Trifluoroacetic acid → (R)-N-(4-(Chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(3-methyl-1H-pyrazol-5-yl)nicotinamide

HRID 73783Notes

Reaction equation

HRID 73783 reaction equation
[CH3:1][C:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[N:4](C2CCCCO2)[N:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:31]1[C:32]([N:51]2[CH2:55][CH2:54][C@@H:53]([OH:56])[CH2:52]2)=[N:33][CH:34]=[C:35]([CH:50]=1)[C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][C:46]([Cl:49])([F:48])[F:47])=[CH:41][CH:40]=1)=[O:37].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:49][C:46]([F:47])([F:48])[O:45][C:42]1[CH:43]=[CH:44][C:39]([NH:38][C:36](=[O:37])[C:35]2[CH:50]=[C:31]([C:5]3[NH:4][N:3]=[C:2]([CH3:1])[CH:6]=3)[C:32]([N:51]3[CH2:55][CH2:54][C@@H:53]([OH:56])[CH2:52]3)=[N:33][CH:34]=2)=[CH:40][CH:41]=1

Participants

8

Reactant 5

HCID 6422Trifluoroacetic acidHCID 10340Sodium CarbonateHCID 62657Potassium Phosphate, TribasicHCID 717576623-methyl-1-(oxan-2-yl)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 72545856(R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

Product 1

HCID 178422793(R)-N-(4-(Chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(3-methyl-1H-pyrazol-5-yl)nicotinamide

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

3-Methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Stage 23.1, 150 mg, 0.359 mmol), K3PO4 (147 mg, 0.692 mmol) and Pd(PPh3)4 (15.98 mg, 0.014 mmol) were added to a solution of (R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 9.2, 80 mg, 0.173 mmol) in toluene (1.5 mL) under an argon atmosphere and the RM was stirred at 110° C. for 2 h. The solvent was evaporated off under reduced pressure and the residue was dissolved in DCM (1.5 mL), treated with TFA (0.533 mL, 6.92 mmol) and stirred at RT for 2 h. The RM was treated with sat. aq. Na2CO3 (20 mL) and extracted with EtOAc. The combined extracts were washed with brine (20 mL), dried over Na2SO4, and the solvent was evaporated off under reduced pressure to give a crude product which was purified by flash chromatography (Silica gel column, 12 g, DCM/MeOH from 99:1 to 92:8) and crystallized from DCM/n-hexane to give the title product as a white solid. HPLC (Condition 5) tR=5.92 min, UPLC-MS (Condition 3) tR=0.94 min, m/z=464.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.89 (m, 2H) 2.19-2.31 (m, 3H) 2.98 (d, J=10.95 Hz, 1H) 3.24-3.35 (m, 2H) 3.39-3.52 (m, 1H) 4.16-4.25 (m, 1H) 4.80-4.90 (m, 1H) 6.11-6.17 (m, 1H) 7.32 (d, J=8.60 Hz, 2H) 7.87 (d, J=8.99 Hz, 2H) 7.97-8.06 (m, 1H) 8.66-8.78 (m, 1H) 10.16 (s, 1H) 12.51-12.70 (m, 1H).

Workup

  1. customThe solvent was evaporated off under reduced pressure
  2. dissolutionthe residue was dissolved in DCM (1.5 mL)
  3. stirringstirred at RT for 2 h
  4. extractionextracted with EtOAc
  5. washThe combined extracts were washed with brine (20 mL)
  6. dry with materialdried over Na2SO4
  7. customthe solvent was evaporated off under reduced pressure
  8. customto give a crude product which
  9. customwas purified by flash chromatography (Silica gel column, 12 g, DCM/MeOH from 99:1 to 92:8)
  10. customcrystallized from DCM/n-hexane

Sources & evidence

ORD record
ord-d14117d015d64eca8747f675f9574131
Source dataset
uspto-grants-2014_09
Patent number
US08829195B2

Reaction notes

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