Synthesis Of Azilsartan Medoxomil And Cationic Surfactant

1.This thesis contains two chapters.The synthetic process of azilsartan medoxomil was studied in chapter one.Azilsartan medoxomil,an angiotensin Ⅱ receptor blocker,is clinically used for the treatment of hypertension.The synthetic routes in reported literatures were reviewed in this chapter.At first methyl 1-（（2’-cyano-[1,1’-biphenyl]-4-yl）methyl）-2-ethoxy-1H-benzoimidazole-7-carboxylate 3 was reacted with hydroxylamine hydrochloride in the presence of NaHCO₃ to produce amidoxime 4.Hydrolysis of in aqueous sodium hydroxide produces intermediate 5,which is treated with medoxomil chloride to give 7.7 was cyclized with1,1’-carbonyldiimidazole to give corresponding azilsastan medoxomil 1.Finally azilsartan medoxomil 1 is treated with with potassium2-ethylhexanoate in acetone to produce azilsartan kamedoxomil in 9.6%total yield.The process has advantages such as mild reaction conditions,simple operation,good yield,which make it attractive in the future large scale production.To strengthen the quality control of azilsartan medoxomil API,13 related substances of azilsartan medoxomil were synthesized and their structures were confirmed by ¹H and ¹³C NMR.2.In second chapter the synthesis of green cationic surfactants was investigated.Traditional surfactants are widely used in both industrial applications and consumer,however they can adversely pollute the environment.Therefore there is a need for the improved process of environmentally benign cationic surfactants.In this thesis two kinds of green cationic surfactants were synthesized from readily available raw material with good yields in 20 g scale.One kind was hydrochloride salts of N（α/ε）-acyl lysine with alkyl chain lengths of 12,14 and 16 carbon atoms,which was synthesized from N（ε/α）-Cbz-lysine.HCl as starting material via esterification with SOCl₂ in MeOH,then acylation the corresponding long chain acid chloride and deprotection of the Cbz group by catalytic hydrogenation on Pd over charcoal.The other kind was decyl esterquat monomeric and gemini surfactants.At first N,N-dimethyl-2-aminoethanol was reacted with decanoyl chloride and lauroyl chloride to give corresponding ester amines which was subsequently quaternized with methyl bromide to form the monomeric surfactant or with 1,3-dibromopropane and 1,6-dibromohexane to give gemini surfactants.The chemical structure of these surfactants were confirmed by ¹H NMR,¹³C NMR.The critical micelle concentrations（CMC）of N（α）-acyl lysine methyl ester hydrochloride salts at 298.15 K were measured and their standard Gibbs energy changes of micellization（?G_m^θ）were calculated.The results indicate that the CMC values decrease,?G_m^θ values become more negative,and the ability of spontaneous micelle formation enhances with the increase of alkyl chain length.The CMC of the dodecyl sulfate salt of L-alanine isopropyl ester and hydrochloride salt of N（α）-decanoyl-L-lysine methyl ester mixed system with equimolar ratio was measured.Its surface activity is much higher than that of the constituent single ionic surfactant,illustrating that the green cationic/anionic surfactant mixed system has wide application prospect.