A Practical Synthesis of the TGF beta RI Inhibitor N-(4-(3-(6-(Difluoromethyl)pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)pyridin-2-yl)acetamide via One-Pot Sequential Sonogashira and Cacchi Reactions Catalyzed by Pd(OAc)(2)/BINAP

摘要

4-(3-(6-(DifluoromethyOpyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)pyridin-2-yl)acetamide (5) is a potent inhibitor of TGF beta RI kinase that provides durable antitumor activity when combined with an anti-PD-1 antibody. In order to conduct a full range of preclinical studies, over 150 g of high-quality material was required. The original discovery route through a stepwise copper-mediated Sonogashira reaction, trifluoroacetamide formation, and Cacchi reaction suffered from scale-up issues, mainly associated with tedious chromatographic purification of intermediates. This communication describes a chromatography-free one-pot synthesis of 5 via sequential Sonogashira and Cacchi reactions promoted by the superior catalyst Pd(OAc)(2)/BINAP, which was discovered by catalyst screening.