SYNTHESIS OF FLUORINE-CONTAINING ANALOGS OF PROCAINAMIDE

Abstract

Methods for the synthesis of (2-N,N-diethylaminoethyl)amides of meta- and parapentafluoroethoxybenzoic acids starting with respective ethyl pentafluoroethoxybenzoates have been developed. Firstly, ethyl m- and p-pentafluoroethoxybenzoates were treated with sodium hydroxide in aqueous-alcoholic solution. The mixture obtained was acidified with concentrated hydrochloric acid giving respective meta- or para-pentafluoroethoxybenzoic acids. The acids obtained were dried and treated with excess of thionyl chloride giving respective acid chlorides that further reacted with N,N-diethylethylene-1,2-diamine. N,N-diethylethylenediamine was obtained by treating N,N-diethyl-2-chloro-ethylamine hydrochloride with aqueous ammonia solution (25%). The resulting product contained secondary and tertiary amines that could not be separated by distillation. In order to purify N,N-diethylethylene-1,2-diamine the mixture was treated with phthalic anhydride, the desired product was separated in the form of respective phthalimide and then phthalimide protecting group was removed by hydrazinolysis. After such purification N,N-diethylethylene-1,2-diamine contained no secondary or tertiary amines. The condensation of meta- and parapentafluoroethoxybenzoic acid chlorides with N,N-diethylethylenediamine was conducted in 1,2-dichloroethane solution with a little molar excess of triethylamine that was used as HCl scavenger. The reaction mixture was heated for two hours, cooled to room temperature, the residue was filtered off and volatile compounds were removed under reduced pressure. It should be noted that triethylamine is necessary, because otherwise the reaction mixture gets dark brown color and the desired product can’t be isolated. Procainamide analogues, obtained in the present paper, were tested for local anesthetic activity in capsaicin test. Both (2-N,N-diethyl-aminoethyl)amides of meta- and para-pentafluoroethoxybenzoic acids showed better local anesthetic activity, compared to anesthesine.

Keywords

• пентафторетоксигрупа
• пентафторетоксибензойні кислоти
• β-діетиламіноетиламін
• місцеві анестетики