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■ Crystal Structures of Intermediates in a New Synthesis of Antitumor Drug Cabozantinib

Gerhard Laus, Erwin Schreiner, Sven Nerdinger,* Volker Kahlenberg, Klaus Wurst, Stefan Vergeiner, and Herwig Schottenberger

*Sandoz GmbH, Biochemiestrasse 10, 6250 Kundl , Austria

Abstract

The heterocyclic antitumor drug cabozantinib was synthesized by condensation of 4-(6,7-dimethoxyquinolin-4-yloxy)aniline and methyl 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylate in the presence of two equivalents of sodium methoxide and azeotropic removal of methanol. In turn, the intermediate methyl 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylate was prepared from 4-fluoroaniline and dimethyl 1,1-cyclopropanedicarboxylate in the presence of one equivalent of sodium methoxide. Four crystal structures of intermediates and a byproduct were determined.