Sodium hydride → (2S)-4-Methylene-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 1006859Notes

Reaction equation

HRID 1006859 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[CH2:13])[CH2:10][C@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:18]=1[CH2:19]Br.[H-].[Na+].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[CH2:13])[CH2:10][C@H:9]1[CH2:14][O:15][CH2:19][C:18]1[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:17]=1[F:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 4

HCID 24758Sodium hydrideHCID 25517Ammonium ChlorideHCID 27770572,4,5-Trifluorobenzyl BromideHCID 66733597tert-butyl (2S)-2-(hydroxymethyl)-4-methylidenepyrrolidine-1-carboxylate

Product 1

HCID 69427718(2S)-4-Methylene-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl esterYield 34%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

To 9.6 g (45 mmol) (2S)-2-Hydroxymethyl-4-methylene-pyrrolidine-1-carboxylic acid tert-butyl ester and 25 g (112.5 mmol, 2.5 eq) 2,4,5-trifluorobenzyl bromide in 950 ml THF were added 3.2 g (73.1 mmol, 50% in mineral oil, 1.6 eq) NaH at 0° C. over a period of 30 min. The reaction was warmed to RT over night, and added to a cooled mixture of saturated aqueous NH4Cl solution and EtOAc, the phases were separated and the inorganic one was extracted with EtOAc, the combined organic ones were washed with brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography using hexane/EtOAc 4:1 as an eluent yielding 5.4 g (34%) (2S)-4-Methylene-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as yellow oil, MS: 358 (MH+) and 1.7 g (13%) recovered starting material.

Workup

  1. customthe phases were separated
  2. extractionthe inorganic one was extracted with EtOAc
  3. washthe combined organic ones were washed with brine
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. customevaporated
  7. customThe crude product was purified by flash chromatography

Sources & evidence

ORD record
ord-bb870c6975e545509cfc0f26f33d7dc3
Source dataset
uspto-grants-2004_09
Patent number
US06790860B2

Reaction notes

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