地诺孕素的合成研究.pdf.pdf

囊◇翳媾霉《霆铡摘要摘要地诺孕素是德国Schering公司开发的避孕新药,由于其强大的排卵抑制作用而应用于口服避孕。它具有疗效确切、毒副作用小等特点,正在成为口服避孕的首选药物。本文对地诺孕素的全合成进行了设计并对所设计的合成路线进行了系统研究,并分别以19一羟甲基一雄甾一4一烯一3,17一二酮(后简称为19一羟基物)、双烯双酮为原料成功地合成了地诺孕素。路线1:以19一羟甲基一雄甾一4一烯一3,17一二酮为原料,经过9步反应制得地诺孕素。以19一羟基物计,%。路线2:以19一羟甲基一雄甾一4一烯一3,17一二酮为原料,经过氧化、脱羧、溴化和脱溴化氢、3位缩酮、17位环氧化、开环、3位水解等7步反应制得地诺孕索。其中使用Collidinc试剂对3位羰基进行缩酮保护,避免了使用剧毒物质丙酮氰醇。以19一羟基物计,%。路线3:以双烯双酮为原料,经过3位缩酮、17位环氧化、开环、3位水解等4步反应制得地诺孕素。本方法的优点是3位缩酮反应采用了新的脱水剂,不仅避免了使用剧毒物质丙酮氰醇,也避免了使用昂贵的Collidine试剂,而且收率显著提高。以双烯双酮计,%;以19一羟基物计,%。几乎所有的中间产物和目标产物都经过核磁共振和/或红外光谱及其他分析鉴定方法确定了结构。同时,本文又对地诺孕素的核磁共振谱图作了全面解析,对其他有类似结构药物的解析将有所帮助。本文合成的地诺孕素的液相色谱纯度为98,9855%,其质量达到了药物的临床应用要求。目前,正在报批三类药。关键词: 口服避孕药;地诺孕素;双烯双酮;合成与表征;核磁共振 ABSTRACT DIENOGEST is anew conlxaceptive thatwas developed pany, and itisused fororalcontraception due toitss订ongability virtueofthedefinitecurative effectand low toxicity,DIENOGEST ing the firstchoice fortheoralcontraception. Total synthesis ofDIENOGEST was designed andinvestigated systematically in this was essfully obtained from 19-hydroxy—androstene一3,17-dione and estra一4(5),9(10)一diene一3,17-dione, respectively. Route 1:19一Hydroxy一4·androstene·3, through 9step overall yield 19·hydroxy一4·androstene-3,17-dione. 17一dionewas converted toDIENOGEST ofDIENOGEST was %based on Route 2:DIENOGEST Was synthesized from . 7-dione by oxidation,decarboxylation,bromination anddehydmhalogenation, 3-position ketalation,1 7一epoxidation,ring cleavage and 3-position hydrolysis reagent was employed for3-position carbonyl proctection instead ofhighly toxic acetone overallyield ofDIENOGEST was % based on 9一hydroxy-4-androstene-3,1 7-dione. Route 3:DIENOGEST Wasobtained fromestra-4(5),9(10)-diene一3,17一dione by 3-position ketalization,1 7一epoxidation,ring cleavage and 3-position hydrolysis reactions·The advantage ofthis route Was the use of anew dehydration reag