Sodium hydride → N-(5-tert-butylisoxazol-3-yl)-5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-1H-indole-1-carboxamide

HRID 45091

반응식

HRID 45091 반응식
[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:12]4[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[C:29]([C:33]1[O:37][N:36]=[C:35]([NH:38][C:39](=O)[O:40]C2C=CC=CC=2)[CH:34]=1)([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[C:29]([C:33]1[O:37][N:36]=[C:35]([NH:38][C:39]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([O:10][C:11]4[C:12]5[CH2:19][NH:18][CH2:17][C:13]=5[N:14]=[CH:15][N:16]=4)=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[O:40])[CH:34]=1)([CH3:32])([CH3:30])[CH3:31]

참가 물질

5

반응물 3

HCID 24758Sodium hydrideHCID 13489605Phenyl 5-tert-butylisoxazol-3-ylcarbamateHCID 59394637Tert-butyl 4-(1H-indol-5-yloxy)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate

생성물 1

HCID 59394335N-(5-tert-butylisoxazol-3-yl)-5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-1H-indole-1-carboxamide

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매

반응 조건

온도
0 °C

실험 절차

Tert-butyl 4-(1H-indol-5-yloxy)-5H-pyrrolo[3,4-d]pyrimidine-6(7 H)-carboxylate (127 mg, 0.360 mmol) is dissolved in THF (8 mL), flushed with nitrogen and cooled to 0° C. Sodium hydride (23 mg, 0.575 mmol, 60% in mineral oil) is added and the mixture is stirred for 10 minutes. Phenyl 5-tert-butylisoxazol-3-ylcarbamate (140 mg, 0.538 mmol) is added neat and the reaction is allowed to stir at room temperature overnight. The reaction is cooled in an ice bath and quenched with a saturated solution of ammonium chloride (100 mL). The mixture is then diluted with ethyl acetate and the product is extracted (2×100 mL EtOAc). The organic layers are combined, dried and concentrated to a brown oil that is dissolved in 10 mL of DCM and cooled in an ice bath and 10 mL of TFA is added. Following completion of the reaction the DCM and TFA are removed and ethyl acetate is added to the residue along with ammonium hydroxide to quench the remaining TFA. The mixture is diluted with water and extracted with ethyl acetate (2×50 mL). The organic layers are removed, dried, and concentrated. The residue is absorbed onto silica and separated via FCC (0-6% Methanol/DCM) to obtain N-(5-tert-butylisoxazol-3-yl)-5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-1H-indole-1-carboxamide. MS (ESI) m/z 419.2 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.56 (s, 1 H)8.29 (d, J=8.84 Hz, 1 H)8.17 (d, J=3.79 Hz, 1 H)7.47 (d, J=2.27 Hz, 1 H)7.15 (dd, J=8.97, 2.40 Hz, 1 H)6.76 (d, J=3.28 Hz, 1 H)6.68 (s, 1 H)4.07-4.14 (m, 4 H)1.34 (s, 9 H).

후처리

  1. customflushed with nitrogen
  2. stirringto stir at room temperature overnight
  3. temperatureThe reaction is cooled in an ice bath
  4. customquenched with a saturated solution of ammonium chloride (100 mL)
  5. additionThe mixture is then diluted with ethyl acetate
  6. extractionthe product is extracted (2×100 mL EtOAc)
  7. customdried
  8. concentrationconcentrated to a brown oil that
  9. dissolutionis dissolved in 10 mL of DCM
  10. temperaturecooled in an ice bath
  11. addition10 mL of TFA is added
  12. customcompletion of the reaction the DCM and TFA
  13. customare removed
  14. additionethyl acetate is added to the residue along with ammonium hydroxide
  15. customto quench the remaining TFA
  16. additionThe mixture is diluted with water
  17. extractionextracted with ethyl acetate (2×50 mL)
  18. customThe organic layers are removed
  19. customdried
  20. concentrationconcentrated
  21. customThe residue is absorbed onto silica
  22. customseparated via FCC (0-6% Methanol/DCM)

출처 및 근거

ORD 기록
ord-ecc093e4347d43ecbdfd0c5f92cfe340
출처 데이터셋
uspto-grants-2013_09
특허 번호
US08541432B2

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