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

HRID 73806Notes

Reaction equation

HRID 73806 reaction equation
CCN(C(C)C)C(C)C.Cl[C:11]1[C:30]([C:31]2[N:35](C3CCCCO3)[N:34]=[CH:33][C:32]=2[CH3:42])=[CH:29][C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([Cl:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:13][N:12]=1.[NH:43]1[CH2:47][CH2:46][C@@H:45]([OH:48])[CH2:44]1.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>CC(O)C.CCOC(C)=O>[Cl:28][C:25]([F:26])([F:27])[O:24][C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:15](=[O:16])[C:14]2[CH:29]=[C:30]([C:31]3[NH:35][N:34]=[CH:33][C:32]=3[CH3:42])[C:11]([N:43]3[CH2:47][CH2:46][C@@H:45]([OH:48])[CH2:44]3)=[N:12][CH:13]=2)=[CH:23][CH:22]=1

Participants

8

Reactant 5

HCID 6422Trifluoroacetic acidHCID 10340Sodium CarbonateHCID 81531DiisopropylethylamineHCID 2759337(R)-3-PyrrolidinolHCID 867026356-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide

Product 1

HCID 72545603(R)-N-(4-(Chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(4-methyl-1H-pyrazol-5-yl)nicotinamide

Reagents, catalysts & solvents 2

HCID 3776IsopropanolSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
140 °C

Procedure

DIPEA (77 μL, 0.44 mmol) was added to a solution of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 33.1, 99 mg, 0.2 mmol) and (R)-pyrrolidin-3-ol, 20.9 mg, 0.24 mmol) in iPrOH (200 μL) in a vial, which was sealed and the RM mixture was stirred at 140° C. for 1.5 h. After cooling at RT, the RM was dissolved in EtOAc, washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The residue was dissolved in DCM (1.1 mL), cooled to 0° C., treated with TFA (0.616 mL, 8 mmol) and stirred at RT for 3 h. The RM was poured in to 10% aq. Na2CO3 (10 mL) and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® silica gel column, DCM/MeOH from 2% to 10% MeOH) to afford the title compound as a beige powder. HPLC (Condition 4) tR=4.79 min, UPLC-MS (Condition 3) tR=0.95 min, m/z=464 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.63-1.92 (m, 5H) 2.81-2.96 (m, 1H) 3.05-3.41 (m, 3H) 4.17 (br. s, 1H) 4.81 (br. s, 1H) 7.30 (d, J=8.60 Hz, 2H) 7.58 (s, 1H) 7.79-8.02 (m, 3H) 8.73 (s, 1H) 10.15 (s, 1H) 12.58-12.85 (m, 1H).

Workup

  1. customwas sealed
  2. temperatureAfter cooling at RT
  3. washwashed with brine
  4. dry with materialdried over Na2SO4
  5. customthe solvent was evaporated off under reduced pressure
  6. dissolutionThe residue was dissolved in DCM (1.1 mL)
  7. temperaturecooled to 0° C.
  8. stirringstirred at RT for 3 h
  9. extractionextracted with EtOAc
  10. dry with materialThe combined extracts were dried over Na2SO4
  11. customthe solvent was evaporated off under reduced pressure
  12. customto give a residue which
  13. customwas purified by flash chromatography (RediSep® silica gel column, DCM/MeOH from 2% to 10% MeOH)

Sources & evidence

ORD record
ord-22ea0c2f7cea47429a29b99d561ddc1d
Source dataset
uspto-grants-2014_09
Patent number
US08829195B2

Reaction notes

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