4-Methylmorpholine → [(3S)-1-methylpiperidin-3-yl]methyl 4-(4-methylphenyl)piperazine-1-carboxylate

HRID 2262480Notes

Reaction equation

HRID 2262480 reaction equation
[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C@@H:18]3[CH2:23][CH2:22][CH2:21][N:20]([CH3:24])[CH2:19]3)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OC1C=CC=CC=1[N+]([O-])=O)=O.Cl.Cl.CC1C=CC(N2CCNCC2)=CC=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C@H:18]3[CH2:23][CH2:22][CH2:21][N:20]([CH3:24])[CH2:19]3)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 81531DiisopropylethylamineHCID 831121-(p-Tolyl)piperazine dihydrochlorideHCID 34143642-Nitrophenyl chloroformateHCID 42633814[(3R)-1-methylpiperidin-3-yl]methyl 4-(4-methylphenyl)piperazine-1-carboxylate

Product 1

HCID 42633815[(3S)-1-methylpiperidin-3-yl]methyl 4-(4-methylphenyl)piperazine-1-carboxylateYield 13.6%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

(S)-(1-Methylpiperidin-3-yl)methanol (1.50 g, 11.6 mmol; prepared according to Example 1 but starting from (S)-tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate) was dissolved in DCM (20 mL) and cooled to 0° C. NMM (1.30 mL, 12.2 mmol) and nitrophenyl chloroformate (2.46 g, 12.2 mmol) were added. The reaction mixture was stirred at 0° C. for 2 hours and then a solution of 4-(4-methylphenyl)piperazine dihydrochloride (1.88 g, 7.5 mmol) and DIPEA (3.70 mL, 22.1 mmol) in DMF (40 mL) was added. The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was dissolved in EtOAc (300 mL) and then washed sequentially with 1M aq Na2CO3 solution (5×200 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography (eluting with DCM, followed by a 85:15 mixture of DCM:MeOH) followed by reverse phase HPLC (Advanced Chromatography Technologies ACE-122-1030 RP silica 100×30 mm column, packed with Ace 5 C8 (5 μm), Pore Size 100 Å, 30 mL/min, gradient of CH3CN in water, with 0.1% TFA in each solvent, 8-38%). The residue was dissolved in DCM (70 mL) and stirred with solid K2CO3 for 20 min, filtered and concentrated in vacuo to give a yellow oil which was recrystallised from heptane/EtOAc to give [(3S)-1-methylpiperidin-3-yl]methyl 4-(4-methylphenyl)piperazine-1-carboxylate (521 mg, 13.5%) as a white solid.

Workup

  1. stirringThe reaction mixture was stirred at room temperature for 2 hours
  2. concentrationconcentrated in vacuo
  3. dissolutionThe residue was dissolved in EtOAc (300 mL)
  4. washwashed sequentially with 1M aq Na2CO3 solution (5×200 mL)
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified by normal phase column chromatography (
  8. washeluting with DCM
  9. additionfollowed by a 85:15 mixture of DCM
  10. dissolutionThe residue was dissolved in DCM (70 mL)
  11. stirringstirred with solid K2CO3 for 20 min
  12. filtrationfiltered
  13. concentrationconcentrated in vacuo
  14. customto give a yellow oil which
  15. customwas recrystallised from heptane/EtOAc

Sources & evidence

ORD record
ord-400800f8164f4cb680d9897bb76c5e4f
Source dataset
uspto-grants-2010_12
Patent number
US07851471B2

Reaction notes

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