Potassium Carbonate → Ethyl 4-[4-methoxy-4-(methoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate

HRID 714541Notes

Reaction equation

HRID 714541 reaction equation
Cl.[CH3:2][O:3][C:4]([C:6]1([O:12][CH3:13])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:20]([O:22][C:23]([N:25]1[CH2:31][CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)=[O:24])[CH3:21].C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-].O>[CH3:13][O:12][C:6]1([C:4]([O:3][CH3:2])=[O:5])[CH2:7][CH2:8][N:9]([CH:28]2[CH2:29][CH2:30][CH2:31][N:25]([C:23]([O:22][CH2:20][CH3:21])=[O:24])[CH2:26][CH2:27]2)[CH2:10][CH2:11]1

Participants

8

Reactant 4

HCID 11430Potassium CarbonateHCID 5003444Sodium cyanoborohydrideHCID 126660861-Carbethoxyazepan-4-oneHCID 74890099Methyl 4-methoxypiperidine-4-carboxylate hydrochloride

Product 1

HCID 89579395Ethyl 4-[4-methoxy-4-(methoxycarbonyl)piperidin-1-yl]azepane-1-carboxylateYield 16.7%

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 887MethanolSolvent2×HCID 962WaterSolvent

Conditions

Temperature
50 °C

Procedure

4-Methoxypiperidine-4-carboxylic acid methyl ester hydrochloride (0.50 g, 2.38 mmol) was dissolved in methanol (10 mL) and treated with K2CO3 (0.328 g, 2.38 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 (0.441 g, 2.38 mmol) were dissolved in methanol (20 mL) at rt and treated with zinc chloride (0.975 g, 7.15 mmol). The reaction mixture was stirred at 50° C. for 2 h. The solution was cooled to room temperature, sodium cyanoborohydride (0.299 g, 4.77 mmol) was added and the reaction mixture was stirred at 50° C. overnight under nitrogen. The solvents were removed in vacuo, and the residue was suspended between DCM and sat. NaHCO3 sol. The turbid mixture, was passed through a pad of celite which was washed with DCM. The organics layers were combined, washed with sat. NaCl sol. and dried by passing through a Biotage Phase Separator cartridge. 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, 50 mL per min, gradient 1% to 6% MeOH in DCM]) to give ethyl 4-[4-methoxy-4-(methoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (0.136 g, 16.4%) as a colourless oil.

Workup

  1. customReaction mixture
  2. concentrationwas concentrated in vacuo
  3. customazeotroped to dryness with toluene
  4. temperatureThe solution was cooled to room temperature
  5. stirringthe reaction mixture was stirred at 50° C. overnight under nitrogen
  6. customThe solvents were removed in vacuo
  7. washwas washed with DCM
  8. washwashed with sat. NaCl sol.
  9. customdried
  10. customThe solvents were removed in vacuo
  11. customthe residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å, 50 mL per min, gradient 1% to 6% MeOH in DCM])

Sources & evidence

ORD record
ord-d5e84852a8dc4344bc40404c4638b932
Source dataset
uspto-grants-2015_11
Patent number
US09187451B2

Reaction notes

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