4-Fluorobenzyl chloride → HCID 89471767, compound

HRID 881979Notes

Reaction equation

HRID 881979 reaction equation
[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[N:10]1([C:15]2[CH:16]=[C:17]([C:21]3[N:26]=[C:25]([N:27]4[CH2:32][CH2:31][CH:30]([CH2:33][NH:34][C:35](=[O:45])[C:36]5[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[C:38]([OH:44])[CH:37]=5)[CH2:29][CH2:28]4)[CH:24]=[CH:23][N:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH:14]=[CH:13][CH:12]=[N:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:10]1([C:15]2[CH:16]=[C:17]([C:21]3[N:26]=[C:25]([N:27]4[CH2:28][CH2:29][CH:30]([CH2:33][NH:34][C:35](=[O:45])[C:36]5[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[C:38]([O:44][CH2:6][C:5]6[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=6)[CH:37]=5)[CH2:31][CH2:32]4)[CH:24]=[CH:23][N:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH:14]=[CH:13][CH:12]=[N:11]1

Participants

5

Reactant 3

HCID 96024-Fluorobenzyl chlorideHCID 10796Cesium carbonateHCID 89464462HCID 89464462, compound

Product 1

HCID 89471767HCID 89471767, compoundYield 65.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
40 °C

Procedure

4-Fluorobenzyl chloride (15 μl, 0.12 mmol) was added to a solution of N-((1-(2-(3-(1H-pyrazol-1-yl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methyl)-3-hydroxy-5-methoxybenzamide (Example 13, 55 mg, 0.11 mmol) and cesium carbonate (80 mg, 0.24 mmol) in DMF (1 ml). The reaction mixture was heated to 40° C. for 5 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organics were filtered through a hydrophobic frit and concentrated under reduced pressure. The crude residue was purified by normal phase chromatography, eluting with iso-hexane and increasing amounts of ethyl acetate to give the title compound N-((1-(2-(3-(1H-pyrazol-1-yl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methyl)-3-(4-fluorobenzoxy)-5-methoxybenzamide as a white solid (42.5 mg). 1H NMR (CDCl3): δ 8.64 (1H, t, J=1.88 Hz), 8.34-8.29 (2H, m), 8.06 (1H, d, J=2.48 Hz), 7.86 (1H, ddd, J=8.02, 2.33, 1.07 Hz), 7.74 (1H, d, J=1.74 Hz), 7.54 (1H, t, J=7.90 Hz), 7.43-7.37 (2H, m), 7.11-7.05 (2H, m), 6.96 (1H, t, J=1.75 Hz), 6.91 (1H, t, J=1.74 Hz), 6.65 (1H, t, J=2.25 Hz), 6.49-6.44 (2H, m), 6.21 (1H, t, J=6.08 Hz), 5.04 (2H, s), 4.60 (2H, s), 3.82 (3H, s), 3.39 (2H, t, J=6.43 Hz), 3.01-2.92 (2H, m), 2.04-1.88 (3H, m), 1.33 (2H, qd, J=12.28, 4.12 Hz).

Workup

  1. customThe solvent was removed under reduced pressure
  2. customthe residue was partitioned between ethyl acetate and water
  3. extractionThe aqueous phase was extracted with ethyl acetate
  4. filtrationthe combined organics were filtered through a hydrophobic frit
  5. concentrationconcentrated under reduced pressure
  6. customThe crude residue was purified by normal phase chromatography
  7. washeluting with iso-hexane
  8. temperatureincreasing amounts of ethyl acetate

Sources & evidence

ORD record
ord-7ad746e4ef6a482cae0bab889aa975b8
Source dataset
uspto-grants-2015_03
Patent number
US08993757B2

Reaction notes

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