Synthesis Of Azimilide Dihydrochloride

Azimilide dyhydrochloride (I), a new class III antiarrhythmic agent, developed by Procter & Gamble Corporation is in the stage of clinic research. It has novel action mechanisms, which lead the new tendency of research. It is no doubt that the research of the synthetic procedure is valuable of application.A new synthetic procedure for azimilide dihydrochloride (I) has been established based on studying the available references and improving the reported methods. The key intermediate, 1-[5-(p-chlorophenyl)furfurylideneamino]hydantoin (V), is obtained by condensation of 1-aminohydantoin hydrochloride (III) with 5-p-chlorophenyl-2- furfural (IV) in an 89.9% yield. Compound III is synthesized from urea and hydrazine hydrate via amination, condensation, cyclization and hydrolysis. Intermediate IV is prepared from p-chloroaniline via diazotization and substitution in an 81.5% yield. Azimilide dihydrochloride (I) is obtained by one-pot reaction of V with 1-bromo-4-chlorobutane and 1-methylpiperazine, then salification in an 85.8% yield. The overall yield is 62.9% of theory (calculated for p-chloroaniline).In order to reduce the costs, 1, 4-dichlorobutane and 1, 4-dibromobutane, two cheaper reagents have been approved to be reacted with the intermediate V to produce azimilide dihydrochloride (I), instead of 1-bromo-4-chlorobutane, in a 64.8% yield. And the final product purity is 99.1% (HPLC).The new procedure effects cheaper materials, mild conditions, higher yields and throughputs and provides a simple preparation methodology which is especially suitable for the scale-up and manufacture of azimilide dihydrochloride (I).The structures of the synthesized target compound and intermediates have been identified by elemental analysis, ¹H-NMR, ¹³C-NMR, MS and X-ray diffraction for single crystal.