Hydrochloric Acid → 5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-methoxy-5 trifluoromethyl-phenyl)-amide

HRID 1887572Notes

Reaction equation

HRID 1887572 reaction equation
C(OC([N:8]1[CH2:16][C:15]2[C:14]([O:17][C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][CH:22]=[CH:21]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=O)(C)(C)C.C1N=CN([C:32]([N:34]2C=N[CH:36]=[CH:35]2)=[O:33])C=1.[CH3:39][O:40][C:41]1[CH:42]=C(N)C=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1.Cl.C(O)(C(F)(F)F)=O>CN(C=O)C.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:39][O:40][C:41]1[CH:42]=[C:35]([NH:34][C:32]([N:23]2[C:24]3[C:20](=[CH:19][C:18]([O:17][C:14]4[C:15]5[CH2:16][NH:8][CH2:9][C:10]=5[N:11]=[CH:12][N:13]=4)=[CH:26][CH:25]=3)[CH:21]=[CH:22]2)=[O:33])[CH:36]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 6422Trifluoroacetic acidHCID 682631,1'-CarbonyldiimidazoleHCID 6056715-(Trifluoromethyl)-m-anisidineHCID 59394637Tert-butyl 4-(1H-indol-5-yloxy)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate

Product 1

HCID 593944905-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-methoxy-5 trifluoromethyl-phenyl)-amide

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of 4-(1H-indol-5-yloxy)-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (158 mg, 0.44 mmol) in DMF (4 mL), CDI (145 mg, 0.89 mmol) is added in one portion, followed by TEA (0.37 mL, 2.7 mmol). After 3 h at rt, 3-methoxy-5-trifluoromethyl-phenylamine (514 mg, 2.7 mmol) and DMAP (5.5 mg, 0.04 mmol) are added and the reaction is left stirring for 40 h. Ethyl acetate (2 mL) is added followed by the addition of 1 N HCl solution (3 mL). The organics are extracted with EtOAc (×3) and concentrated. The crude mixture is dissolved in CH2Cl2 (10 mL) and cooled to 0° C. and TFA (10 mL, 130 mmol) is added. The reaction is allowed to reach it over 2 h. The reaction mixture is evaporated, redissolved in EtOAc and few drops of NH4OH are added to freebase the amine. The solvent is removed and the residue separated by FCC (DCM/MeOH/NH4OH (100:0:0 to 93:6:1)) to give 5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-methoxy-5 trifluoromethyl-phenyl)-amide. MS (ESI) m/z 471.0 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.50-8.56 (m, 1H) 7.93 (d, J=3.54 Hz, 1H) 7.59 (d, J=19.71 Hz, 2H) 7.42 (d, J=2.27 Hz, 1H) 7.12 (dd, J=8.97, 2.40 Hz, 1H) 6.96 (s, 1H) 6.73 (d, J=3.79 Hz, 1H) 6.52 (s, 1H) 4.19 (d, J=8.34 Hz, 4H) 3.76 (s, 3H)

Workup

  1. waitthe reaction is left
  2. extractionThe organics are extracted with EtOAc (×3)
  3. concentrationconcentrated
  4. dissolutionThe crude mixture is dissolved in CH2Cl2 (10 mL)
  5. customover 2 h
  6. customThe reaction mixture is evaporated
  7. dissolutionredissolved in EtOAc
  8. additionfew drops of NH4OH are added
  9. customThe solvent is removed
  10. customthe residue separated by FCC (DCM/MeOH/NH4OH (100:0:0 to 93:6:1))

Sources & evidence

ORD record
ord-06151ddb57584c97abd08db39f3f6550
Source dataset
uspto-grants-2013_08
Patent number
US08501756B2

Reaction notes

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