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9 ml of boron tribromide is added dropwise to a solution containing 20 g of 5-bromo 2-chloro anisole in 200 ml of methylene chloride. Agitation is carried out for 10 minutes at 0 C., then for 24 hours at 20 C. and the reaction medium is poured into a water and ice mixture. The resultant suspension is agitated for 30 minutes, extraction is carried out with methylene chloride, followed by saturation with sodium chloride and extraction twice with methylene chloride. The organic phases are collected, dried over magnesium sulphate, evaporated under reduced pressure and 18.5 g of 5-chloro 2-bromophenol is obtained. M.p.=56 C.
4-(4-chloro-3-methoxy-phenyl)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
15%
To a vial containing piperazine-l,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (907 mg, 4.04 mmol), was added 4-bromo-l-chloro-2-methoxybenzene (913 mg, 4.12 mmol), palladium acetate (33 mg, 0.14 mmol) and 2-(di-tert- butylphosphino)biphenyl (88 mg, 0.29 mmol). The vial was evacuated and back-filled with nitrogen and to it was added toluene (2 mL). The reaction mixture was heated to 80 0C for 5 min to give a homogeneous solution. Upon cooling to room temperature, sodium tert- butoxide (557 mg, 5.80 mmol) was added to the reaction solution. The resultant mixture was again heated to 80 0C. After 4 h, the reaction mixture was cooled to room temperature, then diluted with EtOAc (10 mL) and hexanes (10 mL). The resultant solution was filtered through celite, and the filtrate concentrated in vacuo and purified by silica gel flash chromatography (30 g) (20% EtOAc/Hexanes) to afford 4-(4-chloro-3- methoxyphenyl)piperazine-l,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (63) (239 mg, 15% yield): HPLC retention time = 2.72 minutes. MS (ES) [M+H]+ expected 385.2, found 385.1.
With n-butyllithium; In tetrahydrofuran; ethyl acetate; N,N-dimethyl-formamide;
Step 3 4-chloro-3-methoxybenzaldehyde (19-6) 5-Bromo-2-chloroanisole (19-5) (2.2 g) was dissolved in 200 mL of THF and the solution cooled to -78° C. Butyl lithium (4.4 mL of 2.5M solution) was added slowly, the reaction solution was stirred 5 minutes and DMF (0.93 mL) was added slowly. The reaction mixture was stirred briefly and then poured over sodium bicarbonate and ice. The aqueous mixture was extracted with EtOAc, the organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated under vacuum and the residue then purified by silica gel chromatography 1:9 EtOAc:hexane to provide the aldehyde 19-6 as a white solid.
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