Sodium hydride → HCID 66934466, compound

HRID 2262502Notes

Reaction equation

HRID 2262502 reaction equation
[H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][C@@H:11]1[CH2:16][OH:17])=[O:9])([CH3:6])([CH3:5])[CH3:4].[N+](C1C=CC([O:27][C:28]([N:30]2[CH2:35][CH2:34][N:33]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[CH2:32][CH2:31]2)=O)=CC=1)([O-])=O.C([O-])(O)=O.[Na+]>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][C@H:11]1[CH2:16][O:17][C:28]([N:30]1[CH2:31][CH2:32][N:33]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:27])=[O:9])([CH3:6])([CH3:5])[CH3:4]

Participants

6

Reactant 4

HCID 24758Sodium hydrideHCID 516892Sodium BicarbonateHCID 1514266tert-Butyl (3S)-3-(hydroxymethyl)morpholine-4-carboxylateHCID 595944824-(4-Fluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester2×

Product 1

HCID 66934466HCID 66934466, compoundYield 84.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

NaH (60% in oil, prewashed with hexane; 2.76 g, 69.0 mmol) was suspended in anhydrous THF (100 mL) under nitrogen and the reaction mixture was cooled to 0° C. with stirring. A solution of (S)-3-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (5.00 g, 23.0 mmol) in THF (100 mL) was added dropwise. The reaction mixture was stirred for 30 minutes at 0° C. 4-(4-Fluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 6; 10.0 g, 29.0 mmol) was added and the reaction mixture was stirred overnight at room temperature before standing for 24 h. The reaction mixture was cooled to 5-10° C. A 10% aqueous solution of NaHCO3 (22 mL) was added and the solvents were removed in vacuo. The residue was partitioned between EtOAc (700 mL) and 10% aqueous solution of NaHCO3 (200 mL)/water (400 mL). The EtOAc layer was dried (MgSO4) and the solvent removed in vacuo. The residue was purified by column chromatography (normal phase silica, 100 g Isolute-Si column, gradient of EtOAc in hexane). The residue was dissolved in DCM and evaporated in vacuo and repeated before drying in vacuo to give (3S)-3-[4-(4-fluorophenyl)-piperazine-1-carbonyloxymethyl]-morpholine-4-carboxylic acid tert-butyl ester (8.19 g, 84%) as an orange gum.

Workup

  1. stirringThe reaction mixture was stirred for 30 minutes at 0° C
  2. stirringthe reaction mixture was stirred overnight at room temperature
  3. temperatureThe reaction mixture was cooled to 5-10° C
  4. customthe solvents were removed in vacuo
  5. customThe residue was partitioned between EtOAc (700 mL) and 10% aqueous solution of NaHCO3 (200 mL)/water (400 mL)
  6. dry with materialThe EtOAc layer was dried (MgSO4)
  7. customthe solvent removed in vacuo
  8. customThe residue was purified by column chromatography (normal phase silica, 100 g Isolute-Si column, gradient of EtOAc in hexane)
  9. dissolutionThe residue was dissolved in DCM
  10. customevaporated in vacuo
  11. custombefore drying in vacuo

Sources & evidence

ORD record
ord-91e6591141f54e52a7e773a74bfe4d7d
Source dataset
uspto-grants-2010_12
Patent number
US07851471B2

Reaction notes

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