4-Methylmorpholine → HCID 42633999, compound

HRID 2262487Notes

Reaction equation

HRID 2262487 reaction equation
[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH:3]1[CH2:9][OH:10].CN1CC[O:15][CH2:14]C1.C1C([N+]([O-])=O)=CC=C([Cl-]C([O-])=O)C=1.CCN(C(C)C)C(C)C.[CH2:40]([N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[CH2:40]([N:47]1[CH2:52][CH2:51][N:50]([C:14]([O:10][CH2:9][CH:3]2[CH2:4][N:5]([CH3:8])[CH2:6][CH2:7][N:2]2[CH3:1])=[O:15])[CH2:49][CH2:48]1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 759941-BenzylpiperazineHCID 81531DiisopropylethylamineHCID 2779170(1,4-Dimethylpiperazin-2-yl)methanol

Product 1

HCID 42633999HCID 42633999, compoundYield 26.6%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

1,4-dimethyl-2-hydroxymethyl piperazine (1.00 g, 6.94 mmol) was dissolved in DCM (50 mL) at room temperature and NMM (0.74 g, 7.29 mmol) was added. The reaction mixture was cooled to 0° C. and 4-nitrophenylchloroformate (1.4 g, 6.94 mmol) was added. The reaction mixture was stirred at room temperature for 4 h and then divided into two equal volumes. To one portion was added DIPEA (1.35 g, 10.4 mmol), 1-benzyl piperazine (0.61 g, 3.47 mmol) and the reaction mixture was stirred for 4 h. The solvents were removed in vacuo and the residue was partitioned between EtOAc (300 mL) and 1.0M aq NaOH solution (100 mL). The organic layer was washed with 1.0M aq NaOH solution (5×100 mL), brine (100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was dissolved in DCM (100 mL) and isocyanate resin was added, the reaction mixture was shaken for 16 h, filtered and the solvents were 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 88 min) MeOH in water with 1% formic acid). The residue was de-salted using K2CO3 in DCM to give (1,4-dimethylpiperazin-2-yl)methyl 4-benzylpiperazine-1-carboxylate (0.32 g, 26.3%) as a light yellow oil.

Workup

  1. stirringthe reaction mixture was stirred for 4 h
  2. customThe solvents were removed in vacuo
  3. customthe residue was partitioned between EtOAc (300 mL) and 1.0M aq NaOH solution (100 mL)
  4. washThe organic layer was washed with 1.0M aq NaOH solution (5×100 mL), brine (100 mL)
  5. dry with materialdried (MgSO4)
  6. customthe solvents were removed in vacuo
  7. dissolutionThe residue was dissolved in DCM (100 mL)
  8. additionisocyanate resin was added
  9. stirringthe reaction mixture was shaken for 16 h
  10. filtrationfiltered
  11. customthe solvents were removed in vacuo
  12. 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 88 min) MeOH in water with 1% formic acid)

Sources & evidence

ORD record
ord-4d8bd147e6154562b3a5be02a454ed62
Source dataset
uspto-grants-2010_12
Patent number
US07851471B2

Reaction notes

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