Diisopropylethylamine → (R)-5-(4-Fluoro-1H-pyrazol-5-yl)-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 73739

Reaction equation

HRID 73739 reaction equation
CCN(C(C)C)C(C)C.Cl[C:11]1[C:30]([C:31]2[NH:35][N:34]=[CH:33][C:32]=2[F:36])=[CH:29][C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:13][N:12]=1.[NH:37]1[CH2:41][CH2:40][C@@H:39]([OH:42])[CH2:38]1>CC(O)C.CCOC(C)=O>[F:36][C:32]1[CH:33]=[N:34][NH:35][C:31]=1[C:30]1[C:11]([N:37]2[CH2:41][CH2:40][C@@H:39]([OH:42])[CH2:38]2)=[N:12][CH:13]=[C:14]([CH:29]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1)=[O:16]

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 2759337(R)-3-PyrrolidinolHCID 867026006-chloro-5-(4-fluoro-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Product 1

HCID 72545355(R)-5-(4-Fluoro-1H-pyrazol-5-yl)-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Reagents, catalysts & solvents 2

HCID 3776IsopropanolSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
140 °C

Procedure

DIPEA (71.9 μL, 0.412 mmol) was added to a solution of 6-chloro-5-(4-fluoro-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 5.1, 75 mg, 0.187 mmol) and (R)-pyrrolidin-3-ol (19.97 mg, 0.225 mmol) in iPrOH (187 μL) in a vial which was sealed and heated at 140° C. for 1 h. After cooling at RT, the RM was dissolved in EtOAc and washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 10% MeOH) to afford the title compound as a white foam. HPLC (Condition 4) tR=4.73 min, UPLC-MS (Condition 3) tR=0.93 min, m/z=452.4 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.95 (m, 2H) 3.00 (d, J=11.34 Hz, 1H) 3.18-3.51 (m, 3H) 4.22 (br. s, 1H) 4.86 (br. s, 1H) 7.32 (d, J=8.60 Hz, 2H) 7.77-8.11 (m, 4H) 8.76 (br. s, 1H) 10.17 (s, 1H) 12.90 (br. s, 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. customto give the crude product which
  7. customwas purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 10% MeOH)

Sources & evidence

ORD record
ord-16fdb474cc32455d817c846cd8876e84
Source dataset
uspto-grants-2014_09
Patent number
US08829195B2

Linked notes

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