Sodium hydride → tert-Butyl (3R)-3-(2-tert-butoxy-2-oxoethoxy)pyrrolidine-1-carboxylate

HRID 968434Notes

Reaction equation

HRID 968434 reaction equation
[H-].[Na+].[OH:3][C@@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1.Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>O1CCCC1>[C:21]([O:20][C:18](=[O:19])[CH2:17][O:3][C@@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1)([CH3:24])([CH3:23])[CH3:22]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 79177tert-Butyl bromoacetateHCID 6544479tert-Butyl (3R)-3-hydroxypyrrolidine-1-carboxylate

Product 1

HCID 22883149tert-Butyl (3R)-3-(2-tert-butoxy-2-oxoethoxy)pyrrolidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

Sodium hydride (704 mg, 60% in mineral oil, 17.6 mmol) was added to an ice-cooled solution of tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (J. Med. Chem. 1998, 41(25), 4983) (5 g, 26.7 mmol) in tetrahydrofuran (100 ml), and the mixture was allowed to warm to room temperature and stirred for 20 minutes. tert-Butyl bromoacetate (5.2 g, 26.7 mmol) was added and the mixture was heated under reflux for 18 hours, then cooled and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the phases separated. The organic layer was dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (0:100 to 20:80) to afford the title compound, 1.95 g. 1H-NMR (CDCl3, 400 MHz) δ: 1.42 (s, 9H), 1.44 (s, 9H), 1.85-2.05 (m, 2H), 3.40 (m, 4H), 3.94 (m, 2H), 4.10 (m, 1H). LRMS: m/z (ES+) 324 [MNa+]

Workup

  1. temperaturethe mixture was heated
  2. temperatureunder reflux for 18 hours
  3. temperaturecooled
  4. concentrationconcentrated under reduced pressure
  5. customThe residue was partitioned between ethyl acetate and water
  6. customthe phases separated
  7. dry with materialThe organic layer was dried (MgSO4)
  8. customevaporated under reduced pressure
  9. customThe crude product was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (0:100 to 20:80)

Sources & evidence

ORD record
ord-d29d740c5a424b1e90e6c294c7933d38
Source dataset
uspto-grants-2005_10
Patent number
US06958402B2

Reaction notes

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