Detection And Synthesis Study On Benzenesulfonate Gene Toxic Impurities

In this paper,the synthesis of amlodipine besylate was studied.There are three steps in the reaction,the first step was to react N-（2-hydroxyethyl）phth alimide with ether to give 4-[2-（phthalimido）ethoxy]acetic acid ethyl acetate;the second step is coupled withβ-aminocrotonate methyl ester and o-chlorobe nzaldehyde by Hanqi condensation reaction to obtain 4-（2-chlorobenzene）-3eth oxycarbonyl-5-methoxycarbonyl-6-methyl-2-（2-phthalimidoethoxy）methyl-1,4-dihy dropyridine;The protective reacts with a salt formation reaction with benzene sulfonic acid to obtain amlodipine besylate.In this paper,the detection method was achieved with ODS column using a65:35（v/v）mixture of 1%triethylamine（pH adjusted 3.0 with phosphoric acid）and acetonitrile as the mobile phase.And carry out method validation.The results show that the specificity,system suitability,the limit of detection and limit of quantitation,linearity,repeatability,intermediate precision,recovery,solution stability and durability of methyl benzenesulfonate and ethyl benzenesulfonate are in compliance with the methodological requirements.The laboratory-made amlodipine besylate was tested for the impurity of methyl benzenesulfonate and ethyl benzenesulfonate.The genotoxic impurities in amlodipine besylate were found to be in accordance with the ICH M7.They are safe to use.This paper designed two bisoprolol besylate synthesis methods.The first route first uses Cbz-Cl to protect the bisoprolol;then pyridine as a catalyst and benzenesulfonyl chloride the acylation reaction gives benzyloxy bisoprolol benzenesulfonate;the final step,when reacted with a conventional reagent for removing the CBZ protecting group（Pd/C-H₂）,bisoprolol oxazolidinone（5-[[4-[[2-（1-Methylethoxy）ethoxy]methyl]phenoxy]methyl]-（1-methylethyl）2-oxazo lidinone）is formed.The second route uses（Boc）₂O to protect the bisoprolo;when pyridine is used as a catalyst,with benzenesulfonyl chloride when the a cylation reaction is carried out on the above product,bisoprolol oxazolidinone（5-[[4-[[2-（1-Methylethoxy）ethoxy]methyl]phenoxy]methyl]-（1-methylethyl）-2-oxazolidinone）is formed.We compared the nuclear magnetic resonance and carbon spectra of the intermediates and final product in each step in synthesis experiment.By comparing the synthesis of above two methods,the bisoprolol benzene sulfonate was not obtained,and the final product was bisoprolol oxazo lidinone.Therefore,it can be judged that when the bisoprolol and amlodipine besylate are prepared into a compound preparation,the genotoxic impurities are not formed,and they can be used as a combination preparation.