Hydrogen chloride-ethyl acetate → 1-(2-Cyclopropyl-4-methylphenyl)piperazine hydrochloride
Reaction equation
C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[CH:21]2[CH2:23][CH2:22]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24].C(OCC)(=O)C>C(Cl)(Cl)Cl>[ClH:24].[CH:21]1([C:15]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=2[N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:22][CH2:23]1Participants
Procedure
To a mixture of 4-(2-chloro-4-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester (932 mg), bis(tricyclohexylphosphine)palladium (II) dichloride (132 mg), tripotassium phosphate (3.8 g) and cyclopropylboronic acid (688 mg) were added toluene (10 mL) and water (500 μL) and the mixture was refluxed for 5 hr. After cooling, the mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give 4-(2-cyclopropyl-4-methylphenyl)piperazine-1carboxylic acid tert-butyl ester (1 g). 4-(2-Cyclopropyl-4-methylphenyl)piperazine-1carboxylic acid tert-butyl ester (1 g) was dissolved in chloroform (1 mL), 4N hydrogen chloride/ethyl acetate (1 mL) was added, and the mixture was stirred at room temperature for 3 hr. Filtration gave 1-(2-cyclopropyl-4-methylphenyl)piperazine hydrochloride (160 mg). To tetrahydrofuran (2 mL) were added 4-iodobenzoyl chloride (169 mg), 1-(2-cyclopropyl-4-methylphenyl)piperazine hydrochloride (160 mg) and 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature overnight. Ethyl acetate was added for partitioning, the organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give the title compound (280 mg).
Workup
- filtrationFiltration
Sources & evidence
- ORD record
- ord-fd98df91543043ab9b251de69b03254b
- Source dataset
- uspto-grants-2013_01
- Patent number
- US08354401B2
Reaction notes
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