Improved Synthesis Of Flunarizine Dihydrochloride

Flunarizinedihydrochloride was a kind of calcium channel blockers. Based on a large number of advanced literatures, the purpose of this paper was to redesign and optimize the synthesis route of the product. The structure of product was characterized by means of IR、 HPLC、LC-MS and 1HNMR.Aluminium trichloride as the catalyst, The optimal reaction conditions were as follows: n(fluorobenzene):n(carbon tetrachloride)=l:1.1, fluorobenzene was dropped in 15min, the reaction was at 45 ℃ for 2 h, the yield of product high than 84%, the purity high than 99.5%.Methanol as solvent,4,4’-difluorobenzhydrol was synthesized by the reduction of sodium borohydride. The optimal reaction conditions were as follows:n(bis-(4-fluorop henyl)-methanone):n(sodium borohydride)=1:0.7, reacted at 50 ℃ for 5h, the yield high than 93%, the purity high than 95%.Dichloroethane as solvent, AIBN as initiator, bis-(4-fluoropheny1)methane bromide was synthesized by the reaction of 4,4’-Difluorobenzhydrol and NBS. The optimal reaction conditions of bis-(4-fluorophenyl)methane bromide were as follows:n(4,4’-Difluoroben zhydrol):n(NBS)=1:1.1, reacted at 40 ℃ for 2.5 h, the yield of product high than 95%, the purity of product high than 94%.Cinnamyl chloride was synthesized by the reaction of cinnamic alcohol and SOCl2, dichloroethane as solvent. The optimal reaction conditions of cinnamyl chloride were as follows:n(cinnamic alcohol):n(SOCl2)=1:1.2, the reaction was at 60℃ for 3 h, the yield high than 94%, the purity of product high than 96%.Alcohol as solvent, KI as the catalyst, trans-1-Cinnamylpiperazine was synthesized by the reaction of cinnamyl chloride and 1,4-diazacyclohexane. The optimal reaction conditions of trans-1-Cinnamylpiperazine were as follows:n(cinnamyl chloride):n(1,4-diazacyclohe xane)=1:1.2, the reaction was at 50℃ for 4h, the yield high than 63%, the purity high than 95%.Triethylamine as acide agent, tetrabutyl ammonium bromide as phase transfer catalyst, dichloroethane as solvent, flunarizinedihydrochloride was synthesized by the reaction of bis-(4-fluorophenyl)methane bromide and trans-1-Cinnamylpiperazine. Trans-1-Cinnamylp iperazine was dropped by ice bath in 30min, the reaction was at room temperature for 3 h, the yield was 76.1%, the total yield was 33.2%,the purity was 99.1%.