Synthesis of a Potent Bruton's Tyrosine Kinase Inhibitor Labelled With Carbon-14 and Deuterium

Bruton's tyrosine kinase (BTK) is a cytoplasmic enzyme that plays a crucial role in B cell development, survival, proliferation and differentiation. This enzyme is expressed in several autoimmune diseases and cancers. Therefore, shutting out this enzyme with irreversible inhibitors is one of the strategies used to treat these diseases. The drug candidate 1 is a very potent and selective BTK inhibitor. Herein, we describe the preparation of this compound labelled with deuterium and carbon-14. Deuterium labelled 1 was prepared in 10 chemical steps and in 35% overall yield with more than 98% chemical purity and more than 99% isotopic enrichment. This synthesis was followed with the radioactive one as both synthetic routes were similar. Carbon-14 labelled 1 was prepared in eight radiochemical steps in 26% overall yield and in more than 99% radio and chemical purities and with specific activity of 53.1 mCi/mmol (1.96 GBq/mmol). This isotopically labelled compound was needed for DMPK and other studies.