Synthesis of kinase inhibitors utilizing thiophile-free Eschenmoser reaction of bromoindol-2-ones and thioamides

In the past two decades, compounds with 3-[phenylamino(phenyl)methylidene]indol-2-one pharmacophore have been estabilished in the treatment of several autoimmune diseases and diverse malignancies.

Despite extraordinary medicinal interest, synthetic accesibility of compounds with this structure moiety is somewhat limited. Most of commercial synthetic routes use condensation of protected 3-[alkoxy(phenyl)methylidene]indol-2-ones with anilines as key reaction step.

Recently, we found that the chemical transformation of thioiminium salts derived from 3-bromoindol-2-ones and thioamides can involve Eschenmoser reaction under specific conditions. Our recent findings have confirmed that this reaction could serve as a powerfull tool in synthesis of 3-[amino(phenyl)methylidene]indol-2-ones.

In this work, we would like to further demonstrate the usefulness of our novel synthetic approach for the preparation of some well-known molecules, especially Nintedanib and Hesperadin, which act as potent tyrosine or Aurora A/B kinase inhibitors.

The Eschenmoser sulfide contraction of subst. 3-bromoindol-2-ones with thiobenzanilide derivatives proceeded smoothly in highly polar aprotic solvents and provided the desired indol-2-ones in good to excellent yields.