Methyl Ethyl Ketone → 4-(3,5,6-Trichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

HRID 1803994Notes

Reaction equation

HRID 1803994 reaction equation
Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=2)[CH2:20][CH2:19]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]

Participants

6

Reactant 4

HCID 6569Methyl Ethyl KetoneHCID 11430Potassium CarbonateHCID 169902,3,5,6-TetrachloropyridineHCID 143452tert-Butyl piperazine-1-carboxylate

Product 1

HCID 866587754-(3,5,6-Trichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl esterYield 100.6%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

To a mixture of 2,3,5,6-tetrachloropyridine (10 g), 1-Boc-piperazine (8.6 g) and potassium carbonate (13 g) was added 2-butanone (140 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give 4-(3,5,6-trichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (17 g). To a mixture of 4-(3,5,6-trichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (17 g), palladium (II) acetate (516 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.9 g), potassium fluoride (24 g) and methylboronic acid (12 g) was added tetrahydrofuran (140 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (14 g). 4-(3,5,6-Trimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (14 g) was dissolved in chloroform (28 mL), 4N hydrogen chloride/ethyl acetate (25 mL) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (100 mL) was added, and the mixture was filtered to give the title compound (11 g).

Workup

  1. temperaturethe mixture was refluxed for 8 hr
  2. temperatureAfter cooling
  3. extractionthe mixture was extracted with ethyl acetate
  4. washThe organic layer was washed with saturated brine
  5. customthe solvent was evaporated

Sources & evidence

ORD record
ord-e08e8ceacd2346f7a5cb041091e7e40c
Source dataset
uspto-grants-2013_01
Patent number
US08354401B2

Reaction notes

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