奎扎替尼的改进合成

Improved Synthesis of Quizartinib

关键词:  奎扎替尼  FLT3抑制剂  抗白血病药物  合成

Key words:  quizartinib  FMS-like tyrosine kinase 3 inhibitor  anti-leukemia drug  synthesis

摘要:

目的 改进FMS样酪氨酸激酶3 (FLT3) 抑制剂奎扎替尼的合成工艺。方法 以4-氨基苯酚为起始原料,在苄基三甲基二氯碘酸铵 (BnNMe₃Cl₂I)/二甲基亚砜作用下,与硫氰酸铵、4-硝基苯乙酮发生串联的加成环化/取代/胺化环化反应一锅合成7-羟基-4-(4-硝基苯基)苯并[d]咪唑并[2,1-b]噻唑 (4),接着与4-(2-氯乙基)吗啉醚化得到7-[(2-吗啉基)乙氧基]-4-(4-硝基苯基)苯并[d]咪唑并[2,1-b]噻唑 (6),再用甲脒亚磺酸还原得到4-[7-[(2-吗啉基)乙氧基]苯并[d]咪唑并[2,1-b]噻唑-2-基]苯胺 (7),最后与3-氨基-5-叔丁基异噁唑、碳酸二苯酯在1,8-二氮杂双环[5.4.0]十一碳-7-烯 (DBU) 存在下羰基化制得奎扎替尼 (1)。结果 总收率65% (以4-氨基苯酚计),纯度99.3%,中间体及目标产物结构经₁^H-NMR和₁₃^C-NMR确证。结论 该合成路线原料经济易得、收率高,避免使用有毒的液溴、光气或氯甲酸苯酯,操作简便安全,适合工业化生产。

Abstract:

OBJECTIVE To improve the synthetic process of quinazotinib, a FMS-like tyrosine kinase 3 ( FLT3 ) inhibitor. METHODS The tandem addition cyclization/substitution/amination cyclization of 4-aminophenol, 4-nitroacetophenone and ammonium thiocyanate in the presence of benzyltrimethylammonium dichloroiodate (BnNMe3Cl2I)/dimethyl sulfoxide was achieved successfully in one pot to give 7-hydroxy-4-(4-nitrophenyl)benzo[d]imidazo[2,1-b]thiazole (4), which was subjected to the etherification with 4-(2-chloroethyl)morpholine to afford 7-[(2-morpholinyl)ethoxy]-4-(4-nitrophenyl)benzo[d]imidazo[2,1-b]thiazole (6). Compound 6 was reduced by formamidinesulfinic acid to obtain 4-(7-(2-morpholinoethoxy)benzo[d]imidazo[2,1-b]thiazol-2-yl)aniline (7). Compound 7 was subjected to carbonylation with 3-amino-5-(tert-butyl)isoxazole and diphenyl carbonate in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to deliver quinazotinib (1). RESULTS The total yield was 65% based on 4-aminophenol, and the purity of the product was 99.3%. The structures of intermediates and product were confirmed by 1H-NMR and 13C-NMR. CONCLUSION The new synthetic route has inexpensive and easily available raw materials and higher yield, and it avoids using toxic liquid bromine, toxic triphosgene or phenyl chloroformate, and the operation is simple and safety, which is suitable for industrial production.