抗高血压药奥美沙坦酯合成新路线和相关杂质的研究

抗高血压药奥美沙坦酯合成新路线和相关杂质的研究

吴泰志1

,刘晓华2

,张福利

13

,谢美华

1

(1.上海医药工业研究院,上海200437;2.青岛国风药业股份有限公司,山东青岛266510)

摘要:目的　研究奥美沙坦酯的新合成方法,并对合成中产生的主要杂质进行结构确证和有效控制。方法　42

(12羟基212甲基乙基)222丙基咪唑252羧酸乙酯水解,环合成4,42二甲基222丙基24,62二氢呋喃并[3,42d ]咪唑262酮,与42[22(22三苯甲基四唑252基)苯基]苄基溴缩合,经分离纯化,皂化成钠盐,与42氯甲基252甲基222氧代21,32二氧杂环

戊烯成酯,脱保护基得奥美沙坦酯。对缩合反应的主要杂质应用X 2ray 单晶衍射谱确证其结构为咪唑位置异构体,并用其合成奥美沙坦酯的咪唑位置异构体。通过优化反应条件抑制异构体的量,从而保证奥美沙坦酯的质量。结果　用新路线合成了奥美沙坦酯,总收率60%,纯度大于9910%;成品中异构体含量小于011%。结论　本文合成路线是奥美沙坦酯的新合成方法,并首次报道奥美沙坦酯的咪唑位置异构体。

关键词:奥美沙坦酯;合成;异构体

中图分类号:R916.41 文献标识码:A 文章编号:0513-4870(2006)06-0537-07

收稿日期:2005211203.3

通讯作者　Tel:86-21-55514600,Fax:86-21-65169893,

E 2mail:zhangfl@si p i

A novel synthesis of ol m es art an medoxo m il and exam i n ati on

of its rel ated i m puriti es

WU Tai 2zhi 1

,L I U Xiao 2hua 2

,ZHANG Fu 2li 13

,X I E Mei 2hua

1

(1.Shanghai Institute of Phar m aceutical Industry,Shanghai 200437,China;

2.Q ingdao Gro w ful Phar m aceutical Co .L td .,Q ingdao 266510,China )

Abstract:A i m T o devel op a ne w synthetic r oute for ol m esartan medoxom il .M ethods O l m esartan

medoxom il was p repared fr om ethyl 42(12hydr oxy 212methylethyl )222p r opyli m idaz ole 252carboxylate via hydr olysis and lact onizati on t o aff ord 4,42di m ethyl 222p r opyl 24,62dihydr ofur o [3,42d ]21H 2i m idaz ole 262one which was condensed with 22(tri phenyl m ethyl )252[4′2(br omomethylbi phenyl )222yl]tetraz ole,f oll owed by esterificati on with 42chl or o methyl 252methyl 21,32di ox ol 222one,and dep r otecti on .The che m ical structure of the maj or i m purity in condensati on reacti on is the regi o 2is omer in the i m idaz ole moiety,and confir med by single crystal X 2ray diffracti on .The corres ponding regi o 2is omer of ol m esartan medox om il was synthesized fr om the i m purity by si m ilar method .Op ti m izati on of the condensati on conditi ons reduced the i m purity t o a negligible quantity .Results Synthesis of ol m esartan medoxom il by the ne w r oute gave a p r oduct of 60%yield and above 9910%purity .The content of ol m esartan medoxom il regi o 2is omer was effectively contr olled t o less than 011%.Conclusi on A novel synthetic r oute f or ol m esartan medoxom il was devel oped successfully .The ol m esartan medoxom il regi o 2is omer is reported for the first ti m e .

Key words:ol m esartan medoxom il;synthesis;regi o 2is omer

奥美沙坦酯(ol m esartan medoxom il,1)是由日本三共(Sankyo )株式会社开发成功的新的Ang II 受体拮抗剂。奥美沙坦酯是前药,其代谢产物奥美沙坦

(2)才是生理活性的药物。奥美沙坦酯于2002年

首先在美国上市。奥美沙坦酯与其他沙坦类药物相

比具有对AT 1受体的选择性作用高(其对AT 1受体的亲和力是对AT 2受体的12500倍),能使舒张压和收缩压在24h 内持续平稳降低,故显示出强效和长效的作用,且副反应少,是目前上市的沙坦类药物

・

735・药学学报Acta Phar maceutica Sinica 2006,41(6):537-543