Diisopropylamine → Tert-butyl 3,3-difluoro-2-(2-fluoropyridin-3-yl)-2-hydroxy-4-methylenepyrrolidine-1-carboxylate

HRID 1426690Notes

Reaction equation

HRID 1426690 reaction equation
C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[F:20][C:21]1([F:35])[C:25](=[CH2:26])[CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:22]1=[O:34].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[F:35][C:21]1([F:20])[C:25](=[CH2:26])[CH2:24][N:23]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:22]1([C:19]1[C:14]([F:13])=[N:15][CH:16]=[CH:17][CH:18]=1)[OH:34]

Participants

8

Reactant 5

HCID 7912DiisopropylamineHCID 97462-FluoropyridineHCID 25517Ammonium ChlorideHCID 598268761055306-64-3HCID 178418339Butyllithium

Product 1

HCID 59826899Tert-butyl 3,3-difluoro-2-(2-fluoropyridin-3-yl)-2-hydroxy-4-methylenepyrrolidine-1-carboxylateYield 67%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent3×HCID 8058HexaneSolvent

Procedure

Under a nitrogen atmosphere, to a solution of diisopropylamine (23.9 g) in anhydrous tetrahydrofuran (175 mL) was added dropwise a 1.61 mol/L hexane solution (136 mL) of n-butyllithium at −78° C., and the mixture was stirred at the same temperature for 15 min. To the obtained solution was added dropwise a solution of 2-fluoropyridine (21.9 g) in anhydrous tetrahydrofuran (25 mL) at the same temperature over 30 min, and the mixture was stirred for 2 hr. To the obtained suspension was added dropwise a solution of tert-butyl 3,3-difluoro-4-methylene-2-oxopyrrolidine-1-carboxylate (25.0 g) in anhydrous tetrahydrofuran (50 mL) at the same temperature, and the mixture was stirred for 3 hr. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed successively 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). The obtained crystals were washed with diisopropyl ether to give the title compound as colorless crystals (yield 23.7 g, 67%).

Workup

  1. stirringthe mixture was stirred for 2 hr
  2. stirringthe mixture was stirred for 3 hr
  3. extractionthe mixture was extracted with ethyl acetate
  4. washThe extract was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine
  5. dry with materialdried over anhydrous magnesium sulfate
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=2:1)
  8. washThe obtained crystals were washed with diisopropyl ether

Sources & evidence

ORD record
ord-a7636c220323454abc50f899e4721424
Source dataset
uspto-grants-2015_01
Patent number
US08933105B2

Reaction notes

Loading…