Optimization of the Synthesis Process of Quizartinib

OBJECTIVE  To optimize the synthetic process of quizartinib, a FMS-like tyrosine kinase 3 inhibitor.

METHODS Using 4-aminophenol as the starting material, the tandem addition cyclization/substitution/amination cyclization reaction with ammonium thiocyanate and 4-nitroacetophenone was carried out in the presence of benzyltrimethylammonium dichloroiodate/dimethyl sulfoxide to synthesize 7-hydroxy-4-(4-nitrophenyl)benzodimidazo2,1-bthiazole(4) via a one-pot method, which was subjected to the etherification with 4-(2-chloroethyl)morpholine to afford 7-(2-morpholinyl)ethoxy-4-(4-nitrophenyl)benzodimidazo2,1-bthiazole(6). Compound 6 was reduced by formamidinesulfinic acid to obtain 4-(7-(2-morpholinoethoxy)benzodimidazo2,1-bthiazol-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-diazabicyclo5.4.0undec-7-ene to deliver quizartinib(1).

RESULTS The total yield of quizarthib was 65% based on 4-aminophenol, and the purity of the product was 99.3%. The structures of intermediates and target product were confirmed by ¹H-NMR and ¹³C-NMR.

CONCLUSION  The 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 safe.