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

HRID 1043960Notes

Reaction equation

HRID 1043960 reaction equation
[OH-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([O:17][CH3:18])[C:11]=2[CH3:19])[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:15]([CH3:16])=[CH:14][N:13]=[C:12]([O:17][CH3:18])[C:11]=2[CH3:19])[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 86686392ethyl 5-(2,5-difluoro-4-(2-methoxy-3,5-dimethylpyridin-4-yl)phenyl)-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate

Product 1

HCID 866863945-(2,5-difluoro-4-(2-methoxy-3,5-dimethylpyridin-4-yl)phenyl)-1-((S)-tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxylic acidYield 90.6%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 6212ChloroformSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
65 °C

Procedure

5 N sodium hydroxide (0.5 mL) was added to a solution of ethyl 5-[2,5-difluoro-4-(2-methoxy-3,5-dimethylpyridin-4-yl)phenyl]-1-[(S)-tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxylate (280 mg) in ethanol (3.6 mL), and the mixture was stirred at 65° C. for three hours. 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 saturated ammonium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and the desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to give 5-(2,5-difluoro-4-(2-methoxy-3,5-dimethylpyridin-4-yl)phenyl)-1-((S)-tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxylic acid (238 mg) as a crude purified product. CDI (121 mg) was added to a solution of the carboxylic acid (238 mg) in DMF (3 mL), and the mixture was stirred at room temperature for one hour. A 28% aqueous ammonia solution (0.6 mL) was added to the reaction mixture, followed by stirring overnight. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned by adding chloroform and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate, and the desiccant was removed by filtration. The filtrate was passed through a silica gel pad (NH silica gel; eluting with ethyl acetate), and the resulting filtrate was concentrated under reduced pressure to give the title compound (186 mg).

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 filtrate was concentrated under reduced pressure

Sources & evidence

ORD record
ord-14674d7812814313aeeb9dd6f76509c4
Source dataset
uspto-grants-2013_10
Patent number
US08563565B2

Reaction notes

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