Potassium Carbonate → 1-(5-chloro-pyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid [(S)-1-(3-trifluoromethyl-phenyl)-ethyl]-amide

HRID 2067963Notes

Reaction equation

HRID 2067963 reaction equation
[F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@@H:9]([NH:11][C:12]([C:14]2[CH:15]=[N:16][NH:17][C:18]=2[CH3:19])=[O:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26](I)=[N:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>[Cl-].[NH4+].[Cu]I.CN(C=O)C>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@@H:9]([NH:11][C:12]([C:14]2[CH:15]=[N:16][N:17]([C:26]3[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][N:27]=3)[C:18]=2[CH3:19])=[O:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1

Participants

8

Reactant 4

HCID 11430Potassium CarbonateHCID 2733821trans-N,N'-dimethyl-1,2-cyclohexanediamineHCID 111181485-Chloro-2-iodopyridineHCID 584434065-methyl-1H-pyrazole-4-carboxylic acid [(S)-1-(3-trifluoromethyl-phenyl)-ethyl]-amide

Product 1

HCID 444796041-(5-chloro-pyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid [(S)-1-(3-trifluoromethyl-phenyl)-ethyl]-amideYield 40%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 6228DimethylformamideSolventHCID 25517Ammonium ChlorideSolvent

Conditions

Temperature
120 °C

Procedure

5-Methyl-1H-pyrazole-4-carboxylic acid [(S)-1-(3-trifluoromethyl-phenyl)-ethyl]-amide (70 mg, 0.24 mmol), copper(I) iodide (10 mg, 0.05 mmol), 5-chloro-2-iodopyridine (75 mg, 0.31 mmol) and potassium carbonate (75 mg, 0.54 mmol) are added to a reaction vial with a septum top which is then evacuated and filled with argon for 3 cycles. DMF (2 mL, degassed) and racemic trans-N,N′-dimethylcyclohexane-1,2-diamine (15 μL, 0.10 mmol) are added and the reaction is heated at 120° C. for 17 hours. The resultant mixture is cooled to room temperature, diluted with saturated aqueous ammonium chloride (15 mL) and extracted with EtOAc (3×20 mL). The combined organic layers is washed with saturated aqueous sodium bicarbonate (15 mL) followed by brine (15 mL), dried over sodium sulfate, filtered and concentrated in vacuo to provide a crude solid. Recrystallization from ether/hexanes provides 1-(5-chloro-pyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid [(S)-1-(3-trifluoromethyl-phenyl)-ethyl]-amide as a colorless solid (38 mg, 40%). (For references, see Buchwald, et al., J. Org. Chem. 2004, 69, 5578; Buchwald, et al., J. Am. Chem. Soc. 2002, 124, 11684).

Workup

  1. customis then evacuated
  2. additionfilled with argon for 3 cycles
  3. extractionextracted with EtOAc (3×20 mL)
  4. washThe combined organic layers is washed with saturated aqueous sodium bicarbonate (15 mL)
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customto provide a crude solid
  9. customRecrystallization from ether/hexanes

Sources & evidence

ORD record
ord-da6de3ce2b6245238f9c7aa299cd6ced
Source dataset
uspto-grants-2012_10
Patent number
US08293917B2

Reaction notes

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