Manufacturable Process of a Novel EGFR Inhibitor (Larotinib) for the Treatment of ESCC

The development of an efficient synthetic process for a clinical candidate Larotinib (4), which is an epidermal growth factor receptor (EGFR) inhibitor for the treatment of esophageal squamous cell carcinoma (ESCC), is reported for scale-up. The process used 3,4-dihydro-7-methoxy-4-oxoquinazolin-6-yl acetate (12) as the regulatory starting material and provided a stable and industrializable intermediate chloroquinazoline 11 under the process control. Further optimization of the process obviously improved the reaction yield and reduced the impurity level including alkyl halide potential genotoxic impurities (PGIs), at the same time avoiding the use of laborious and time-consuming column chromatography. More than 110 kg of Larotinib (4) in one batch can be finally produced stably for clinical research. Compared to our initial synthetic route in preclinical research, the overall yield of this optimized process increased significantly from 16.2 to 55.6%.