Study On The Process Of Synthesizing ANTI-IPF Drug Nintedanib (BIBF 1120)

Nintedanib is a promising drug for the treatment of idiopathic pulmonary fibrosis with chemical name:(Z)-methyl 3-(((4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)phenyl)amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate.In this article two main synthesis methods of Nintedanib have been optimized, one takes 4-chloro-3-nitrobenzoic acid and N-methyl-4-nitroaniline as raw materials, the other takes 2-chloro-N-methyl-N-(4-nitrophenyl)acetamide and methyl 3-nitrobenzoate as starting compounds. The total yields of optimized method is 70.0%, which is calculated from the common intermediate (E)-methyl 3-(methoxy(phenyl)methylene)-2-oxoindoline-6-carboxylate. We also start the study on the impurity of Nintedanib.Also, a new synthesis method of Nintedanib has been studied on. The most outstanding advantage is the mild reaction conditions compared with previous methods. The total yield of this new method is 77.2%.The results show that the process of synthesis of Nintedanib can be conducted in a new method with more simple operations and higher yield, which is superior to those existed ones.