반응 #73441

반응 방정식

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

triethylamine

NH3

MeOH

TFA

→

title compound

5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid [5-(1-aminomethyl-cyclopropyl)-isoxazol-3-yl]-amide

용매

THF

반응 조건

후처리

1. 1
   기타is quenched with water
2. 2
   추출the organics extracted with EtOAc
3. 3
   농축concentrationis
4. 4
   workup.DISSOLUTIONthen dissolved in THF (30 mL)
5. 5
   기타At this point the volatiles are removed
6. 6
   workup.DISSOLUTIONthe crude product is dissolved in DCM (10 mL)
7. 7
   기타After 10 minutes the volatiles are removed in vacuo
8. 8
   workup.DISSOLUTIONThe product is dissolved in EtOAc
9. 9
   workup.ADDITIONNH4OH is added
10. 10
    기타The organics are removed
11. 11
    기타the crude product separated via FCC
12. 12
    세척eluting with DCM:MeOH:NH4OH (100:0:0 to 92:7:1)

실험 절차

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, 1 H)8.35 (d, J=8.84 Hz, 1 H)8.15 (d, J=3.54 Hz, 1 H)7.44 (d, J=2.53 Hz, 1 H)7.11 (dd, J=9.09, 2.53 Hz, 1 H)6.77 (s, 1 H)6.70 (d, J=4.04 Hz, 1 H)4.09 (d, J=11.87 Hz, 4 H)2.94 (s, 2 H)1.05 (d, J=3.03 Hz, 4 H).

출처