Hydrochloric Acid → 4-[(2-benzyloxyphenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one

HRID 2116480Notes

Reaction equation

HRID 2116480 reaction equation
[C:1]([CH2:6][C:7]([O:9]C)=O)(=O)[CH:2]([CH3:4])[CH3:3].[H-].[Na+].S(O[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=O)(=O)C.Cl.O.[NH2:35][NH2:36]>C(COC)OC.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:26]([O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C:6]1[C:7](=[O:9])[NH:35][NH:36][C:1]=1[CH:2]([CH3:4])[CH3:3])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 24654Hydrazine hydrate (1:1)HCID 24758Sodium hydrideHCID 2759969Methyl 4-methyl-3-oxopentanoateHCID 22932188(2-Benzyloxyphenyl)methyl mesylate

Product 1

HCID 229321724-[(2-benzyloxyphenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneYield 25%

Reagents, catalysts & solvents 3

HCID 1140TolueneSolventHCID 80711,2-DimethoxyethaneSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
70 °C

Procedure

To a solution of 2-benzyloxybenzyl alcohol (2.1 g, 9.42 mmol) in tetrahydrofuran (10 mL), triethylamine (1.38 mL, 9.89 mmol) and methanesulfonyl chloride (0.766 mL, 9.89 mmol) were added under ice cooling and stirred at room temperature for 30 minutes. After filtration to remove the insoluble materials, the filtrate was concentrated to give (2-benzyloxyphenyl)methyl mesylate (3.24 g). To a suspension of methyl isobutyrylacetate (1.43 g, 9.89 mmol), sodium hydride (60% in oil; 396 mg, 9.89 mmol) and dimethoxyethane (10 mL), a solution of (2-benzyloxyphenyl)methyl mesylate (3.24 g) in dimethoxyethane (10 mL) was added and stirred at 70° C. overnight. After addition of 0.5 M HCl, the reaction mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give an oil. To this oil, toluene (20 mL) and hydrazine monohydrate (317 mg, 9.89 mmol) were added and the resulting mixture was heated under reflux for 3 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The reaction mixture was concentrated and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=50:1 to 8:1) to give the titled compound (750 mg, 25%) as a light-yellow amorphous substance.

Workup

  1. extractionthe reaction mixture was extracted twice with ethyl acetate
  2. washThe combined organic layers were washed with saturated aqueous sodium chloride
  3. dry with materialdried over anhydrous magnesium sulfate
  4. distillationThe solvent was distilled off under reduced pressure
  5. customto give an oil
  6. temperaturethe resulting mixture was heated
  7. temperatureunder reflux for 3 hours
  8. temperatureAfter cooling to room temperature
  9. washwashed with water
  10. dry with materialdried over anhydrous magnesium sulfate
  11. concentrationThe reaction mixture was concentrated
  12. customthe resulting residue was purified by silica gel column chromatography (chloroform:methanol=50:1 to 8:1)

Sources & evidence

ORD record
ord-41ba64ddd62e4ada9a10c80b14f76e0e
Source dataset
uspto-grants-2008_10
Patent number
US07439232B2

Reaction notes

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