p-Toluenesulfonic acid → [1-Acetyl-3-(2,5-difluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-5-yl]methanol

HRID 1864758Notes

Reaction equation

HRID 1864758 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=O)[CH:10]=[C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12][O:13]C1CCCCO1.O.[NH2:28][NH2:29].[C:30](Cl)(=[O:32])[CH3:31].C1(C)C=CC(S(O)(=O)=O)=CC=1>N1C=CC=CC=1>[C:30]([N:28]1[C:11]([CH2:12][OH:13])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:10][C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])=[N:29]1)(=[O:32])[CH3:31]

Participants

6

Reactant 4

HCID 6101p-Toluenesulfonic acidHCID 6367Acetyl chlorideHCID 24654Hydrazine hydrate (1:1)HCID 688779571-(2,5-Difluorophenyl)-3-phenyl-4-(tetrahydro-2H-pyran-2-yloxy)but-2-en-1-one

Product 1

HCID 57975500[1-Acetyl-3-(2,5-difluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-5-yl]methanol

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Conditions

Temperature
90 °C

Procedure

To a solution of 5.8 g (16.2 mmol) 1-2 in 100 mL of pyridine was added 1.18 mL (24.3 mmol) hydrazine hydrate. The reaction was heated at 90° C. for 45 minutes, cooled to room temperature, and then to 0° C. Following the addition of 5.75 mL (80.9 mmol) of acetyl chloride, the cooling bath was removed and the reaction was stirred for 7 h. The reaction was then dumped into a separatory funnel with EtOAc and brine. The layers were separated, the organic phase was washed twice with 1M HCl, then with brine, dried over Na2SO4, and concentrated. The residue was twice dissolved in toluene and again concentrated to remove any remaining pyridine. The reside was dissolved in 100 mL of MeOH, 1.5 g (7.9 mmol) of p-toluenesulphonic acid was added, and the mixture was stirred for 2 h at room temperature. The reaction was then concentrated, the residue was dissolved in EtOAc, washed twice with a saturated solution of NaHCO3, then brine, dried over Na2CO3, and concentrated. The residue was triturated with Et2O and filtered to provide 1-3 as a white solid. Data for 1-3: LC-MS: rt=2.20 min, m/z=331 (M+1).

Workup

  1. temperaturecooled to room temperature
  2. customto 0° C
  3. customthe cooling bath was removed
  4. customThe reaction was then dumped into a separatory funnel with EtOAc and brine
  5. customThe layers were separated
  6. washthe organic phase was washed twice with 1M HCl
  7. dry with materialwith brine, dried over Na2SO4
  8. concentrationconcentrated
  9. dissolutionThe residue was twice dissolved in toluene
  10. concentrationagain concentrated
  11. customto remove any remaining pyridine
  12. dissolutionThe reside was dissolved in 100 mL of MeOH
  13. stirringthe mixture was stirred for 2 h at room temperature
  14. concentrationThe reaction was then concentrated
  15. dissolutionthe residue was dissolved in EtOAc
  16. washwashed twice with a saturated solution of NaHCO3
  17. dry with materialbrine, dried over Na2CO3
  18. concentrationconcentrated
  19. customThe residue was triturated with Et2O
  20. filtrationfiltered

Sources & evidence

ORD record
ord-9960363444684f4592d6b545cd614caf
Source dataset
uspto-grants-2009_12
Patent number
US07625936B2

Reaction notes

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