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

Abstract

(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 [14 C]carbon disulfide to obtain [14 C]-1 in five steps at a 55% overall yield. [14 C]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 [14 C]-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, [2 H8 ]piperazine was used to prepare [2 H8 ]-1 in three steps in 72% overall yield, while [13 C6 ]phenol was used to prepare [13 C6 ]-2 in four steps in 18% overall yield.