Hydrochloric Acid → N-(4-(Chlorodifluoromethoxy)phenyl)-6-(3-hydroxy-3-methylpyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)nicotinamide

HRID 525717

Reaction equation

HRID 525717 reaction equation
Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.Cl.[CH3:34][C:35]1([OH:40])[CH2:39][CH2:38][NH:37][CH2:36]1.CCN(C(C)C)C(C)C.Cl.C([O-])(O)=O.[Na+]>CO.CC(O)C>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:37]3[CH2:38][CH2:39][C:35]([OH:40])([CH3:34])[CH2:36]3)=[N:3][CH:4]=2)=[CH:14][CH:13]=1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 533465593-Methylpyrrolidin-3-ol hydrochlorideHCID 867026376-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide

Product 1

HCID 89908076N-(4-(Chlorodifluoromethoxy)phenyl)-6-(3-hydroxy-3-methylpyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)nicotinamide

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 3776IsopropanolSolvent

Procedure

A mixture of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2, 500 mg, 1.035 mmol), 3-methylpyrrolidin-3-ol hydrochloride (244 mg, 1.77 mmol), DIPEA (0.723 mL, 4.14 mmol) and iPrOH (1.4 mL) in a MW vial was subjected to MW irradiation at 140° C. for 1.5 h. The cooled mixture was treated with aqueous HCl (37%) and MeOH (2 mL) and stirred for 1 h. The mixture was basified with sat. aq. NaHCO3, extracted with EtOAc and the combined extracts were washed with water and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was crystallized from toluene/EtOAc to afford the title product as a white solid. UPLC-MS (Condition 3) tR=0.95 min, m/z=464.1 [M+H]+, m/z=508.1 [M+formic acid-H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (s, 3H) 1.60-1.85 (m, 2H) 2.93-3.12 (m, 2H) 3.25-3.31 (m, 1H) 3.42-3.54 (m, 1H) 4.61-4.76 (m, 1H) 6.31-6.42 (m, 1H) 7.33 (d, J=8.80 Hz, 2H) 7.51-7.84 (m, 1H) 7.87 (d, J=9.05 Hz, 2H) 8.03 (d, J=2.32 Hz, 1H) 8.73 (m, J=2.32 Hz, 1H) 10.19 (s, 1H) 12.86-13.15 (m, 1H).

Workup

  1. customwas subjected to MW irradiation at 140° C. for 1.5 h
  2. extractionextracted with EtOAc
  3. washthe combined extracts were washed with water and brine
  4. dry with materialdried over Na2SO4
  5. customthe solvent was evaporated off under reduced pressure
  6. customto give the crude product which
  7. customwas crystallized from toluene/EtOAc

Sources & evidence

ORD record
ord-868cbc36bc6b4f5192e4c0f70b9269a3
Source dataset
uspto-grants-2016_05
Patent number
US09340537B2

Linked notes

Loading…