Dimethylformamide → 1-Tert-butyloxycarbonyl-4-(3-chloro-5-(trifluoromethyl)pyridin-2-YL)piperazine

HRID 1803991Notes

Reaction equation

HRID 1803991 reaction equation
Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C1(C)C=CC=CC=1>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=2)[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 11430Potassium CarbonateHCID 1122342,3-Dichloro-5-(trifluoromethyl)pyridineHCID 143452tert-Butyl piperazine-1-carboxylate

Product 1

HCID 573664161-Tert-butyloxycarbonyl-4-(3-chloro-5-(trifluoromethyl)pyridin-2-YL)piperazineYield 108%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

To 2,3-dichloro-5-trifluoromethylpyridine (25 g) were added 1-BOC-piperazine (23.84 g), potassium carbonate (32.08 g), N,N-dimethylformamide (50 mL) and toluene (50 mL), and the mixture was stirred at 100° C. for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3-chloro-5-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (45.71 g). To 4-(3-chloro-5-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (11 g) were added palladium (II) acetate (0.726 g), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (2.692 g), potassium fluoride (15.06 g), methylboronic acid (7.88 g) and tetrahydrofuran (300 mL), and the mixture was refluxed under a nitrogen stream for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3-methyl-5-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9.14 g). To 4-(3-methyl-5-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9.14 g) were added 4N hydrogen chloride/ethyl acetate (26 mL) and chloroform (64 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture were added water and sodium hydrogen carbonate, and the mixture was extracted with chloroform. The solvent was evaporated to give the title compound (6.38 g).

Workup

  1. extractionthe mixture was extracted with ethyl acetate
  2. washThe organic layer was washed with water and saturated brine
  3. customthe solvent was evaporated
  4. customThe residue was purified by column chromatography (hexane:ethyl acetate)

Sources & evidence

ORD record
ord-868a1967f2794d6d9af254e13df0ee46
Source dataset
uspto-grants-2013_01
Patent number
US08354401B2

Reaction notes

Loading…