Sodium hydride → 3-[4-(2,4-Difluoro-phenyl)-piperazine-1-carbonyloxymethyl]-morpholine-4-carboxylic acid tert-butyl ester

HRID 2262509Notes

Reaction equation

HRID 2262509 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[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][C:37]=3[F:43])[CH2:32][CH2:31]2)=O)=CC=1)([O-])=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[CH2:14][O:15][C:28]([N:30]1[CH2:31][CH2:32][N:33]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=2[F:43])[CH2:34][CH2:35]1)=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 5058359Tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate2×HCID 533966704-nitrophenyl 4-(2,4-difluorophenyl)tetrahydro-1(2H)-pyrazinecarboxylate2×

Product 1

HCID 669345373-[4-(2,4-Difluoro-phenyl)-piperazine-1-carbonyloxymethyl]-morpholine-4-carboxylic acid tert-butyl esterYield 50.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

3-Hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (Intermediate 7; 250 mg, 0.76 mmol) in THF (5 mL) was added dropwise to a suspension of NaH (60% dispersion in oil, prewashed with hexane; 138 mg, 3.45 mmol) in anhydrous THF (5 mL) at 0° C. and stirred under nitrogen for 35 minutes. 4-(2,4-Difluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 12; 501 mg, 1.38 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with the addition of aqueous NaHCO3 (0.5 mL) at 0° C. and the solvents removed in vacuo. The residue was suspended between aq Na2CO3 (20 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (2×20 mL). The combined organic layers were washed with aq Na2CO3 (20 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by column chromatography (normal phase, Apollo silica, 1% MeOH in DCM) and the solvents were removed in vacuo to give 3-[4-(2,4-difluoro-phenyl)-piperazine-1-carbonyloxymethyl]-morpholine-4-carboxylic acid tert-butyl ester (170 mg, 34%).

Workup

  1. stirringthe reaction mixture was stirred at room temperature overnight
  2. customThe reaction mixture was quenched with the addition of aqueous NaHCO3 (0.5 mL) at 0° C.
  3. customthe solvents removed in vacuo
  4. extractionThe aqueous phase was extracted with EtOAc (2×20 mL)
  5. washThe combined organic layers were washed with aq Na2CO3 (20 mL)
  6. dry with materialdried (MgSO4)
  7. customthe solvent removed in vacuo
  8. customThe residue was purified by column chromatography (normal phase, Apollo silica, 1% MeOH in DCM)
  9. customthe solvents were removed in vacuo

Sources & evidence

ORD record
ord-5789db3a8c3c4889a8b68cb1834774f3
Source dataset
uspto-grants-2010_12
Patent number
US07851471B2

Reaction notes

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