Sodium hydride → 3-(4-Phenyl-piperazine-1-carbonyloxymethyl)-morpholine-4-carboxylic acid tert-butyl ester

HRID 2262507Notes

Reaction equation

HRID 2262507 reaction equation
[H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH:11]1[CH2:16][OH:17])=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:18]1([N:24]2[CH2:29][CH2:28][N:27]([C:30](OC3C=CC([N+]([O-])=O)=CC=3)=[O:31])[CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH:11]1[CH2:16][O:17][C:30]([N:27]1[CH2:28][CH2:29][N:24]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:25][CH2:26]1)=[O:31])=[O:9])([CH3:6])([CH3:5])[CH3:4]

Participants

6

Reactant 4

HCID 24758Sodium hydrideHCID 516892Sodium BicarbonateHCID 5058359Tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate2×HCID 595944814-Nitrophenyl 4-phenylpiperazine-1-carboxylate2×

Product 1

HCID 669345083-(4-Phenyl-piperazine-1-carbonyloxymethyl)-morpholine-4-carboxylic acid tert-butyl esterYield 80.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

NaH (60% in oil, prewashed with hexane; 1.23 g, 30.1 mmol) was suspended in anhydrous THF (50 mL) under nitrogen and cooled to 0° C. with stirring. A solution of 3-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (Intermediate 7; 2.23 g, 10.3 mmol) in THF (50 mL) was added dropwise. The reaction mixture was stirred for 20 min at 0° C. 4-Nitrophenyl 4-phenylpiperazine-1-carboxylate (Intermediate 2; 4.03 g, 12.3 mmol) was added and the reaction mixture was stirred for 48 h at room temperature. A sat aq NaHCO3 solution (10 mL) was added and the solvents were removed in vacuo. The residue was partitioned between water and EtOAc, the aqueous phase was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with sat aq NaHCO3 (3×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by flash normal column chromatography (Apollo silica, 40-63 μm, 60 A) eluting with 1% MeOH in DCM to give 3-(4-phenyl-piperazine-1-carbonyloxymethyl)-morpholine-4-carboxylic acid tert-butyl ester (3.35 g, 80%).

Workup

  1. stirringThe reaction mixture was stirred for 20 min at 0° C
  2. stirringthe reaction mixture was stirred for 48 h at room temperature
  3. customthe solvents were removed in vacuo
  4. customThe residue was partitioned between water and EtOAc
  5. extractionthe aqueous phase was extracted with EtOAc (2×100 mL)
  6. washThe combined organic extracts were washed with sat aq NaHCO3 (3×100 mL)
  7. dry with materialdried (MgSO4)
  8. customthe solvents were removed in vacuo
  9. customThe residue was purified by flash normal column chromatography (Apollo silica, 40-63 μm, 60 A)
  10. washeluting with 1% MeOH in DCM

Sources & evidence

ORD record
ord-3ed4b35797c34d808cbe9fbfbdd204ca
Source dataset
uspto-grants-2010_12
Patent number
US07851471B2

Reaction notes

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