Diisopropylethylamine → 6-((R)-3-hydroxypyrrolidin-1-yl)-5-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 73736

Reaction equation

HRID 73736 reaction equation
CCN(C(C)C)C(C)C.Cl[C:11]1[C:30]([C:31]2[N:35]([CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[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]([F: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>CC(O)C.CCOC(C)=O>[OH:48][C@@H:45]1[CH2:46][CH2:47][N:43]([C:11]2[C:30]([C:31]3[N:35]([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[N:34]=[CH:33][C:32]=3[CH3:42])=[CH:29][C:14]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([F:27])([F:26])[F:28])=[CH:22][CH:23]=3)=[O:16])=[CH:13][N:12]=2)[CH2:44]1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 2759337(R)-3-PyrrolidinolHCID 867025986-chloro-5-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Product 1

HCID 867025976-((R)-3-hydroxypyrrolidin-1-yl)-5-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Reagents, catalysts & solvents 2

HCID 3776IsopropanolSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
140 °C

Procedure

DIPEA (43.9 μL, 0.252 mmol) was added to a solution of 6-chloro-5-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 4.1, 55 mg, 0114 mmol) and (R)-pyrrolidin-3-ol (11.96 mg, 0.137 mmol) in iPrOH (114 μL) in a vial, which was sealed and heated at 140° C. for 18 h. After cooling to RT, the RM was dissolved in EtOAc, washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure and the crude product was purified by flash chromatography (RediSep® Silica gel column, EtOAc/MeOH 98:2) to afford 6-((R)-3-hydroxypyrrolidin-1-yl)-5-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide as an off-white foam. This intermediate (39 mg, 0.073 mmol) was dissolved in DCM (0.8 mL), treated with TFA (0.262 mL, 3.4 mmol) and stirred at RT for 3 h. The RM was poured into 25 mL Na2CO3 10% and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure and the crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 10% MeOH) to afford the title compound as an off-white powder. HPLC (Condition 4) tR=4.46 min, UPLC-MS (Condition 3) tR=0.92 min, m/z=448.4 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.81 (m, 2H) 1.86 (s, 3H) 2.78-2.97 (m, 1H) 3.07-3.41 (m, 3H) 4.18 (br. s, 1H) 4.81 (br. s, 1H) 7.32 (d, J=8.60 Hz, 2H) 7.58 (br. s, 1H) 7.85 (d, J=9.38 Hz, 2H) 7.93 (br. s, 1H) 8.73 (br. s, 1H) 10.14 (s, 1H) 12.63 (br. s, 1H).

Workup

  1. customwas sealed
  2. temperatureAfter cooling to RT
  3. washwashed with brine
  4. dry with materialdried over Na2SO4
  5. customthe solvent was evaporated off under reduced pressure
  6. customthe crude product was purified by flash chromatography (RediSep® Silica gel column, EtOAc/MeOH 98:2)

Sources & evidence

ORD record
ord-d34f7937b6fd40cf99234e6d850a5625
Source dataset
uspto-grants-2014_09
Patent number
US08829195B2

Linked notes

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