Synthesis of One Carbon-14 Labelled [¹⁴C-pyrazolo]-Ibrutinib

A safe and economical synthetic method for one new carbon-14 labelled 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-[¹⁴C-pyrazolo]-1Hpyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one, [¹⁴C-pyrazolo]-Ibrutinib (2) was prepared with [¹⁴C]-barium carbonate as starting material, achieving a total yield of 19% with radiochemical and chemical purities exceeding 98%. The synthesis pathway was compared with existing methods, particularly those described in Janssen's patent applications, which offer higher yields but with more complex synthetic processes and lower purity. Despite the existing literature reporting the synthesis of ¹³C-labelled Ibrutinib, the ¹⁴C labelled method described here provides a viable alternative, particularly in some application fields necessitating the radioactive isotopic tracer technique. This work underscores the ongoing need for improved synthetic routes that offer higher yields, milder reaction conditions, and lower costs in light of the growing interest in Ibrutinib due to its clinical efficacy and commercial potential.