Sodium hydride → 5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (2-methyl-benzofuran-5-yl)-amide

HRID 450286Notes

Reaction equation

HRID 450286 reaction equation
[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+].[CH3:29][C:30]1[O:31][C:32]2[CH:38]=[CH:37][C:36]([NH:39][C:40](=O)[O:41]C3C=CC=CC=3)=[CH:35][C:33]=2[CH:34]=1>C1COCC1>[CH3:29][C:30]1[O:31][C:32]2[CH:38]=[CH:37][C:36]([NH:39][C:40]([N:1]3[C:9]4[C:8](=[CH:7][C:6]([O:10][C:11]5[C:12]6[CH2:19][NH:18][CH2:17][C:13]=6[N:14]=[CH:15][N:16]=5)=[CH:5][CH:4]=4)[CH:3]=[CH:2]3)=[O:41])=[CH:35][C:33]=2[CH:34]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 59394637Tert-butyl 4-(1H-indol-5-yloxy)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylateHCID 67423596Phenyl 2-methylbenzofuran-5-ylcarbamate

Product 1

HCID 593946635-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (2-methyl-benzofuran-5-yl)-amide

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

tert-Butyl 4-(1H-indol-5-yloxy)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (152.2 mg, 0.432 mmol) is suspended in THF (5 mL), flushed with nitrogen and cooled to 0° C. NaH (33 mg, 0.825 mmol, 60% in mineral oil) is added and mixture is stirred for 10 minutes. Phenyl 2-methylbenzofuran-5-ylcarbamate (280 mg, 1.048 mmol) is added neat and the reaction is allowed to stir to room temperature overnight. The reaction is cooled in an ice bath and quenched with a saturated solution of ammonium chloride (100 mL). The solution is then diluted with ethyl acetate and the product is extracted (2×100 mL ethyl acetate). 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 upon which 10 mL of TFA is added. The TFA is removed and ethyl acetate is added to the residue and ammonium hydroxide is added to quench the remaining TFA. The solution is concentrated and dissolved in DMSO and is purified via semi-prep HPLC (C18; 20-100% I/H2O with 0.1% TFA) to give 5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (2-methyl-benzofuran-5-yl)-amide. MS (ESI) m/z 426.0 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.53 (s, 1H) 8.30 (d, J=8.84 Hz, 1H) 8.15-8.20 (m, 1H) 7.88-7.92 (m, 1H) 7.58 (ddd, J=6.13, 3.98, 2.27 Hz, 1H) 7.39-7.46 (m, 2H) 7.12 (dd, J=9.09, 2.02 Hz, 1H) 6.74 (d, J=3.79 Hz, 1H) 6.46 (s, 1H) 4.19 (d, J=9.35 Hz, 4H) 2.45 (s, 3H).

Workup

  1. customflushed with nitrogen
  2. stirringto stir to 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 solution is then diluted with ethyl acetate
  6. extractionthe product is extracted (2×100 mL ethyl acetate)
  7. customdried
  8. concentrationconcentrated to a brown oil that
  9. dissolutionis dissolved in 10 mL of DCM
  10. temperaturecooled in an ice bath upon which 10 mL of TFA
  11. additionis added
  12. customThe TFA is removed
  13. additionethyl acetate is added to the residue and ammonium hydroxide
  14. additionis added
  15. customto quench the remaining TFA
  16. concentrationThe solution is concentrated
  17. dissolutiondissolved in DMSO
  18. customis purified via semi-prep HPLC (C18; 20-100% I/H2O with 0.1% TFA)

Sources & evidence

ORD record
ord-6f7cd48cc1794dafa76fc3f854ada4c5
Source dataset
uspto-grants-2013_07
Patent number
US08486954B2

Reaction notes

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