Continuous Flow Synthesis of a Key Intermediate Common to Gefitinib and Larotinib

Herein, we demonstrate a continuous flow synthesis method for 4-(3-chloro-4- fluorophenylamino)-6-hydroxy-7-methoxyquinazoline, a key intermediate of Gefitinib and Larotinib. The process comprises three chemical transformations, chlorination, amination, and hydrolysis, in three sequential continuous flow devices. First, a single-step continuous flow chlorination is demonstrated in an agitated tube reactor with a yield of 92.7% and a residence time of 10 min. Second, the combined continuous flow chlorination and amination are demonstrated in 96.1% yield with a residence time of 12.5 min. Finally, continuous flow synthesis of the target compound is demonstrated in 85.1% total yield with a total residence time of 18.5 min.