Sodium hydride → 5-[6-(2-Oxo-pyrrolidin-1-ylmethyl)-pyrimidin-4-yloxy]-indole-1-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide

HRID 45135Notes

Reaction equation

HRID 45135 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:20][C:21]4[CH:26]=[C:25]([CH2:27][NH:28][C:29](=[O:34])[CH2:30][CH2:31][CH2:32]Br)[N:24]=[CH:23][N:22]=4)=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)=[O:10])=[CH:4][C:3]=1[C:35]([F:38])([F:37])[F:36].[H-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:20][C:21]4[CH:26]=[C:25]([CH2:27][N:28]5[CH2:32][CH2:31][CH2:30][C:29]5=[O:34])[N:24]=[CH:23][N:22]=4)=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)=[O:10])=[CH:4][C:3]=1[C:35]([F:38])([F:37])[F:36]

Participants

4

Reactant 2

HCID 24758Sodium hydrideHCID 593944875-{6-[(4-Bromo-butyrylamino)-methyl]-pyrimidin-4-yloxy}-indole-1-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide

Product 1

HCID 593940095-[6-(2-Oxo-pyrrolidin-1-ylmethyl)-pyrimidin-4-yloxy]-indole-1-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

5-{6-[(4-Bromo-butyrylamino)-methyl]-pyrimidin-4-yloxy}-indole-1-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide (0.353 g, 0.595 mmol) is dissolved in 10 mL THF and cooled to 0° C. Sodium hydride (63 mg, 1.5 mmol, 60% in mineral oil) is added and the reaction is allowed to warm to room temperature overnight. The reaction is quenched with water and diluted with ethyl acetate. The organic layer is removed, dried, and concentrated and the residue is separated via semi-prep HPLC (C18; 20-100% I/H2O with 0.1% TFA) to provide the title compound. MS (ESI) m/z 514.9 (M+1); 1H NMR (400 m/z, DMSO-d6) δ ppm 10.40 (s, 1 H), 8.68 (d, J=1.01 Hz, 1 H), 8.28 (d, J=9.09 Hz, 1 H), 8.09-8.12 (m, 2 H), 7.99-8.03 (m, 1 H), 7.57 (t, J=9.85 Hz, 1 H), 7.49 (d, J=2.27 Hz, 1 H), 7.15 (dd, J=8.97, 2.40 Hz, 1 H), 6.94 (d, J=1.01 Hz, 1 H), 6.81 (d, J=3.79 Hz, 1 H), 4.45 (s, 2 H), 3.42 (t, J=6.95 Hz, 2 H), 2.29-2.34 (m, 3 H), 2.00 (t, J=7.58 Hz, 2 H).

Workup

  1. temperatureto warm to room temperature overnight
  2. customThe reaction is quenched with water
  3. additiondiluted with ethyl acetate
  4. customThe organic layer is removed
  5. customdried
  6. concentrationconcentrated
  7. customthe residue is separated via semi-prep HPLC (C18; 20-100% I/H2O with 0.1% TFA)

Sources & evidence

ORD record
ord-acfc703961a44231962566e60cce0e6f
Source dataset
uspto-grants-2013_09
Patent number
US08541432B2

Reaction notes

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