Exploratory Process Development of Lorlatinib

The original synthesis of lorlatinib (1) was applied and improved in the first GMP campaign. In this approach, a slow addition of the boronate ester was critical in suppressing the formation of a homocoupled impurity in the Suzuki–Miyaura coupling, and the chemoselective hydrolysis of methyl ester was accomplished by potassium trimethylsilanoate. The synthesis was completed with macrocyclic amidation followed by deprotection of the Boc groups. A thorough process safety evaluation of HATU enabled its use as the coupling reagent for the macrocylic amidation, which improved the yield and eliminated the only chromatographic operation in the synthetic sequence.