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 450239

反応式

HRID 450239 の反応式
[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]

参加物

5

反応物 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

生成物 1

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

試薬・触媒・溶媒 1

HCID 8028Tetrahydrofuran溶媒

反応条件

温度
0 °C

実験手順

Tert-butyl 4-(1H-indol-5-yloxy)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-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, 1H) 8.29 (d, J=8.84 Hz, 1H) 8.17 (d, J=3.79 Hz, 1H) 7.47 (d, J=2.27 Hz, 1H) 7.15 (dd, J=8.97, 2.40 Hz, 1H) 6.76 (d, J=3.28 Hz, 1H) 6.68 (s, 1H) 4.07-4.14 (m, 4H) 1.34 (s, 9H).

後処理

  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)

出典と根拠

ORDレコード
ord-f56026fbbdb94fc2bf6a4dc96abf4bbe
出典データセット
uspto-grants-2013_07
特許番号
US08486954B2

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