Hydrogen chloride-ethyl acetate → tert-Butyl 3,3-difluoro-4-{[(4-methylphenyl)sulfonyl]oxy}-2-oxopyrrolidine-1-carboxylate

HRID 869733Notes

Reaction equation

HRID 869733 reaction equation
[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([O:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:11]([F:18])([F:17])[C:12]([O:14]CC)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.Cl>C(OCC)(=O)C>[F:18][C:11]1([F:17])[CH:10]([O:19][S:20]([C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)(=[O:21])=[O:22])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:12]1=[O:14]

Participants

4

Reactant 2

HCID 21866389Hydrogen chloride-ethyl acetateHCID 58349842Ethyl 4-[(tert-butoxycarbonyl)amino]-2,2-difluoro-3-{[(4-methylphenyl)sulfonyl]oxy}butanoate

Product 1

HCID 58349825tert-Butyl 3,3-difluoro-4-{[(4-methylphenyl)sulfonyl]oxy}-2-oxopyrrolidine-1-carboxylateYield 80%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of ethyl 4-[(tert-butoxycarbonyl)amino]-2,2-difluoro-3-{[(4-methylphenyl)sulfonyl]oxy}butanoate (44.8 g) in ethyl acetate (50 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (100 mL), and the mixture was stirred for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was azeotropically distilled twice with toluene. The obtained mixture was dissolved in acetonitrile (20 mL), triethylamine (15.6 g) was added, and the mixture was stirred for 3 hr. Di-tert-butyl bicarbonate (33.6 g) and 4-dimethylaminopyridine (3.76 g) were added at room temperature and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, and washed with 1 mol/L hydrochloric acid. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=2:1) to give the title compound as a pale-yellow oil (yield 32.0 g, 80%).

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. distillationthe residue was azeotropically distilled twice with toluene
  3. dissolutionThe obtained mixture was dissolved in acetonitrile (20 mL)
  4. additiontriethylamine (15.6 g) was added
  5. stirringthe mixture was stirred for 3 hr
  6. additionDi-tert-butyl bicarbonate (33.6 g) and 4-dimethylaminopyridine (3.76 g) were added at room temperature
  7. stirringthe mixture was stirred for 1 hr
  8. concentrationThe reaction mixture was concentrated under reduced pressure
  9. dissolutionthe residue was dissolved in ethyl acetate
  10. washwashed with 1 mol/L hydrochloric acid
  11. extractionThe separated aqueous layer was extracted again with ethyl acetate
  12. washCombined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine
  13. dry with materialdried over anhydrous magnesium sulfate
  14. concentrationconcentrated under reduced pressure
  15. customThe residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=2:1)

Sources & evidence

ORD record
ord-2a41dc661a154388beb6627ca7c873f3
Source dataset
uspto-grants-2015_03
Patent number
US08969387B2

Reaction notes

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