Dimethylformamide → (2R,3S)-3-(Benzyloxy)-2-[Boc-(methyl)amino]butanoic Acid

HRID 530529Notes

Reaction equation

HRID 530529 reaction equation
[H-].[Na+].CI.[CH3:5]N(C=O)C.[CH2:10]([O:17][C@@H:18]([CH3:31])[C@@H:19]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:20]([OH:22])=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([O:17][C@@H:18]([CH3:31])[C@@H:19]([N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH3:5])[C:20]([OH:22])=[O:21])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 6992573(2R,3S)-3-(benzyloxy)-2-{[(tert-butoxy)carbonyl]amino}butanoic acid

Product 1

HCID 86699954(2R,3S)-3-(Benzyloxy)-2-[Boc-(methyl)amino]butanoic AcidYield 67%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

In a round bottom flask, under argon atmosphere, commercially available (2R,3S)-3-benzyloxy-2-(tert-butoxycarbonyl-amino)-butanoic acid was dissolved in dry THF (15 mL). Subsequently at 0° C., NaH (60% dispersion in mineral oil, 0.21 g, 5.33 mmol) was added in one portion. The reaction mixture was left to stir at the same temperature for 10 min and then MeI (0.95 mL, 15.22 mmol) followed by DMF (0.75 mL) were sequentially added. The reaction was left for 2.0 h at 0° C. and for 15 h at rt, then quenched with H2O (15 mL), diluted with EtOAc (30 mL) and acidified to pH 2 by dropwise addition of 2.0 N HCl aqueous solution. The organic layer was separated and the aqueous phase was back-extracted with EtOAc (2×30 mL). The organic phase was dried over Na2SO4, filtered and concentrated to dryness. The crude mixture was purified by column chromatography using a Teledyne ISCO apparatus eluting with Cy:TBME (60:40) to give the title compound (1.1 g, 67%), as a mixture of two rotamers (2:1 ratio), as a colorless oil. 1H NMR (DMSO-d6) δ 1.13-1.20 (m, 6H), 1.36 (s, 9H, minor rotamer), 1.41 (s, 9H, major rotamer), 2.84 (s, 3H, minor rotamer), 2.87 (s, 3H, major rotamer), 4.13-4.24 (m, 2H), 4.34-4.40 (m, 2H), 4.49 (d, J=5.5 Hz, 1H, minor rotamer), 4.57-4.62 (m, 2H), 4.71 (d, J=5.2 Hz, 1H, major rotamer), 7.23-7.35 (m, 10H).

Workup

  1. waitThe reaction mixture was left
  2. additionwere sequentially added
  3. waitThe reaction was left for 2.0 h at 0° C. and for 15 h at rt
  4. customquenched with H2O (15 mL)
  5. additiondiluted with EtOAc (30 mL)
  6. additionacidified to pH 2 by dropwise addition of 2.0 N HCl aqueous solution
  7. customThe organic layer was separated
  8. extractionthe aqueous phase was back-extracted with EtOAc (2×30 mL)
  9. dry with materialThe organic phase was dried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated to dryness
  12. customThe crude mixture was purified by column chromatography
  13. washeluting with Cy

Sources & evidence

ORD record
ord-f82aee3b89e94f1eb0118bf6acb4d4d5
Source dataset
uspto-grants-2016_05
Patent number
US09353075B2

Reaction notes

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