Ethanol → 5-({[1-(4-Fluoro-phenyl)-1H-indazole-4-carbonyl]-amino}-methyl)-pyridine-2-carboxylic acid ethyl ester

HRID 2382940Notes

Reaction equation

HRID 2382940 reaction equation
Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[N:15][N:16]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:17]=3[CH:18]=[CH:19][CH:20]=2)=[O:11])=[CH:4][CH:3]=1.C(N([CH2:33][CH3:34])CC)C.[C]=[O:36].[CH2:37]([OH:39])C>[Cl-].[NH4+].[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[Fe+2]>[CH2:33]([O:36][C:37]([C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[N:15][N:16]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:17]=3[CH:18]=[CH:19][CH:20]=2)=[O:11])=[CH:6][N:7]=1)=[O:39])[CH3:34]

Participants

7

Reactant 4

HCID 702EthanolHCID 8471TriethylamineHCID 444696611-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid (6-bromo-pyridin-3-ylmethyl)-amideHCID 178418416HCID 178418416, compound

Product 1

HCID 581389055-({[1-(4-Fluoro-phenyl)-1H-indazole-4-carbonyl]-amino}-methyl)-pyridine-2-carboxylic acid ethyl ester

Reagents, catalysts & solvents 2

HCID 152416121,1`-Bis(diphenylphosphino)ferroceneCatalystHCID 25517Ammonium ChlorideSolvent

Conditions

Temperature
140 °C

Procedure

In a pressure reactor with stirring, a mixture of the 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (6-bromo-pyridin-3-ylmethyl)-amide (260 mg, 0.61 mmol), triethylamine (0.17 mL, 1.2 mmol), dichloro(bisbenzonitrile) palladium (4.7 mg, 0.011 mmol), and 1,1-bis(diphenylphosphino)ferrocene (dppf) (20.3 mg, 0.0365 mmol) in absolute ethanol (10 mL) was charged with 15 bars of carbon monoxide and warmed at 140° C. After 4 hours, the pressure reactor was then cooled to room temperature, chilled on ice and returned to atmospheric pressure. The solution was diluted with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (2×25 mL), brine (25 mL), dried over magnesium sulfate, filtered and concentrated. The resulting orange solid was purified by silica gel chromatography, eluting with a gradient of 0-10% MeOH in CH2Cl2. The resulting solid was purified again by silica gel chromatography, eluting with a gradient of 70-100% ethyl acetate in hexanes to afford the title compound.

Workup

  1. temperaturethe pressure reactor was then cooled to room temperature
  2. temperaturechilled on ice
  3. extractionextracted with ethyl acetate (3×20 mL)
  4. washThe combined organic layers were washed with saturated aqueous ammonium chloride (2×25 mL), brine (25 mL)
  5. dry with materialdried over magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe resulting orange solid was purified by silica gel chromatography
  9. washeluting with a gradient of 0-10% MeOH in CH2Cl2
  10. customThe resulting solid was purified again by silica gel chromatography
  11. washeluting with a gradient of 70-100% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-69f715a5cb9343c78340ccd5bf9fedc6
Source dataset
uspto-grants-2012_09
Patent number
US08263597B2

Reaction notes

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