Ammonia → 5-(2,5-difluoro-4-(2-methoxy-4,6-dimethylpyridin-3-yl)phenyl)-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxamide

HRID 1043964Notes

Reaction equation

HRID 1043964 reaction equation
C1N=C[N:3](C(N2C=NC=C2)=O)C=1.[F:13][C:14]1[CH:19]=[C:18]([C:20]2[C:21]([O:28][CH3:29])=[N:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])[C:17]([F:30])=[CH:16][C:15]=1[C:31]1[N:35]([C@H:36]2[CH2:40][CH2:39][O:38][CH2:37]2)[N:34]=[CH:33][C:32]=1[C:41]([OH:43])=O.N>CN(C=O)C>[F:13][C:14]1[CH:19]=[C:18]([C:20]2[C:21]([O:28][CH3:29])=[N:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])[C:17]([F:30])=[CH:16][C:15]=1[C:31]1[N:35]([C@H:36]2[CH2:40][CH2:39][O:38][CH2:37]2)[N:34]=[CH:33][C:32]=1[C:41]([NH2:3])=[O:43]

Participants

5

Reactant 3

HCID 222AmmoniaHCID 682631,1'-CarbonyldiimidazoleHCID 866863995-(2,5-difluoro-4-(2-methoxy-4,6-dimethylpyridin-3-yl)phenyl)-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylic acid

Product 1

HCID 866864005-(2,5-difluoro-4-(2-methoxy-4,6-dimethylpyridin-3-yl)phenyl)-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxamideYield 43.6%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A 5 N aqueous sodium hydroxide solution (0.8 mL) was added to a solution of ethyl 5-(2,5-difluoro-4-(2-methoxy-4,6-dimethylpyridin-3-yl)phenyl)-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate (397 mg) in ethanol (5 mL), and the reaction mixture was stirred at 70° C. for 1 hour. After cooling the reaction mixture to room temperature, chloroform and brine were added, and the mixture was adjusted to pH 6 with 5 N hydrochloric acid and a saturated aqueous ammonium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and the desiccant was removed by filtration. The filtrates was concentrated under reduced pressure to give 5-(2,5-difluoro-4-(2-methoxy-4,6-dimethylpyridin-3-yl)phenyl)-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylic acid (457 mg) as a crude. CDI (211 mg) was added to a solution of the carboxylic acid (457 mg) in DMF (6 mL), and the reaction mixture was stirred at room temperature. After 75 minutes, a 28% aqueous ammonia solution (0.88 mL) was added to the reaction mixture and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned by adding ethyl acetate and a saturated aqueous ammonium chloride solution. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and the desiccant was removed by filtration. After the filtrate was concentrated under reduced pressure, the precipitated solid was removed by filtration and washed with dichloromethane and ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (ethyl acetate/n-heptane, 60% to 80% to 85%) to give title compound (199 mg). This title compound was used for the next reaction without further purification.

Workup

  1. stirringthe reaction mixture was stirred at room temperature overnight
  2. concentrationThe reaction mixture was concentrated under reduced pressure
  3. customthe residue was partitioned
  4. additionby adding ethyl acetate
  5. washThe organic layer was washed with a saturated aqueous sodium bicarbonate solution
  6. dry with materialdried over anhydrous magnesium sulfate
  7. customthe desiccant was removed by filtration
  8. concentrationAfter the filtrate was concentrated under reduced pressure
  9. customthe precipitated solid was removed by filtration
  10. washwashed with dichloromethane and ethyl acetate
  11. concentrationThe filtrate was concentrated under reduced pressure
  12. customthe residue was purified by silica gel chromatography (ethyl acetate/n-heptane, 60% to 80% to 85%)

Sources & evidence

ORD record
ord-ff3e800ef4e54b1794e4aed29656decd
Source dataset
uspto-grants-2013_10
Patent number
US08563565B2

Reaction notes

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