A Practical Synthesis of the TGFβRI Inhibitor N -(4-(3-(6-(Difluoromethyl)pyridin-2-yl)-1 H -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

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N -(4-(3-(6-(Difluoromethyl)pyridin-2-yl)-1 H -pyrrolo[3,2- b ]pyridin-2-yl)pyridin-2-yl)acetamide ( 5 ) is a potent inhibitor of TGFβRI 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.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.