The Synthesis of Mavacamten(Camzyos)

A kilogram scale synthesis of mavacamten was exemplified in the patent published in 2021 (Ref. 1). The synthesis contains four synthesis steps and one purification step. The synthesis started with the synthesis of mono-substituted urea 4 from propanamine 2 and isocyanato-trimethylsilane 3. The urea 4 was converted to pyrimdinetrione 6 upon exposure to propanedioate 5 and sodium methoxide in methanol. Then phosphorus oxychloride (POCl3) promoted chlorination transformed trione 6 to dione chloride 7. The SNAr reaction of chloride 7 and (S)-phenylethylamine 8 in propanol delivered the final product mavacamten in 92%. The material was further purified via recrystallization in ethanol to provide the API with a purity of 99.97%.

Step 1. Mono-substituted urea synthesis: 3, DCM, 85%.

Step 2. Pyrimidinetrione synthesis: 5, NaOMe, MeOH, 79%.

Step 3. Trione Chlorination: POCl3, CAN, 69%.

Step 4. SNAr reaction: 8, 1-propanol, 104 °C, 92%.

Step 5.  Trituration Purification: 95% EtOH, 87%.

References

  1. Carlson, T.; Del Rio, C. L.; Edelberg, J. M.; Fernandes, S.; Henze, M. P.; et al. Methods of treatment with myosin modulator of diseases such as hypertrophic cardiomyopathy. WO2021092598 A1 2021.
  2. Semigran, M. J.; Lee, J. H.; Lambing, J.; Green, E.; Evanchik, M. Mavacamten for use in the treatment of hypertrophic cardiomyopathy. WO2019028360 A1 2019.
  3. Oslob, J.; Anderson, R.; Aubele, D.; Evanchik, M.; Fox, J. C.; et al. Preparation of pyrimidinedione compounds for treating hypertrophic cardiomyopathy (HCM) and other cardiac conditions. WO2014205223 A1 2014.