Potassium Phosphate, Tribasic → N-(1-{[4-cyclopropyl-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-3-fluoro-4-pyridinecarboxamide

HRID 1946410Notes

Reaction equation

HRID 1946410 reaction equation
[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:15]=[CH:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][C:18]=2[C:24]([F:27])([F:26])[F:25])[N:12]=1)=[O:9].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P([CH:49]2[CH2:54][CH2:53]CCC2)C2CCCCC2)CCCCC1.C1(B(O)O)CC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH:53]1([C:20]2[CH:21]=[CH:22][C:17]([CH2:16][N:13]3[CH:14]=[CH:15][C:11]([NH:10][C:8]([C:7]4[CH:6]=[CH:5][N:4]=[CH:3][C:2]=4[F:1])=[O:9])=[N:12]3)=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH2:54][CH2:49]1

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 2760897Cyclopropylboronic acidHCID 595480203-Fluoro-N-(1-{[4-iodo-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-4-pyridinecarboxamide

Product 1

HCID 59547933N-(1-{[4-cyclopropyl-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-3-fluoro-4-pyridinecarboxamide

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 3-fluoro-N-(1-{[4-iodo-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-4-pyridinecarboxamide (for a preparation see Example 88)(40 mg, 0.082 mmol) in toluene (2 ml) was added potassium phosphate tribasic (52 mg, 0.245 mmol, Aldrich), tricyclohexyl phosphine (7 mg, 0.025 mmol, Aldrich), cyclopropyl boronic acid (21 mg, 0.244 mmol, Fluorochem), water (0.1 ml) and then palladium (II) acetate (6 mg, 0.027 mmol. ABCR). The resulting slight suspension was heated to 100° C. and stirred under nitrogen overnight. The reaction mixture was partitioned between DCM (10 ml) and water (10 ml). The phases were separated using a hydrophobic frit and the aqueous phase washed with DCM (10 ml). The organic phases were combined and the solvent removed in vacuo. The residue was dissolved in 1:1 MeOH:DMSO (1 ml) and purified by MDAP on Sunfire C18 column (Method B) using Acetonitrile-Water with a Formic acid modifier. The solvent was evaporated in vacuo to give the title compound as a white solid (16 mg); LCMS: (System 4) MH+=405, tRET=2.98 min.

Workup

  1. customThe reaction mixture was partitioned between DCM (10 ml) and water (10 ml)
  2. customThe phases were separated
  3. washthe aqueous phase washed with DCM (10 ml)
  4. customthe solvent removed in vacuo
  5. dissolutionThe residue was dissolved in 1:1 MeOH
  6. customDMSO (1 ml) and purified by MDAP on Sunfire C18 column (Method B)
  7. customThe solvent was evaporated in vacuo

Sources & evidence

ORD record
ord-8d5663af4f1d4ffbb4147e545e859456
Source dataset
uspto-grants-2013_03
Patent number
US08399436B2

Reaction notes

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