Acetic Acid → Ethyl 4-[4-(ethoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate

HRID 714527Notes

Reaction equation

HRID 714527 reaction equation
[NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[CH2:12]([O:14][C:15]([N:17]1[CH2:23][CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)=[O:16])[CH3:13].C(O)(=O)C>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:8]([O:7][C:5]([CH:4]1[CH2:3][CH2:2][N:1]([CH:20]2[CH2:21][CH2:22][CH2:23][N:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])[CH2:18][CH2:19]2)[CH2:11][CH2:10]1)=[O:6])[CH3:9]

Participants

6

Reactant 3

HCID 176Acetic AcidHCID 70770Ethyl 4-piperidinecarboxylateHCID 126660861-Carbethoxyazepan-4-one

Product 1

HCID 89579373Ethyl 4-[4-(ethoxycarbonyl)piperidin-1-yl]azepane-1-carboxylateYield 48.4%

Reagents, catalysts & solvents 2

HCID 11026Titanium isopropoxideCatalystHCID 6344DichloromethaneSolvent

Procedure

Ethyl isonipecotate (2.54 g, 2.50 mL, 16.2 mmol) and 4-oxoazepane-1-carboxylic acid ethyl ester (3.00 g, 16.2 mmol) were dissolved in DCM (100 mL) at rt and titanium isopropoxide (5.07 g, 5.40 mL, 17.8 mmol) was added. The reaction mixture was stirred at rt for 1 h. STAB (13.7 g, 32.4 mmol) and acetic acid (0.5 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 50 g, 40-63 μm, 60 Å, 50 mL per min, gradient 2% to 4% MeOH in DCM]) to give ethyl 4-[4-(ethoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (2.56 g, 48%) as a pale yellow oil.

Workup

  1. stirringthe reaction mixture was stirred at rt overnight under nitrogen
  2. customThe reaction mixture was quenched with the addition of water (5 mL)
  3. stirringstirred for 5 minutes
  4. additionThe reaction mixture was diluted with DCM
  5. filtrationfiltered through a pad of celite
  6. washThe filtrate was washed with sat. NaHCO3 sol., sat. NaCl sol.
  7. dry with materialdried over MgSO4
  8. customThe solvents were removed in vacuo
  9. customthe residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 50 g, 40-63 μm, 60 Å, 50 mL per min, gradient 2% to 4% MeOH in DCM])

Sources & evidence

ORD record
ord-a024c909a46345068599e7b5f4da7e91
Source dataset
uspto-grants-2015_11
Patent number
US09187451B2

Reaction notes

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