Xenipentone

Originator

Xenipentone ,ZYF Pharm Chemical

Manufacturing Process

a). 3-(4-Biphenylyl)-2-butenoic acid ethyl ester:
6.45 g (0.1 mole) of activated zinc metal (20 mesh) is placed in a flask fitted with a septum inlet and a magnetic stirrer. The system is maintained under a nitrogen atmosphere and kept at a temperature of 25°C. A solution of 19.6 g (0.1 mole) of 4-acetylbiphenyl in 75 ml of dry tetrahydrofuran and 75 ml of trimethyl borate (distilled from calcium hydride) is injected and the mixture stirred. 11.1 ml (0.1 mole) of freshly distilled ethyl bromoacetate is injected in one shot and the mixture stirred at 25°C for 12 hours. A mixture of 25 ml of concentrated ammonium hydroxide and 75 ml of glycerin is added, and the aqueous phase is separated and extracted thrice with 25 ml portions of diethyl ether. The combined organic extracts are dried over anhydrous magnesium sulphate and the diethylether removed on a rotary evaporator, the residue is vacuum distilled and the fraction distilling at 0.125 mm at 171-172°C is collected. Recrystallisation of 3-(4-biphenylyl)-2-butenoic acid ethyl ester from petroleum ether yields the heading compound, substantially in trans form.
b). 3-(4-Biphenylyl)-2-butenoic acid:
The 3-(4-biphenylyl)-2-butenoic acid ethyl ester is mixed with 6 g of 85% potassium hydroxide in 100 ml of aqueous ethanol and the resulting mixture heated on a steam bath for 30 min. The mixture is then cooled, poured into ice and extracted twice with 25 ml portions of diethylether. The aqueous phase is filtered over Celite and the filtrate acidified with 2 N hydrochloric acid to pH 4 and cooled. The resulting precipitate is filtered, washed with ether, air dried with suction and then dried under high vacuum at 50°C to yield the 3- (4-biphenylyl)-2-butenoic acid substantially in trans form.
c). 3-(4-Biphenylyl)-2-butenoic acid chloride:
The crude 3-(4-biphenylyl)-2-butenoic acid is dissolved in 200 ml of dry tetrahydrofuran and 4 ml (0.055 mole) of thionyl chloride is added. The solution is refluxed under a nitrogen atmosphere for 3 hours and the solvent and excess thionyl chloride then distilled off. The resulting residue is flash distilled in a microdistillation apparatus at 145-153°C/0.075 mm to yield the 3-(4-biphenylyl)-2-butenoic acid chloride, substantially in trans form.
d). 2-(p-Biphenylyl-2-pentene-4-one: 10.0 g. (0.039 mole) of crude 3-(4- biphenylyl)-2-butenoic acid chloride, is dissolved in 200 ml of dry tetrahydrofuran. The solution placed in a 500 ml round bottom flask fitted with a septum inlet and magnetic stirrer, and held under a nitrogen atmosphere. The solution is cooled to -30°C in a dry ice/isopropanol bath and 19.5 ml (0.039 mole) of a commercial 2 M methyl magnesium bromide solution in dry toluene is added, dropwise, over 30 min. After the addition is complete, the mixture is allowed to warm to room temperature and then stirred for 1 hour. The reaction is quenched by the addition of 20 ml of saturated ammonium chloride solution and the organic layer is separated. The aqueous layer is extracted twice with 20 ml portions of ether and the combined organic extracts are then dried over anhydrous magnesium sulphate and evaporated to yield the heading compound, m.p. 130° to 133°C, after recrystallization from petroleum ether.

Therapeutic Function

Antiinflammatory