Water → Ethyl 4-[4-methyl-4-(ethoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate

HRID 714531Notes

Reaction equation

HRID 714531 reaction equation
Cl.[CH2:2]([O:4][C:5]([C:7]1([CH3:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6])[CH3:3].C([O-])([O-])=O.[K+].[K+].O.[CH2:21]([O:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)=[O:25])[CH3:22]>CO.C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)(=O)C>[CH3:13][C:7]1([C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH2:12][CH2:11][N:10]([CH:29]2[CH2:30][CH2:31][CH2:32][N:26]([C:24]([O:23][CH2:21][CH3:22])=[O:25])[CH2:27][CH2:28]2)[CH2:9][CH2:8]1

Participants

9

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 126660861-Carbethoxyazepan-4-oneHCID 19361804Ethyl 4-methylpiperidine-4-carboxylate hydrochloride

Product 1

HCID 89579337Ethyl 4-[4-methyl-4-(ethoxycarbonyl)piperidin-1-yl]azepane-1-carboxylateYield 45%

Reagents, catalysts & solvents 4

HCID 11026Titanium isopropoxideCatalystHCID 176Acetic AcidSolventHCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

Ethyl-4-methylpiperidine-4-carboxylate hydrochloride (0.50 g, 2.42 mmol) was dissolved in methanol (10 mL) and treated with K2CO3 (0.33 g, 2.42 mmol) in a minimum of water to de-salt. Reaction mixture was concentrated in vacuo and azeotroped to dryness with toluene. The residue and 4-oxoazepane-1-carboxylic acid ethyl ester (0.45 g, 2.42 mmol) were dissolved in DCM (20 mL) at rt and titanium isopropoxide (0.76 g, 0.8 mL, 2.66 mmol) was added. The reaction mixture was stirred at rt for 5 h. STAB (2.05 g, 9.66 mmol) and acetic acid (0.3 mL) were added and the reaction mixture was stirred at rt overnight under nitrogen. The reaction mixture was quenched with the addition of water (5 mL) and stirred for 5 minutes. The reaction mixture was diluted with DCM and filtered through a pad of celite. The filtrate was washed with sat. NaHCO3 sol., sat. NaCl sol. and dried over MgSO4. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å, 25 mL per min, gradient 0% to 4% MeOH in DCM]) to give ethyl 4-[4-methyl-4-(ethoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (0.37 g, 45.0%) as a pale yellow oil.

Workup

  1. customReaction mixture
  2. concentrationwas concentrated in vacuo
  3. customazeotroped to dryness with toluene
  4. stirringthe reaction mixture was stirred at rt overnight under nitrogen
  5. customThe reaction mixture was quenched with the addition of water (5 mL)
  6. stirringstirred for 5 minutes
  7. additionThe reaction mixture was diluted with DCM
  8. filtrationfiltered through a pad of celite
  9. washThe filtrate was washed with sat. NaHCO3 sol., sat. NaCl sol.
  10. dry with materialdried over MgSO4
  11. customThe solvents were removed in vacuo
  12. customthe residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å, 25 mL per min, gradient 0% to 4% MeOH in DCM])

Sources & evidence

ORD record
ord-d823b1bc79f04ac093cb45326e756173
Source dataset
uspto-grants-2015_11
Patent number
US09187451B2

Reaction notes

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