A Novel and Scalable Synthesis of Anlotinib Dihydrochloride via Titanium-Catalyzed Kulinkovich–Szymoniak Cyclopropanation

Abstract A novel, scalable, and column chromatography-free synthesis of Anlotinib dihydrochloride is described in this report. Synthesis of Anlotinib dihydrochloride is accomplished employing Kulinkovich–Szymoniak cyclopropanation reaction as the pivotal reaction for the first time for the installation of the key cyclopropylamine moiety in Anlotinib dihydrochloride. The aforesaid pivotal reaction circumvents the usage of an expensive key starting material (16) and potentially unsafe reagents such as azides, which are particularly not amenable for producing Anlotinib dihydrochloride on a commercial scale. The reported route avoids palladium in one of the key steps of the synthesis.