Hydrochloric Acid → N-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)acetamide

HRID 383566Notes

Reaction equation

HRID 383566 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([NH2:14])=[CH:12][CH:11]=[N:10]1.[CH3:15][C:16](OC(C)=O)=[O:17].CCN(CC)CC.[OH-].[K+].Cl>ClCCCl.CN(C1C=CN=CC=1)C.C(Cl)Cl.CCO.CC(O)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([NH:14][C:16](=[O:17])[CH3:15])=[CH:12][CH:11]=[N:10]1

Participants

11

Reactant 5

HCID 313Hydrochloric AcidHCID 7918Acetic Anhydride2×HCID 8471TriethylamineHCID 14797Potassium HydroxideHCID 433167681-(2,4-Difluorophenyl)-1H-pyrazol-5-amine

Product 1

HCID 67199804N-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)acetamide

Reagents, catalysts & solvents 5

HCID 142844-(Dimethylamino)pyridineCatalystHCID 111,2-DichloroethaneSolventHCID 176Acetic AcidSolventHCID 702EthanolSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
80 °C

Procedure

A solution of 1-(2,4-difluorophenyl)-1H-pyrazol-5-amine (5.00 g, 26 mmol), in 80 mL of 1,2-DCE was added DMAP (0.94 g, 7.7 mmol), Ac2O (12 mL, 128 mmol) and Et3N (18 mL, 128 mmol). The dark brown reaction mixture was heated at 80° C. in an oil bath for 18 h. After cooling to RT, it was diluted with 20 mL of DCM and washed with saturated aqueous solution of sodium bicarbonate, and brine. The resulting organic solution was then dried over magnesium sulfate and concentrated under reduced pressure to give viscous brown oil which contains the bis-acylated product along with residual amount of Ac2O and AcOH. The viscous brown oil was dissolved in 50 mL of EtOH and treated with KOH (5.0 g 129 mmol). After the reaction mixture was stirred at RT for 4 h, it was acidified with 2 N HCl to pH 4. The volatile portion was removed on the rotovap. The residue was diluted with 150 mL of EtOAc, washed with saturated aqueous solution of sodium bicarbonate, and brine. The resulting organic solution was then dried over magnesium sulfate and concentrated under reduced pressure. Purification of the crude material on an ISCO 80 g column (60-100% EtOAc in hexanes) afforded N-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)acetamide as an off-white solid. MS (ES+): 238.1 (M+H)+.

Workup

  1. temperatureAfter cooling to RT
  2. washwashed with saturated aqueous solution of sodium bicarbonate, and brine
  3. dry with materialThe resulting organic solution was then dried over magnesium sulfate
  4. concentrationconcentrated under reduced pressure
  5. customto give viscous brown oil which
  6. customThe volatile portion was removed on the rotovap
  7. additionThe residue was diluted with 150 mL of EtOAc
  8. washwashed with saturated aqueous solution of sodium bicarbonate, and brine
  9. dry with materialThe resulting organic solution was then dried over magnesium sulfate
  10. concentrationconcentrated under reduced pressure
  11. customPurification of the crude material on an ISCO 80 g column (60-100% EtOAc in hexanes)

Sources & evidence

ORD record
ord-e76ac1841d114f8aabc2b15d1f452ecb
Source dataset
uspto-grants-2013_02
Patent number
US08367671B2

Reaction notes

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