反应详情

To a solution of 4-{1-[5-(1-hydroxymethyl-cyclopropyl)-isoxazol-3-ylcarbamoyl]-1H-indol-5-yloxy}-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (500 mg, 0.939 mmol) in THF (10 mL), at 0° C., triethylamine (0.262 mL, 1.88 mmol) methanesulfonyl chloride (0.110 mL, 1.41 mmol) and DMAP (11.5 mg, 0.094 mmol) are added. After 2 h the reaction is complete and is quenched with water and the organics extracted with EtOAc. The crude product following concentrationis then dissolved in THF (30 mL), and NH3 in MeOH (1.82 mL, 12.8 mmol) is added. The reaction is stirred for 36 h. At this point the volatiles are removed and the crude product is dissolved in DCM (10 mL) and then TFA (10 mL, 130 mmol) is added. After 10 minutes the volatiles are removed in vacuo. The product is dissolved in EtOAc and then NH4OH is added. The organics are removed and the crude product separated via FCC eluting with DCM:MeOH:NH4OH (100:0:0 to 92:7:1) to give the title compound. MS (ESI) m/z 432.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.55 (s, 1H) 8.35 (d, J=8.84 Hz, 1H) 8.15 (d, J=3.54 Hz, 1H) 7.44 (d, J=2.53 Hz, 1H) 7.11 (dd, J=9.09, 2.53 Hz, 1H) 6.77 (s, 1H) 6.70 (d, J=4.04 Hz, 1H) 4.09 (d, J=11.87 Hz, 4H) 2.94 (s, 2H) 1.05 (d, J=3.03 Hz, 4H).

1. customis quenched with water
2. extractionthe organics extracted with EtOAc
3. concentrationconcentrationis
4. dissolutionthen dissolved in THF (30 mL)
5. customAt this point the volatiles are removed
6. dissolutionthe crude product is dissolved in DCM (10 mL)
7. customAfter 10 minutes the volatiles are removed in vacuo
8. dissolutionThe product is dissolved in EtOAc
9. additionNH4OH is added
10. customThe organics are removed
11. customthe crude product separated via FCC
12. washeluting with DCM:MeOH:NH4OH (100:0:0 to 92:7:1)