阿法替尼的合成工艺改进

Process Improvement on the Synthesis of Afatinib

以2-氨基-4-氯苯甲酸为原料,经环合、硝化、氯代和胺化后,采用一锅两步法制得关键中间体4-[(3-氯-4-氟苯基)氨基]-6-硝基-7-[(S)-四氢呋喃-3-基氧基]-喹唑啉(4);4依次经还原、酰胺化、HWE反应合成阿法替尼,总收率55.7%,含量98%,其结构经~1H NMR和LC-MS确证。

The key intermediate, 4- [ （ 3-Chloro-4-fluorophenyl ） amino ] -6-nitro-7- L （ S ） -tetrahydrotU- ran-3-yloxy ] quinazolin （4） , was prepared from 2-amino-4-chlorobenzoic acid by cyclization, nitrification, chlorine generation and amination, then a ＂one-pot＂ process. Afatinib with total yield of 55.7% and purity of 98% was synthesized by reduction, amidation and HWE from 4. The structure was confirmed by 1H NMR and LC-MS.