Sodium hydride → (4-Methylmorpholin-3-yl)methyl 4-(2,4-difluorophenyl)piperazine-1-carboxylate

HRID 2262511Notes

Reaction equation

HRID 2262511 reaction equation
[CH3:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[CH2:8][OH:9].[H-].[Na+].[N+](C1C=CC([O:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])[CH2:26][CH2:25]2)=O)=CC=1)([O-])=O>C1COCC1>[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[N:27]1[CH2:28][CH2:29][N:24]([C:22]([O:9][CH2:8][CH:3]2[CH2:4][O:5][CH2:6][CH2:7][N:2]2[CH3:1])=[O:21])[CH2:25][CH2:26]1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 23541157(4-Methylmorpholin-3-yl)methanolHCID 533966704-nitrophenyl 4-(2,4-difluorophenyl)tetrahydro-1(2H)-pyrazinecarboxylate2×

Product 1

HCID 42634522(4-Methylmorpholin-3-yl)methyl 4-(2,4-difluorophenyl)piperazine-1-carboxylateYield 19%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

(4-Methyl-morpholin-3-yl)-methanol (387 mg, 2.95 mmol) in THF (7.5 mL) was added dropwise to a suspension of NaH (60% dispersion in oil, prewashed with hexane; 354 mg, 8.85 mmol) in anhydrous THF (7.5 mL) at 0° C. and stirred under nitrogen for 40 minutes. 4-(2,4-Difluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 12; 1.28 g, 3.54 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. The reaction mixture was stirred for 1 h and then the solvents were removed in vacuo. The residue was suspended between water and EtOAc. The aqueous phase was extracted with EtOAc (×3). The combined organic layers were washed with aqueous Na2CO3, 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 (4-methylmorpholin-3-yl)methyl 4-(2,4-difluorophenyl)piperazine-1-carboxylate (197 mg, 19%) as a colourless oil.

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. stirringThe reaction mixture was stirred for 1 h
  4. customthe solvents were removed in vacuo
  5. extractionThe aqueous phase was extracted with EtOAc (×3)
  6. washThe combined organic layers were washed with aqueous Na2CO3
  7. dry with materialdried (MgSO4)
  8. customthe solvent removed in vacuo
  9. customThe residue was purified by column chromatography (normal phase, Apollo silica, 1% MeOH in DCM)
  10. customthe solvents were removed in vacuo

Sources & evidence

ORD record
ord-54b1bc1071aa4e42afe47ebd6631e075
Source dataset
uspto-grants-2010_12
Patent number
US07851471B2

Reaction notes

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