阿西替尼的合成

Synthesis of axitinib

目的合成具有抗肿瘤活性的小分子酪氨酸激酶抑制剂阿西替尼。方法以6-硝基吲唑为原料,其3-位经碘代、1-位氮原子经四氢吡喃保护,再与2-乙烯基吡啶发生Heck反应,6-位硝基再经过硝基还原、重氮化、碘代,与硫代水杨酸甲酯在钯催化剂作用下发生偶联,最后经脱保护基和酯的氨解反应得到抗肿瘤药阿西替尼。结果与结论经过8步反应合成目标化合物阿西替尼,总收率为33.4%,目标化合物和中间体的结构经1H-NMR和MS谱确证。

Axitinib, an inhibitor of vascular endothelial growth factor （VEGF） under investigation as an on- cology drug,was developed by Pfizer and was approved by FDA in January 2012 with the trade name Inly- ta. Based on the synthetic method of axitinib in one patent , we optimized and improved the existing process. For example, we used 2-mercapto-benzoic acid methyl ester in the coupling reaction instead of 2-mercapto- benzoic acid methyl amide to improve the yield and avoid using column chromatography in the reaction. In summary, In our designing route, axitinib was synthesized from 6-nitro-1H-indazole by iodination, THP pro- tection, Heck reaction, reduction, and then coupled with 2-mercapto-benzoic acid methyl ester, deprotection and ammonolysis with an overall yield of about 33.4% ,which is higher than that of the reference（23.2% ）. The structures of axitinib and intermediates were confirmed by ^1H-NMR and MS.