Synthesis of stable isotope-labelled firocoxib

Firocoxib (ML-1,785,713) is a nonsteroidal, potent, and selective COX-2 inhibitor, approved for the control of pain and inflammation associated with osteoarthritis in dogs and horses, as well as to control postoperative pain and inflammation in dogs. We employed a six-step synthesis to prepare firocoxib-[¹³ C₆ ] in an overall yield of 35% from the commercially available bromobenzene-[¹³ C₆ ]. The synthetic route involved the preparation of the key intermediate phenyl-¹³ C₆ -methyl sulfide using cesium carbonate and S-methylthiourea sulfate under transition-metal free conditions. A two-step preparation of firocoxib-[¹³ C,² H₃ ] via the sulfinic acid derivative of firocoxib and methyl iodide-[¹³ C,² H₃ ] using the procedure of Gauthier and Yoshikawa was first undertaken. However, the deuterium atoms of the methyl sulfone undergo extensive exchange in aqueous media even at neutral pH. The isotope-labelled firocoxib is intended as an internal standard for bioanalyses of firocoxib from biological matrices.