4-Methylmorpholine → [1-(2-Methoxyethyl)piperidin-4-yl]methyl 4-(4-methoxyphenyl)piperazine-1-carboxylate

HRID 417962Notes

Reaction equation

HRID 417962 reaction equation
[C:1](=[O:24])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][CH3:13])[CH2:6][CH2:5]1.CN1CCOCC1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.[CH3:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([N:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)=[CH:49][CH:48]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:45][O:46][C:47]1[CH:48]=[CH:49][C:50]([N:53]2[CH2:58][CH2:57][N:56]([C:1]([O:2][CH2:3][CH:4]3[CH2:5][CH2:6][N:7]([CH2:10][CH2:11][O:12][CH3:13])[CH2:8][CH2:9]3)=[O:24])[CH2:55][CH2:54]2)=[CH:51][CH:52]=1

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 81531DiisopropylethylamineHCID 821294-Nitrophenyl chloroformateHCID 2697221-(4-Methoxyphenyl)piperazineHCID 57955470(1-(2-Methoxyethyl)piperidin-4-yl)methyl 4-nitrophenyl carbonate2×

Product 1

HCID 42635438[1-(2-Methoxyethyl)piperidin-4-yl]methyl 4-(4-methoxyphenyl)piperazine-1-carboxylateYield 21.6%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

(1-(2-methoxyethyl)piperidin-4-yl)methanol (Intermediate 3, step 2; 1.34 g, 7.74 mmol) was dissolved in DCM (20 mL) and cooled to 0° C. NMM (0.94 mL, 8.51 mmol) and 4-nitrophenyl chloroformate (1.56 g, 7.74 mmol) were added. The reaction mixture was stirred at 0° C. for 20 minutes and then added to a solution of 4-(4-methoxyphenyl)piperazine (1.64 g, 8.51 mmol) and DIPEA (6.10 mL, 35.0 mmol) in DMF (30 mL). The reaction mixture was stirred at room temperature for 4 h and then concentrated in vacuo. The residue was dissolved in EtOAc (300 mL) and then washed sequentially with 1M aq NaOH solution (5×125 mL), brine (100 mL), and then dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%). The resulting residue was dissolved in DCM (70 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo to give the title compound [1-(2-methoxyethyl)piperidin-4-yl]methyl 4-(4-methoxyphenyl)piperazine-1-carboxylate (0.637 g, 21.6%) as a pale yellow oil.

Workup

  1. stirringThe reaction mixture was stirred at room temperature for 4 h
  2. concentrationconcentrated in vacuo
  3. dissolutionThe residue was dissolved in EtOAc (300 mL)
  4. washwashed sequentially with 1M aq NaOH solution (5×125 mL), brine (100 mL)
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified by reverse phase chromatography (gradient
  8. washeluting with MeOH in water, with 1% formic acid in each solvent, 0-30%)
  9. dissolutionThe resulting residue was dissolved in DCM (70 mL)
  10. stirringstirred with solid K2CO3 for 20 minutes
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-6ce10ae350034b9c9321b7ff154fe79e
Source dataset
uspto-grants-2012_01
Patent number
US08093248B2

Reaction notes

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