Sodium hydride → tert-butyl (2S,5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-[(2-fluoro-6-nitrophenoxy)methyl]morpholine-4-carboxylate

HRID 629743Notes

Reaction equation

HRID 629743 reaction equation
[H-].[Na+].[Si:3]([O:10][CH2:11][C@H:12]1[N:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][C@@H:15]([CH2:25][OH:26])[O:14][CH2:13]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[C:29]=1F>CN(C=O)C>[Si:3]([O:10][CH2:11][C@H:12]1[N:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][C@@H:15]([CH2:25][O:26][C:29]2[C:30]([N+:34]([O-:36])=[O:35])=[CH:31][CH:32]=[CH:33][C:28]=2[F:27])[O:14][CH2:13]1)([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:5])[CH3:4]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 813351,2-Difluoro-3-nitrobenzeneHCID 86726301Tert-butyl (2S,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(hydroxymethyl)morpholine-4-carboxylate

Product 1

HCID 86726343tert-butyl (2S,5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-[(2-fluoro-6-nitrophenoxy)methyl]morpholine-4-carboxylateYield 74.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent3×

Conditions

Temperature
0 °C

Procedure

To a stirring solution of sodium hydride (0.257 g, 6.43 mmol) (pre-washed in hexanes) in DMF (15.30 mL) at 0° C., tert-butyl (2S,5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-(hydroxymethyl)morpholine-4-carboxylate (Example 1, Step 5) (1.66 g, 4.59 mmol) in DMF (2 mL) was added dropwise. The resulting mixture was stirred at 0° C. for 1 hour. At this point, 1,2-difluoro-3-nitrobenzene (0.494 mL, 4.50 mmol) in 0.5 mL of DMF was added dropwise and the final solution was slowly warmed toward room temperature and stirred for 1 hour. Complete by LC/MS at this time. The contents were quenched by adding saturated aqueous sodium bicarbonate and then extracted between water and EtOAc (3×75 mL). The organic layer was dried over MgSO4, filtered and concentrated. Purification on silica gel (120 g) eluting with a gradient of 0-60% EtOAc/hexanes afforded the title compound (1.68 g, 3.36 mmol, 73% yield) as a yellow oil, MS (ESI): m/z=401.11 (M+H-boc).

Workup

  1. stirringstirred for 1 hour
  2. customThe contents were quenched
  3. additionby adding saturated aqueous sodium bicarbonate
  4. extractionextracted between water and EtOAc (3×75 mL)
  5. dry with materialThe organic layer was dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customPurification on silica gel (120 g)
  9. washeluting with a gradient of 0-60% EtOAc/hexanes

Sources & evidence

ORD record
ord-e9ed9e102eec44a1b72b5c684282f7a3
Source dataset
uspto-grants-2016_04
Patent number
US09315475B2

Reaction notes

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