Short and sustainable synthesis of the anticancer agent tepotinib

Around 2.5 million people are diagnosed with lung cancer worldwide each year, and overall survival is typically only 8-10 months. Since 2021, tepotinib has offered a new treatment for patients with MET exon 14 skipping non-small cell lung cancer, extending median survival to 25.5 months. However, Merck’s original synthesis requires 11 linear steps, affords only 27% overall yield, and generates 109.4 kg of waste per kilogram of drug. This work aimed to redesign tepotinib synthesis using greener and more efficient conditions. A convergent 5-step route was developed from commercially available materials. Two nucleophilic substitutions were performed in ethanol and acetonitrile, while an Eschweiler-Clarke reduction enabled one-pot N-Boc deprotection and N-methylation. Micelles from TPGS-750-M surfactant enabled two Suzuki couplings with remarkable achievements, such as ppm-level Pd catalysis. Tepotinib was obtained in 75% overall yield with an E-factor of 26, substantially reducing waste and potentially supporting more affordable generic API production.