Sodium hydride → 2-(4-Phenylpiperazine-1-carbonyloxymethyl)-morpholine-4-carboxylic acid tert-butyl ester

HRID 2262488Notes

Reaction equation

HRID 2262488 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[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>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][C:30]([N:27]2[CH2:28][CH2:29][N:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:25][CH2:26]2)=[O:31])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

5

Reactant 3

HCID 24758Sodium hydride2×HCID 5201202tert-Butyl 2-(hydroxymethyl)morpholine-4-carboxylateHCID 595944814-Nitrophenyl 4-phenylpiperazine-1-carboxylate2×

Product 1

HCID 669344832-(4-Phenylpiperazine-1-carbonyloxymethyl)-morpholine-4-carboxylic acid tert-butyl esterYield 87%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

2-Hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (4.13 g, 19.0 mmol) was dissolved in anhydrous THF (20 mL) and the solution cooled to 0° C. NaH (60% wt dispersion in oil; 2.28 g, 57.0 mmol) was added and the grey suspension stirred for 10 minutes before 4-nitrophenyl 4-phenylpiperazine-1-carboxylate (Intermediate 2; 7.46 g, 22.8 mmol) was added. The reaction was stirred at room temperature over the weekend. A further 1.5 equivalents of NaH (60% wt dispersion in oil) (1.14 g, 28.5 mmol) was added and the reaction stirred at room temperature overnight. The reaction mixture was cooled to 0° C. and quenched with sat aq NaHCO3 solution (50 mL) before the THF was removed in vacuo. The organic product was extracted with EtOAc (3×50 mL) and the organic layers combined, washed with sat aq NaHCO3 solution (3×50 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by reverse phase column chromatography (LiChroprep RP-18, 40-63 μm, 460×36 mm (200 g), 30 mL/min, gradient 0% to 80% (over 120 mins) MeOH in water with 1% formic acid) to afford 2-(4-phenylpiperazine-1-carbonyloxymethyl)-morpholine-4-carboxylic acid tert-butyl ester (6.67 g, 87% yield) as a dark brown oil.

Workup

  1. additionwas added
  2. stirringthe reaction stirred at room temperature overnight
  3. temperatureThe reaction mixture was cooled to 0° C.
  4. customquenched with sat aq NaHCO3 solution (50 mL) before the THF
  5. customwas removed in vacuo
  6. extractionThe organic product was extracted with EtOAc (3×50 mL)
  7. washwashed with sat aq NaHCO3 solution (3×50 mL)
  8. dry with materialdried (MgSO4)
  9. customthe solvent removed in vacuo
  10. customThe residue was purified by reverse phase column chromatography (LiChroprep RP-18, 40-63 μm, 460×36 mm (200 g), 30 mL/min, gradient 0% to 80% (over 120 mins) MeOH in water with 1% formic acid)

Sources & evidence

ORD record
ord-57a662ff9d99432b9c5b18761db79d70
Source dataset
uspto-grants-2010_12
Patent number
US07851471B2

Reaction notes

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