奎扎替尼的合成

对硝基苯酚(2)与4-(2-氯乙基)吗啉盐酸盐(3)发生亲核取代反应得到4-2-(4-硝基苯氧基)乙基]吗啉(4),4经10%钯炭氢化还原得到4-2-(4-吗啉基)乙氧基]苯胺(5)。5经2步环化反应得到7-2-(4-吗啉基)乙氧基]-2-(4-硝基苯基)咪唑并2,1-b]1,3]苯并噻唑(8)。8经铁粉和氯化铵还原得到4-7-2-(4-吗啉基)乙氧基]咪唑并2,1-b]1,3]-苯并噻唑-2-基]苯胺(9)。另以3-氨基-5-叔丁基异?唑(10)和氯甲酸苯酯反应得苯基(5-叔丁基异?唑-3-基)氨基甲酸酯(11)。用9与11反应得到奎扎替尼(1),终产物纯度为99.17%,总收率为55%(以2计)。该方法所使用起始原料2价廉易得,且3的用量大大降低,反应条件相对温和,后处理操作简便,可为工业化生产提供参考。

Synthesis of Quizartinib

4-Nitrophenol(2) reacted with 4-(2-chloroethyl)morpholine hydrochloride(3) to obtain 4-2-(4-nitrophenoxy)ethyl]morpholine(4) through nucleophilic substitution. 4-2-(4-Morpholinyl)ethoxy]aniline(5) was obtained by hydrogenation of compound 4 with 10%Pd/C, which was used to prepare the 7-2-(4-morpholinyl)-ethoxy]-2-(4-nitrophenyl)imidazo2,1-b]1,3]benzothiazole(8) via two steps of cyclization. 4-7-2-(4-Morpholinyl)-ethoxy]-imidazo2,1-b]1,3]benzothiazole-2-yl]aniline(9) was prepared from the compound 8 by reduction of the nitro group with iron and ammonium chloride. Phenyl-5-(t-butyl)isoxazol-3-yl]carbamate(11) was synthesized from 3-amino-5-t-butyl-isoxazole(10) by treatment with phenyl chloroformate. Compound 9 reacted with compound 11 to give quizartinib(1) in a purity of 99.17%, and the total yield was 55%(based on 2). In this reported route, starting material was inexpensive and easy to obtain, and the amount of 3 was greatly reduced. This method had mild reaction conditions and simple work-up, and it could provide reference for industrial production.