反应详情

A mixture of 5-chloro-7-morpholin-4-yl-2-(3-morpholin-4-yl-azetidin-1-ylmethyl)thiazolo[4,5-d]pyrimidine (50 mg, 0.12 mmol), 2-methyl-1H-benzoimidazole (18 mg, 0.13 mmol), Pd2(dba)3 (5.5 mg, 0.006 mmol), XPhos (5.7 mg, 0.02 mmol) and cesium carbonate (78 mg, 0.24 mmol) in 1,4-dioxane (1.5 mL) was purged with argon gas for 15 min. The resulting reaction mixture was irradiated with microwaves at 145° C. for 30 min. The crude residue was loaded on an Isolute® SCX-2 cartridge (5 g). The cartridge was washed with DCM/MeOH and the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM. The resulting residue was further purified by column chromatography (Si—PCC, 2 M NH3 in MeOH:DCM: gradient 0:100 to 4:96). The solvents were reduced in vacuo to afford 256 as a brown solid (43 mg, 70%). LCMS (Method G): RT 5.52 min, [M+H]+ 507. 1H NMR (400 MHz, CDCl3): δ 8.22-8.21 (1 H, m), 7.71-7.70 (1 H, m), 7.30-7.27 (2 H, m), 4.18 (2 H, s), 4.03 (4 H, t, J=4.80 Hz), 3.89 (4 H, t, J=4.80 Hz), 3.76-3.72 (6 H, m), 3.27 (2 H, m), 3.15 (1 H, m), 3.00 (3 H, s), 2.37 (4 H, br s)

1. customwas purged with argon gas for 15 min
2. customThe resulting reaction mixture
3. customwas irradiated with microwaves at 145° C. for 30 min
4. washThe cartridge was washed with DCM/MeOH
5. washthe desired product was subsequently eluted
6. additiona mixture of 2M NH3 in MeOH and DCM
7. customThe resulting residue was further purified by column chromatography (Si—PCC, 2 M NH3 in MeOH:DCM: gradient 0:100 to 4:96)