抗高血压药洛沙坦的合成工艺研究.pdf

浙江大学硕士学位论文摘要摘要洛沙坦是用于治疗高血压的1:2服选择性的血紧张素II受体拮抗剂。其钾盐洛沙坦钾最先由杜邦一默克公司发现并命名为可素亚,该药具有耐受性好、受体选择性高等优点。本文结合文献与原料供应状况,以2一丁基-4-氯-5-甲酰基一咪唑和2一氰基一4’一溴甲基联苯为基本原料合成洛沙坦,通过N一烷基化、羟基化、四唑化和成盐结晶反应得到终产物洛沙坦钾,该工艺省去了原来路线的三苯甲基保护与脱保护反应,并从温度、时间、催化剂、溶剂等方面对反应进行优化,提高了反应收率。其结构经1H-NMR确证。通过N一烷基化和羟基化反应,合成2一丁基-4-氯-5-甲酰基-1-(2’一氰基一联苯基-4-)甲基咪唑,优化的工艺参数为:反应溶剂为DMF,N一烷基化反应原料配比为nBm啪oTBN:ribc兀--:1,反应温度35。C,反应时间4h;羟基化反应配比为nNaBH4:nBcFl=:1,反应温度40。C,反应时间1h,,%,%(以2一丁基一4一氯一5一甲酰基一咪唑计),熔点162-163℃。通过四唑化,合成洛纱坦,优化的工艺参数为:反应溶剂为DMF中,以三乙胺盐酸盐为催化剂,原料配比为neyano alcohoI:n叠氪钠:n三乙胺盐酸盐=l:3:,在130 ℃下反应,反应时间24h,,%,%(以2一丁基-4-氯-5-羟甲基-1-(2’一氰基一联苯基-4-)甲基咪唑计),熔点182-184℃。通过成盐反应,最终合成洛纱坦钾,熔点269-274。C。关键词:高血压,洛沙坦,N一烷基化,羟基化,四唑浙江大学硕士学位论文 Abstract Abstract Losartan was an orally active selective angiotensin II receotor antagonist employed totreat potassium was firstdeveloped by Dupont Merck Pharmaceutical Co.,called Cozaar,谢廿l thechamcterstics oflong—lasting, good tolerance andhi曲receptor-selectivity. The synthesis of losartan starting from 2'-cyano··4·-bromomethylbiphenyl and 2-n-butyl-4-chloro-5-imidazolecarboxaldehyde Was finalproduct losartan potassium Was obtained by N-alkyltion,hydroxylation,synthesis oftetrazole and salt-formingreaction,eliminating the need forprotection and de-protection reaction conditions oftemperature,time,catalysts,solvents, been extensively investigated tooptimize structure of losartan was confm-ned . The product cyano alcohol was obtained byN-alkyltion optimal reaction conditions ofN—alkyltion Was asfollows:themolar ratioofnBromo OTBN:: the solvent DMF and reaction time 4h at35℃.The optimal reaction conditions ofhydroxylation Was asfollows:nNaBH4:nBCFl= 5:l,reaction time lhat40。 massofcyano alcohol Was ,purity>%by HPLC,The molaryield ofcyano alcohol %.melting point Was 62-163℃.. The product losartanWasobtained byN