Application of 1-(2,4-dichlorophenyl)piperazine dihydrochloride_Kain Industrial Additive

Background and overview^[1]

1-(2,4-Dichlorophenyl)piperazine dihydrochloride can be used as a pharmaceutical synthesis intermediate. Its free base can be prepared by Buchward reaction from piperazine and 2,4-dichlorobromobenzene.

Preparation^[1]

The free base of 1-(2,4-dichlorophenyl)piperazine dihydrochloride is prepared as follows:

Mix and dissolve BINAP (219mg), palladium(II) acetate (397mg, 0.176mmol), tBuONa (1.19g, 12.3mmol), piperazine (837mg, 9.73mmol) in THF (40mL) and keep at room temperature Stir under nitrogen atmosphere for 30 minutes. A solution of 2,4-dichlorobromobenzene (2 g, 8.84 mmol) in THF (10 mL) was added dropwise to the mixture and heated at 70 °C for 14 h. Excess THF was then evaporated and extracted with ethyl acetate. After washing with brine and drying, the ethyl acetate layer was concentrated to obtain crude product. Flash chromatography on silica gel, eluting with 2% MeOH in CHCl, afforded 1-(2,4-dichlorophenyl)piperazine.

Apply^[2]

For the preparation of 2-chloro-1-[4-(2,4-dichloro-phenyl)-piperazin-1-yl]-ethanone.

Add 1-(2,4-dichlorophenyl)piperazine dihydrochloride (1.0g, 3.29mmol) and chloroform (7mL) into a 50mL round-bottomed flask equipped with a stirring rod. The solution was cooled to 0 °C and triethylamine (1.38 mL, 9.87 mmol) was added, followed by chloroacetyl chloride (0.29 mL, 3.62 mL) added dropwise. The reaction mixture was stirred at 0 °C for 2.5 h, quenched with water (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel using a gradient from hexane diethyl ether = 70:30 to 40:60 to give an oil. Trituration of the oil with hexane afforded the desired product as an off-white solid (934 mg, 92%). ¹H NMR (300MHz, CDCl₃): δ7.41 (d, 1H), 7.22 (dd, 1H), 6.96 (d, 1H), 4.12 (s , 2H), 3.82 (t, 2H), 3.71 (t, 2H) ), 3.06 (m, 4H).

Main reference materials

[1]PCT Int. Appl., 2005056015, 23 Jun 2005

[2] (WO2007087135) PIPERAZINES AND PIPERIDINES AS mGluR5 POTENTIATORS