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.