Hydrochloric Acid → 5-(2,5-difluoro-4-(2-methoxy-4,6-dimethylpyridin-3-yl)phenyl)-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylic acid

HRID 1043963Notes

Reaction equation

HRID 1043963 reaction equation
[OH-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[CH:14][C:15]=2[CH3:16])[C:7]([F:20])=[CH:6][C:5]=1[C:21]1[N:25]([C@H:26]2[CH2:30][CH2:29][O:28][CH2:27]2)[N:24]=[CH:23][C:22]=1[C:31]([O:33]CC)=[O:32].Cl.[Cl-].[NH4+]>C(O)C.[Cl-].[Na+].O.C(Cl)(Cl)Cl>[F:3][C:4]1[CH:9]=[C:8]([C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[CH:14][C:15]=2[CH3:16])[C:7]([F:20])=[CH:6][C:5]=1[C:21]1[N:25]([C@H:26]2[CH2:30][CH2:29][O:28][CH2:27]2)[N:24]=[CH:23][C:22]=1[C:31]([OH:33])=[O:32]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 25517Ammonium ChlorideHCID 86686396ethyl 5-(2,5-difluoro-4-(2-methoxy-4,6-dimethylpyridin-3-yl)phenyl)-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate

Product 1

HCID 866863995-(2,5-difluoro-4-(2-methoxy-4,6-dimethylpyridin-3-yl)phenyl)-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylic acidYield 122.6%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 6212ChloroformSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
70 °C

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. temperatureAfter cooling the reaction mixture to room temperature
  2. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
  3. customthe desiccant was removed by filtration
  4. concentrationThe filtrates was concentrated under reduced pressure

Sources & evidence

ORD record
ord-f4f09c0c39504fba8e0be89beae4779b
Source dataset
uspto-grants-2013_10
Patent number
US08563565B2

Reaction notes

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