4-Methylmorpholine → Tert-butyl 4-((2-oxo-2-(3-(trifluoromethyl)phenyl)ethyl)carbamoyl)piperidine-1-carboxylate

HRID 419698Notes

Reaction equation

HRID 419698 reaction equation
CN1CCOCC1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=O)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.Cl.[NH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=1)=[O:36]>C1COCC1>[O:36]=[C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:44])([F:45])[F:46])[CH:38]=1)[CH2:34][NH:33][C:21]([CH:18]1[CH2:17][CH2:16][N:15]([C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:14])[CH2:20][CH2:19]1)=[O:23]

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 3928711-(tert-Butoxycarbonyl)-4-piperidinecarboxylic acidHCID 133658852-Amino-1-(3-(trifluoromethyl)phenyl)ethan-1-one hydrochloride

Product 1

HCID 57751897Tert-butyl 4-((2-oxo-2-(3-(trifluoromethyl)phenyl)ethyl)carbamoyl)piperidine-1-carboxylateYield 60.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

Add N-methylmorpholine (13.0 mL, 118 mmol) to a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (11.2 g, 48.8 mmol) in THF (400 mL) at −10° C. and stir for 5 min. Add isobutyl chloroformate (5.1 mL, 38.8 mmol) and continue stirring at −10° C. for 2 h. Add 2-amino-1-(3-(trifluoromethyl)phenyl)ethanone hydrochloride (9.35 g, 39.0 mmol) and continue stirring for 1 h. Add methylene chloride (500 mL) to the mixture and filter. Wash the filtrate with sat. aqueous sodium bicarbonate (400 mL) and concentrate in vacuo. Purify the residue by silica gel chromatography (330 g RediSep column, eluting with a gradient of 0% to 100% ethyl acetate:hexane, 6.0 L) to provide tert-butyl 4-(2-oxo-2-(3-(trifluoromethyl)phenyl)ethylcarbamoyl)piperidine-1-carboxylate (9.72 g, 60%).

Workup

  1. filtrationAdd methylene chloride (500 mL) to the mixture and filter
  2. washWash the filtrate with sat. aqueous sodium bicarbonate (400 mL)
  3. concentrationconcentrate in vacuo
  4. customPurify the residue by silica gel chromatography (330 g RediSep column
  5. washeluting with a gradient of 0% to 100% ethyl acetate

Sources & evidence

ORD record
ord-cba451bc92a44d7baed86f5a90e726b8
Source dataset
uspto-grants-2012_01
Patent number
US08093383B2

Reaction notes

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