Morpholine → HCID 118522590, compound

HRID 529848Notes

Reaction equation

HRID 529848 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH:26]3[CH2:28][O:27]3)[N:9]=2)[CH:7]=1.CCN(C(C)C)C(C)C.[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH:26]([OH:27])[CH2:28][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[N:9]=2)[CH:7]=1

Participants

6

Reactant 3

HCID 8083MorpholineHCID 81531DiisopropylethylamineHCID 118522918HCID 118522918, compound

Product 1

HCID 118522590HCID 118522590, compoundYield 67%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(oxiran-2-ylmethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (50 mg, 0.11 mmol) in N,N-dimethylformamide (1 mL), DIEA (67 mg, 0.518 mmol) and morpholine (14 mg, 0.161 mmol) was added at room temperature. The resulting solution was stirred at 60° C. overnight, cooled, diluted with 30 mL of ethyl acetate, washed with 2×10 mL of water and 2×10 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane/methanol (95/5). This resulted in 50 mg of crude product, which was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column: X Bridge C18, 19*150 mm, 5 um; Mobile Phase A: Water/0.05% NH4HCO3, Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 70% B in 10 min; 254 nm to obtain 40 mg (67%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-hydroxy-3-(morpholin-4-yl)propyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. LCMS (Method 35) [M+H]+=548.2, RT=2.28 min. 1H-NMR (300 MHz, DMSO-d6): δ (ppm) 9.73 (s, 1H), 9.33 (dd, 1H, J=1.5, 7.2 Hz), 8.68-8.67 (m, 2H), 8.34 (s, 1H), 7.65 (d, 1H, J=2.7 Hz), 7.61 (s, 1H), 7.44 (d, 1H, J=8.7 Hz), 7.27 (dd, 1H, J=4.2, 6.9 Hz), 7.00 (t, 1H, J=73.5 Hz), 4.99 (d, 1H, J=4.5 Hz), 4.31-4.28 (m, 1H), 4.13-4.07 (m, 2H), 3.56 (t, 4H, J=4.5 Hz), 2.42 (t, 4H, J=4.5 Hz), 2.32 (d, 2H, J=4.8 Hz).

Workup

  1. temperaturecooled
  2. washwashed with 2×10 mL of water and 2×10 mL of brine
  3. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  4. concentrationconcentrated under vacuum
  5. customThe residue was purified by flash chromatography on silica gel eluting with dichloromethane/methanol (95/5)
  6. customThis resulted in 50 mg of crude product, which
  7. customwas purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1)
  8. waitGradient: 30% B to 70% B in 10 min

Sources & evidence

ORD record
ord-49a6a63e657443aa9b87c55a570dba9a
Source dataset
uspto-grants-2016_05
Patent number
US09346815B2

Reaction notes

Loading…