2-Methylsulfanyl-4-morpholin-4-yl-6-morpholin-4-ylmethyl-thieno[3,2-d]pyrimidine → 2-(1-benzenesulfonyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-morpholin-4-yl-6-morpholin-4-ylmethyl-thieno[3,2-d]pyrimidine

Participants

Reaction Conditions

Reaction Steps

A solution of 2-methylsulfanyl-4-morpholin-4-yl-6-morpholin-4-ylmethyl-thieno[3,2-d]pyrimidine (40 mg, 0.11 mmol) and 1-benzenesulfonyl-4-(tributylstannanyl)-1H-pyrrolo[2,3-c]pyridine (129 mg, 0.24 mmol) in DME (2 mL) was treated with copper(I)bromide-dimethyl sulfide complex (50 mg, 2.43 mmol) in a sealed tube and the solution was degassed with argon for 5 min. Pd(PPh3)4 (19 mg, 0.016 mmol) was added and the reaction mixture heated at 100° C. for 3 hours. The mixture was filtered through celite, which was washed with DME and the combined filtrate was evaporated to give a yellow gum. The gum was purified by flash chromatography on silica, eluting with EtOAc to afford 2-(1-benzenesulfonyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-morpholin-4-yl-6-morpholin-4-ylmethyl-thieno[3,2-d]pyrimidine (34 mg, 54%). The sulfone intermediate was dissolved in IMS (1 mL) and 1,4-dioxane (1 mL) and the stirring solution was treated with NaOH solution (0.1 mL from 2.5 g NaOH in 5 mL H2O). After 10 min the reaction mixture was treated with HCl (10 N) until at pH 7. The reaction mixture was filtered to remove insoluble material. The solids were washed with 1,4-dioxane, and the filtrate was evaporated. The resulting residue was taken up in DCM and washed with brine; the isolated organic phase was dried (MgSO4), filtered and evaporated. The resultant crude residue was purified by flash chromatography, (Si—PPC) eluting with 2-8% MeOH in DCM to afford 103 as a white solid (14 mg, 29%). 1H NMR (MeOD, 400 MHz): δ 8.99 (s, 1 H); 8.75 (s, 1 H); 7.66 (d, J=3.95 Hz, 1 H); 7.40-7.36 (m, 2 H); 4.14-4.05 (m, 4 H); 3.94-3.85 (m, 6 H); 3.73 (t, J=4.6 Hz, 4 H); 2.59 (t, J=4.35 Hz, 4 H). LCMS (Method F): RT=4.59 min, [M+H]+ 437.2

Provenance & Evidence