Carbon 14 and stable isotope synthesis of two potent and selective phosphodiesterase type 4 inhibitors

(R)‐2‐(4‐(Benzo[d]oxazol‐2‐yl)piperazin‐1‐yl)‐4‐((tetrahydro‐2H‐pyran‐4‐yl)amino)‐6,7‐dihydrothieno[3,2‐d]pyrimidine 5‐oxide (1) and (R)‐2‐(4‐(4‐chlorophenoxy)piperidin‐1‐yl)‐4‐((tetrahydro‐2H‐pyran‐4‐yl)amino)‐6,7‐dihydrothieno[3,2‐d]pyrimidine 5‐oxide (2) are two potent and selective inhibitors of phosphodiesterase type 4 (PDE4). In this manuscript, we report the detailed synthesis of these two compounds labeled with carbon 14 and with stable isotopes. The core (R)‐4‐((tetrahydro‐2H‐pyran‐4‐yl)amino)‐6,7‐dihydrothieno[3,2‐d]pyrimidine 5‐oxide is common in both inhibitors. In the radioactive synthesis, the carbon 14 atom was introduced in the benzoxazole moiety using [¹⁴C]carbon disulfide to obtain [¹⁴C]‐1 in five steps at a 55% overall yield. [¹⁴C]Urea was used to incorporate the carbon 14 atom in two steps in the dihydrothieno[3,2‐d]pyrimidine intermediate, which was then transformed in four more steps to [¹⁴C]‐2 at a 30% overall yield. Both compounds were isolated with specific activities higher than 54 mCi/mmol, radio‐ and chemical‐purities higher than 99%, and with excellent enantiomeric excess. In the stable isotope synthesis, [²H₈]piperazine was used to prepare [²H₈]‐1 in three steps in 72% overall yield, while [¹³C₆]phenol was used to prepare [¹³C₆]‐2 in four steps in 18% overall yield.