Development of a Practical and Scalable Synthetic Route for DBPR112: A Clinical Candidate for the Treatment of Non-Small Cell Lung Cancer

A practical manufacturing process for DBPR112, a furanopyrimidine EGFR inhibitor targeting exon 20 insertion, is reported. The first-generation route afforded DBPR112 in 9 steps with an overall yield of 2.2%. A laboratory second-generation process enabled hundred-gram synthesis with an improved yield of 8.8% by streamlining purification and simplifying the introduction of the dimethylamino Michael acceptor. The kilogram-scale third-generation route was further optimized by using IPC data to minimize side product formation, particularly in the Suzuki coupling reaction and amide bond formation steps. Ultimately, 8.8 kg of DBPR112 were produced under GMP conditions with a 24.9% overall yield, supplying API for nonsmall cell lung cancer clinical trials.