反应详情

To a solution of tert-butyl 4-(1H-indol-5-yloxy)-5-methyl-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (150 mg, 0.409 mmol) in DMF (4 mL) at rt, di(1H-imidazol-1-yl)methanone (86 mg, 0.532 mmol) is added followed by TEA (0.34 mL, 2.46 mmol). After 3 h at room temperature 5-tert-butyl-1H-pyrazol-3-amine (342 mg, 2.46 mmol) is added and the reaction left stirring at rt for 48 h. At this point as 1N HCl solution in water (2 mL) is added and EtOAc (5 mL) is added. The layers are separated and the water layer extracted 3 times with EtOAc. The organics are dried and evaporated. DCM (4 mL) and TFA (10 mL, 130 mmol) are added at 0° C. and the reaction allowed to warm to rt over 1 h. At this point the reaction is complete. TFA/DCM is evaporated and then the product is taken up in EtOAc (100 mL). NH4OH (20 mL) is added and then water. The organics are separated and the water layer extracted with EtOAc (2 times). The organics are dried and evaporated. The crude prduct is added to a silica gel column (ISCO) and eluted with DCM/MeOH/NH4OH (100:0:0 to 93:6:1) to isolate 5-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (5-tert-butyl-2H-pyrazol-3-yl)-amide. MS (ESI) m/z 432.0 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.50 (s, 1H) 8.33 (d, J=9.09 Hz, 1H) 7.89 (d, J=3.54 Hz, 1H) 7.41 (d, J=2.27 Hz, 1H) 7.10 (dd, J=8.97, 2.40 Hz, 1H) 6.71 (d, J=3.54 Hz, 1H) 6.37 (s, 1H) 4.71 (d, J=6.57 Hz, 1H) 4.10-4.22 (m, 2H) 1.60 (d, J=6.82 Hz, 3H) 1.37 (s, 9H).

1. waitthe reaction left
2. customThe layers are separated
3. extractionthe water layer extracted 3 times with EtOAc
4. customThe organics are dried
5. customevaporated
6. temperatureto warm to rt over 1 h
7. customTFA/DCM is evaporated
8. additionNH4OH (20 mL) is added
9. customThe organics are separated
10. extractionthe water layer extracted with EtOAc (2 times)
11. customThe organics are dried
12. customevaporated
13. additionThe crude prduct is added to a silica gel column (ISCO)
14. washeluted with DCM/MeOH/NH4OH (100:0:0 to 93:6:1)