Sodium hydride → [(2R)-1,4-dimethylpiperazin-2-yl]methyl 4-(4-fluorophenyl)piperazine-1-carboxylate

HRID 2262512Notes

Reaction equation

HRID 2262512 reaction equation
[H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][C@@H:5]1[CH2:11][OH:12].[N+](C1C=CC([O:22][C:23]([N:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)=O)=CC=1)([O-])=O>C1COCC1>[F:37][C:34]1[CH:33]=[CH:32][C:31]([N:28]2[CH2:27][CH2:26][N:25]([C:23]([O:12][CH2:11][C@H:5]3[CH2:6][N:7]([CH3:10])[CH2:8][CH2:9][N:4]3[CH3:3])=[O:22])[CH2:30][CH2:29]2)=[CH:36][CH:35]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 28765199(2R)-1,4-Dimethyl-2-piperazinemethanol2×HCID 595944824-(4-Fluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester2×

Product 1

HCID 42633819[(2R)-1,4-dimethylpiperazin-2-yl]methyl 4-(4-fluorophenyl)piperazine-1-carboxylateYield 35%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

NaH (60% dispersion in mineral oil; 0.45 g, 11.3 mmol) was suspended in anhydrous THF (20 mL) under nitrogen and the reaction mixture was cooled to 0° C. with stirring. A solution of 1,4-dimethyl-(R)-2-hydroxymethyl piperazine (Intermediate 4; 0.50 g, 3.47 mmol) in THF (20 mL) was added dropwise. The reaction mixture was stirred for 10 minutes at 0° C. 4-(4-Fluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 6; 1.50 g, 4.34 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with sat. aq. NaHCO3 (40 mL) and the THF was removed in vacuo. The aqueous phase was extracted with EtOAc (100 mL). The organic layer was washed with sat. aq. NaHCO3 (5×100 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by reverse phase column chromatography (LiChroprep RP-18, 40-63 μm, 460×26 mm (100 g), 30 mL/min, gradient 0% to 30% (over 75 min) to 100% (over 13 min) MeOH in water with 1% formic acid). The residue was de-salted using K2CO3 in DCM to give [(2R)-1,4-dimethylpiperazin-2-yl]methyl 4-(4-fluorophenyl)piperazine-1-carboxylate (0.42 g, 35%) as a colourless gum.

Workup

  1. stirringThe reaction mixture was stirred for 10 minutes at 0° C
  2. stirringthe reaction mixture was stirred overnight at room temperature
  3. customThe reaction mixture was quenched with sat. aq. NaHCO3 (40 mL)
  4. customthe THF was removed in vacuo
  5. extractionThe aqueous phase was extracted with EtOAc (100 mL)
  6. washThe organic layer was washed with sat. aq. NaHCO3 (5×100 mL)
  7. dry with materialdried (MgSO4)
  8. customthe solvent removed in vacuo
  9. customThe residue was purified by reverse phase column chromatography (LiChroprep RP-18, 40-63 μm, 460×26 mm (100 g), 30 mL/min, gradient 0% to 30% (over 75 min) to 100% (over 13 min) MeOH in water with 1% formic acid)

Sources & evidence

ORD record
ord-1f425b196e3346358cf8893b606fe9c4
Source dataset
uspto-grants-2010_12
Patent number
US07851471B2

Reaction notes

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