An Improved Synthesis Process of Mavacamten: The First-in-Class Cardiac Myosin Inhibitor

Mavacamten, a first-in-class cardiac myosin inhibitor, was approved by the FDA in 2022 for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (HCM). Herein, we developed a practical and environmentally benign process for its preparation, employing inexpensive and readily available starting materials. The key innovation lies in replacing the costly and hazardous trimethylsilyl isocyanate (TMS-NCO) step with a two-step sequence: isopropylamine reacts with diphenyl carbonate, followed by ammonolysis to afford the urea intermediate. Furthermore, instead of the traditional carbonyl chlorination–amination sequence, an optimized BOP-type phosphonium reagent was employed to directly accomplish the coupling step under mild conditions. This streamlined process simplifies operation while providing a consistent yield and scalability. On a 100 g scale, the overall yield reached 39.6% with a purity of 99.86% (100% ee chiral purity). Meanwhile, the optical isomer of mavacamten was synthesized by using this method, and the structures of both enantiomers were first further confirmed by single-crystal X-ray diffraction.