Acetonitrile → Tert-butyl 4-(2-cyanoacetyl)piperidine-1-carboxylate

HRID 489434Notes

Reaction equation

HRID 489434 reaction equation
[C:1](#[N:3])[CH3:2].[Li]CCCC.[C:9]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24]CC)=O)[CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>C1COCC1>[C:9]([N:16]1[CH2:17][CH2:18][CH:19]([C:22](=[O:24])[CH2:2][C:1]#[N:3])[CH2:20][CH2:21]1)([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]

Participants

5

Reactant 3

HCID 6342AcetonitrileHCID 27588121-Tert-butyl 4-ethyl piperidine-1,4-dicarboxylateHCID 178418339Butyllithium

Product 1

HCID 22265410Tert-butyl 4-(2-cyanoacetyl)piperidine-1-carboxylateYield 72.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of ethyl isonipecotate (10.0 g) in THF (200 mL) was added triethylamine (7.8 g), 4-dimethylaminopyridine (0.8 g) and di-tert-butyldicarbonate (15.3 g) at 0° C. and the mixture was stirred for an hour. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give ethyl N-Boc-piperidine-4-carboxylate (16.3 g) as a colorless oil. To a solution of acetonitrile (3.2 g) in THF (300 mL) was added n-BuLi (44 mmol) at −78° C. and stirred for three hours. Further, ethyl N-Boc-piperidine-4-carboxylate (16.3 g) was added and the mixture was stirred for an hour. After acidification with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (5:1)) to give 1-(N-Boc-piperidin-4-yl)-2-cyanoethan-1-one (11.6 g) as a colorless oil. A solution of 2,1,3-benzoxadiazole-4-aldehyde (1.0 g), 3-aminopyrazole (0.6 g) and 2-(N-Boc-piperidin-4-yl)-1-cyanoethan-2-one (1.7 g) in acetonitrile (10 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (2.0 g) as colorless crystals.

Workup

  1. stirringthe mixture was stirred for an hour
  2. extractionAfter acidification with hydrochloric acid, the mixture was extracted with ethyl acetate
  3. customThe solvent was evaporated under reduced pressure
  4. customthe residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (5:1))

Sources & evidence

ORD record
ord-e748712fd6004835b75910e8fa97d253
Source dataset
uspto-grants-2005_12
Patent number
US06977262B2

Reaction notes

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