4-(3-氟苯甲氧基)苯胺;2-氨基苯氰通过碘代反应制备2-氨基-5碘苯腈;2-氨基-5碘苯腈在DMF-DME体系下进行胺-醛缩合得到N′-(4-碘-2-氰基苯基)-N,N-二甲基甲酰胺;N′-(4-碘-2-氰基苯基)-N,N-二甲基甲酰胺与3-氯-4-(3-氟苯甲氧基)苯胺经Dimroth重排得到目标产物;通过熔点测定、LC-MS、 1H-NMR确定产物。为提高碘化效率,对3种碘化体系进行评价,其中NH2I/H2O2碘化体系虽反应耗时较长,但产物转化率和选择性较为理想,反应90 h,2-氨基苯腈转化率63%,选择性91.2%,较为符合绿色化学的要求。

The preparation of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-bromoquinazole,an important intermediate for the targeted antitumor drug lapatinib,starts with 2-aminobenzonitrile porphyrin-4-amine. 2-chloro-4-nitrophenol and m-fluorobenzyl chloride were prepared in Zn/NH 4Cl reduction system to prepare 3-chloro-4-(3-fluorobenzyloxy) aniline;2-aminobenzene cyanide was subjected to iodine reaction preparation of 2-amino-5iodobenzonitrile;2-amino-5iodobenzonitrile under amine-aldehyde condensation in DMF-DME system to give N′-(4-iodo-2-cyanophenyl)-N, N-Dimethylformamide;N′-(4-iodo-2-cyanophenyl)-N,N-dimethylformamide and 3-chloro-4-(3-fluorobenzyloxy) aniline via Dimroth rearrangement. The rearrangement gave the desired product which was determined by melting point,LC-MS,1H-NMR. In order to improve the efficiency of iodine,three kinds of iodine systems were evaluated. The NH2I/H2O2 iodine system takes a long time to react,but the conversion and selectivity of the product are ideal. The reaction rate is 90h,and the conversion rate of 2-aminobenzonitrile is 63%,selectivity 91.2%,these are more in line with the requirements of green chemistry.