Sodium hydride → HCID 42633816, compound

HRID 2262481Notes

Reaction equation

HRID 2262481 reaction equation
[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][C@H:3]1[CH2:9][OH:10].[H-].[Na+].[C:13]1([N:19]2[CH2:24][CH2:23][N:22]([C:25](OC3C=CC([N+]([O-])=O)=CC=3)=[O:26])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[C:13]1([N:19]2[CH2:20][CH2:21][N:22]([C:25]([O:10][CH2:9][C@@H:3]3[CH2:4][N:5]([CH3:8])[CH2:6][CH2:7][N:2]3[CH3:1])=[O:26])[CH2:23][CH2:24]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 7035990(S)-(1,4-Dimethylpiperazin-2-YL)methanol2×HCID 595944814-Nitrophenyl 4-phenylpiperazine-1-carboxylate2×

Product 1

HCID 42633816HCID 42633816, compoundYield 36.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of 1,4-dimethyl-(S)-2-hydroxymethyl piperazine (Intermediate 3; 1.49 g, 10.3 mmol) in THF (20 mL) at 0° C. was added sodium hydride (1.24 g, 60% dispersion in mineral oil, 31.0 mmol). The reaction mixture was stirred for several minutes at 0° C. and then 4-nitrophenyl 4-phenylpiperazine-1-carboxylate (Intermediate 2; 3.72 g, 11.4 mmol) in THF (20 mL). The reaction mixture was allowed to warm to room temperature and stirred for 7 hours. The reaction mixture was then cooled to 0° C. and quenched with the drop-wise addition of sat aq NaHCO3 solution. The THF was removed in vacuo, the aqueous phase extracted with EtOAc (×3), combined organic phases washed with sat aq NaHCO3 solution (×6), dried (MgSO4) and concentrated in vacuo. The residue was suspended in water: formic acid solution [1:1] (20 mL), filtered and the filtrate was purified by reverse phase column chromatography (gradient eluting with methanol in water, with 1% formic acid in each solvent, 0-15%). The resulting residue was dissolved in DCM (50 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo to give [(2S)-1,4-dimethylpiperazin-2-yl]methyl 4-phenylpiperazine-1-carboxylate (1.25 g, 36%) as a pale yellow solid.

Workup

  1. temperatureto warm to room temperature
  2. stirringstirred for 7 hours
  3. temperatureThe reaction mixture was then cooled to 0° C.
  4. customquenched with the drop-wise addition of sat aq NaHCO3 solution
  5. customThe THF was removed in vacuo
  6. extractionthe aqueous phase extracted with EtOAc (×3)
  7. washwashed with sat aq NaHCO3 solution (×6)
  8. dry with materialdried (MgSO4)
  9. concentrationconcentrated in vacuo
  10. filtrationformic acid solution [1:1] (20 mL), filtered
  11. customthe filtrate was purified by reverse phase column chromatography (gradient
  12. washeluting with methanol in water, with 1% formic acid in each solvent, 0-15%)
  13. dissolutionThe resulting residue was dissolved in DCM (50 mL)
  14. stirringstirred with solid K2CO3 for 20 minutes
  15. filtrationfiltered
  16. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-ccff4d17c97a437a890330a348de7e1a
Source dataset
uspto-grants-2010_12
Patent number
US07851471B2

Reaction notes

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