Development of an efficient chemo-enzymatic process for the synthesis of Nilotinib

Abstract

Nilotinib is one of the important second-generation tyrosine kinase inhibitors used in the treatment of chronic myeloid leukemia. The synthesis of Nilotinib involves expensive intermediates like carboxylic acids. Traditional methods of such intermediates involve chemical hydrolysis using acids or bases, leading to the formation of toxic compounds and high consumption of energy. This study focused on the development of a green and economical chemo-enzymatic approach to nilotinib synthesis by making use of a nitrilase biocatalyst. In this study, thirteen nitrilases were screened for their ability to produce carboxylic acid from nitrile, an intermediate of nilotinib under mildly buffered aqueous medium, and NIT-EW 101 was found to be the best enzyme. Time course study of this enzyme showed that 99.37% of the reaction was complete after 48 h. The isolated acid intermediate was then used to synthesize nilotinib by using the Curtius rearrangement and amide coupling. This route offers a sustainable and industry-feasible alternative to the conventional synthesis of Nilotinib.