4-Piperidinecarboxylic acid → Benzyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate

HRID 1506132Notes

Reaction equation

HRID 1506132 reaction equation
Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=O)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+].Cl.[CH3:30][NH:31][O:32][CH3:33].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[Cl-].[NH4+]>O.C(Cl)(Cl)Cl>[CH3:33][O:32][N:31]([CH3:30])[C:18]([CH:15]1[CH2:16][CH2:17][N:12]([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH2:13][CH2:14]1)=[O:20]

Participants

12

Reactant 9

HCID 37734-Piperidinecarboxylic acidHCID 8471TriethylamineHCID 10340Sodium CarbonateHCID 10387Benzyl chloroformateHCID 14798Sodium HydroxideHCID 25517Ammonium ChlorideHCID 757711-HydroxybenzotriazoleHCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride

Product 1

HCID 22574154Benzyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylateYield 66.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 6212ChloroformSolvent

Procedure

Benzyl chloroformate (1.64 mL, 11.6 mmol) was gradually added dropwise to piperidine-4-carboxylic acid (1.00 g, 7.74 mmol) and sodium carbonate (1.64 g, 15.5 mmol) in water (20 mL) under cooling with ice, and the resulting reaction mixture was stirred for 2 hours. After addition of 1 M aqueous sodium hydroxide, the reaction mixture was allowed to separate by adding ethyl acetate. The resulting aqueous layer was adjusted to pH 4 with 1 M hydrochloric acid and extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a colorless oil. The oil was dissolved in chloroform (30 mL) and stirred with N,O-dimethylhydroxylamine hydrochloride (1.50 g, 15.4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.00 g, 15.4 mmol), 1-hydroxybenzotriazole (2.00 g, 15.4 mmol) and triethylamine (3.2 mL, 23.1 mmol) at room temperature for 3 days. After addition of water and saturated aqueous ammonium chloride, the reaction mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)) to give the title compound as a colorless oil (1.57 g, yield 66%).

Workup

  1. temperatureunder cooling with ice
  2. customthe resulting reaction mixture
  3. customto separate
  4. additionby adding ethyl acetate
  5. extractionextracted with ethyl acetate
  6. dry with materialthe organic layer was dried over anhydrous sodium sulfate
  7. concentrationconcentrated under reduced pressure
  8. customto give a colorless oil
  9. extractionthe reaction mixture was extracted with chloroform
  10. dry with materialthe organic layer was dried over anhydrous sodium sulfate
  11. concentrationconcentrated under reduced pressure
  12. customThe residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v))

Sources & evidence

ORD record
ord-647e70aec8be4e6380a20fc5265d62f1
Source dataset
uspto-grants-2015_12
Patent number
US09216999B2

Reaction notes

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