Trifluoroacetic acid → N-(3-(isopropylcarbamoyl)-5-(trifluoromethyl)phenyl)-5-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yloxy)-1H-indole-1-carboxamide

HRID 45122Notes

Reaction equation

HRID 45122 reaction equation
C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[CH:22]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[CH:30]([NH:33][C:34]([C:36]1[CH:37]=[C:38]([NH:46][C:47](=O)[O:48]C2C=CC=CC=2)[CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)=[O:35])([CH3:32])[CH3:31].C(O)(C(F)(F)F)=O>C1COCC1.C(Cl)Cl.CN(C=O)C>[CH:30]([NH:33][C:34]([C:36]1[CH:37]=[C:38]([NH:46][C:47]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:18][C:14]4[C:15]5[CH2:16][CH2:17][NH:8][CH2:9][C:10]=5[N:11]=[CH:12][N:13]=4)=[CH:27][CH:26]=3)[CH:22]=[CH:23]2)=[O:48])[CH:39]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:41]=1)=[O:35])([CH3:32])[CH3:31]

Participants

8

Reactant 4

HCID 6422Trifluoroacetic acidHCID 24758Sodium hydrideHCID 59394410HCID 59394410, compoundHCID 59394633HCID 59394633, compound

Product 1

HCID 59394360N-(3-(isopropylcarbamoyl)-5-(trifluoromethyl)phenyl)-5-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yloxy)-1H-indole-1-carboxamide

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 4-(1H-Indol-5-yloxy)-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (0.16 g, 0.437 mmol) in 4 mL of THF at 0° C., NaH (0.105 g, 2.62 mmol) is added. After stirring for 45 min a solution of phenyl 3-(isopropylcarbamoyl)-5-(trifluoromethyl)phenylcarbamate, Example 13-B, (0.224 g, 0.611 mmol) in 2 mL of THF and 1 mL of DMF is added dropwise. The resulting mixture is stirred for 4 h before being partitioned between EtOAc and cold H2O. The aq layer is extracted further with EtOAc and the combined organic layers are washed with saturated aqueous NaHCO3, brine and dried over Na2SO4. Following concentration the residue is separated by FCC (heptane/EtOAc). The resulting product (0.23 g, 0.360 mmol) is then treated with 70 mL of 50% TFA in DCM at rt for 1 h. After concentration the residue is separated by semi-prep HPLC (10-100% CAN/H2O with 0.1% NH4OH) to provide the title compound. MS (ESI) m/z 539.2 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.49 (br. S., 1 H), 8.54 (d, J=7.8 Hz, 1 H), 8.38-8.46 (m, 2 H), 8.25-8.32 (m, 2 H), 8.15 (d, J=3.8 Hz, 1 H), 7.98 (s, 1 H), 7.46 (d, J=2.3 Hz, 1 H), 7.13 (dd, J=9.0, 2.4 Hz, 1 H), 4.07-4.21 (m, J=13.9, 6.9, 6.7, 6.7 Hz, 2 H), 3.85 (s, 2 H), 3.07 (t, J=5.8 Hz, 2 H), 2.75 (t, J=5.7 Hz, 2 H), 1.20 (d, J=6.6 Hz, 6 H).

Workup

  1. custombefore being partitioned between EtOAc and cold H2O
  2. extractionThe aq layer is extracted further with EtOAc
  3. washthe combined organic layers are washed with saturated aqueous NaHCO3, brine
  4. dry with materialdried over Na2SO4
  5. concentrationconcentration the residue
  6. customis separated by FCC (heptane/EtOAc)
  7. concentrationAfter concentration the residue
  8. customis separated by semi-prep HPLC (10-100% CAN/H2O with 0.1% NH4OH)

Sources & evidence

ORD record
ord-d98fbfe1ed8c44e9b8a25b3dd337bebd
Source dataset
uspto-grants-2013_09
Patent number
US08541432B2

Reaction notes

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