4-Fluorobenzyl bromide → (2S,4R)-1-tert-butyl 2-ethyl 4-(4-fluorobenzyl)-5-oxopyrrolidine-1,2-dicarboxylate

HRID 1630039Notes

Reaction equation

HRID 1630039 reaction equation
[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[O:11]=[C:12]1[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14][CH2:13]1.[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1>C1COCC1>[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][C@H:13]2[C:12](=[O:11])[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14]2)=[CH:32][CH:31]=1

Participants

5

Reactant 3

HCID 680214-Fluorobenzyl bromideHCID 2733832Lithium HexamethyldisilazideHCID 54611861-(1,1-Dimethylethyl) 2-ethyl (2S)-5-oxo-1,2-pyrrolidinedicarboxylate

Product 1

HCID 67009146(2S,4R)-1-tert-butyl 2-ethyl 4-(4-fluorobenzyl)-5-oxopyrrolidine-1,2-dicarboxylateYield 39.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

Step (b) 1M LiHMDS (27.5 mL, 27.5 mmol) was added to a solution of (S)-1-tert-butyl 2-ethyl 5-oxopyrrolidine-1,2-dicarboxylate (6.4 g, 25 mmol) in THF (20 mL) at −78° C. The mixture was stirred for 50 minutes and then 4-fluorobenzyl bromide (3.25 mL, 26.5 mmol) in THF (2 mL) was added dropwise. The mixture was stirred for 1 hour and 40 minutes and quenched with excess saturated ammonium chloride. The mixture was warmed to ambient temperature and extracted with ethyl acetate. The extract was washed with water and then brine, dried over magnesium sulfate, filtered and concentrated. The solid residue was dissolved in a 3:1 hexane/methyl tert-butyl ether solvent mixture (100 mL) and slow crystallization was allowed at ambient temperature. The mixture was cooled to 0° C. and the solid was collected by filtration, washed with a 3:1 hexane/methyl tert-butyl ether solvent mixture (50 mL) and dried to give (2S,4R)-1-tert-butyl 2-ethyl 4-(4-fluorobenzyl)-5-oxopyrrolidine-1,2-dicarboxylate (3.59 g, 39%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.15-7.12 (m, 2H), 7.01-6.96 (m, 2H), 4.47 (dd, J=2.0, 9.2, 1H), 4.22-4.17 (m, 2H), 3.22 (dd, J=4.4, 14.4, 1H), 2.94-2.85 (m, 1H), 2.71-2.65 (m, 1H), 2.08-1.94 (m, 2H), 1.50 (s, 9H), 1.26 (t, 3H).

Workup

  1. stirringThe mixture was stirred for 1 hour and 40 minutes
  2. customquenched with excess saturated ammonium chloride
  3. extractionextracted with ethyl acetate
  4. washThe extract was washed with water
  5. dry with materialbrine, dried over magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. dissolutionThe solid residue was dissolved in a 3:1 hexane/methyl tert-butyl ether solvent mixture (100 mL) and slow crystallization
  9. customwas allowed at ambient temperature
  10. temperatureThe mixture was cooled to 0° C.
  11. filtrationthe solid was collected by filtration
  12. washwashed with a 3:1 hexane/methyl tert-butyl ether solvent mixture (50 mL)
  13. customdried

Sources & evidence

ORD record
ord-7252ea00c8194d8cba21b6e3831ff51c
Source dataset
uspto-grants-2014_07
Patent number
US08791102B2

Reaction notes

Loading…