雌酮的合成工艺

474中国医药工业杂志 Chinese journal of pharmaceuticals2002,33(10)674-676L5]徐鸣夏,周国川,杨艳,等.取代芳甲酰哌嗪新衍生物L4 Silvia ZT, Cesare C, Franco DM, et al. Hydroxyimi的合成及其药理活性[J].化学研究与应用,199,11no and alkoxyimino derivatives of 1, 4-dihydropyridine(5):523-524.[P]1.EP:96299,1983-12-21.(CA1984,100:209627nStudy on Synthesis and Ca2t Antagonizing Activity ofPiperazine Substituted New Dihydropyridine derivativesXU Ming-Xi(Pharmacy School of Sichuan University, Chengdu 610041)ABSTRACT: Five new piperazine substituted dihydropyridine derivatives were designed and synthesized. Their inhibitive effects on potential-dependent calcium ion channels(PDC)in rat aorta were determined by Ca transmembrane influx technique. The results showed that their inhibitive effects on Pdcwere better than that of nifedipine, and they possessed Ca+ antagonizing activity.Key Words: 1, 4-dihydropyridine; Ca2 antagonizing activity radionuclide 5Ca; piperazine; synthesis文章编号:1001-8255(2002)10-0474-02雌酮的合成工艺刘巍,姚咏梅南药业公司,湖南长沙410005)摘要:以雄甾-1,4-二烯-3,17-二酮为原料,经缩酮化、芳构化和水解三步反应合成雌酮,并对此工艺进行中试放大总收率可达53.3%关键词:合成;雌酮;中试中图分类号:O629.8文献标识码:A雌酮(Ⅰ)是合成雌二醇、雌三醇、炔雌醇、炔雌醚试规模以雄甾-1,4-二烯-3,1-二酮(ADD,2)为原等雌甾药物及炔诺酮等19-去甲甾体化合物的关键料,经缩酮化、芳构化和水解反应制得1。操作简中间体。现行生产路线系以瞽芋皂素为起始原料,经便,总收率53.3%(τ/)。2可由天然甾醇经微生物开环、乙酰化、氧化、水解、消除等反应制得醋酸妊娠发酵,再切除17-位边链制得双烯醇酮,再经肟化、重排、水解、加成、环氧、水解、反应式如下:氧化、消除、还原、开环、氧化等反应制得。本文在中中国煤化工CNMHG实验部分收稿日期:2001-12-04作者简介:刘巍(1967),男,工程师,从事药品研发及生产工17-环次乙二氧基雄甾-1,4二烯3酮(3)Tel:0731-2232900在200L反应罐中加入2(3.0kg,10.55mol)中国医药工业杂志 Chinese Journal of Pharmaceuticals2002.33(10)和苯(150L),回流分水20min,滴加乙二醇(2.04体,自然晾干过夜。次日,将上述固体投入50L反应L,36.58mol),加毕后继续反应1.5h。稍冷,迅速罐中,加石油醚(60kg)并回流1h,趁热过滤,滤饼加入对甲基苯磺酸(0.15kg),回流4h,其间毎隔用少量石油醚洗涤,抽干,干燥,得浅黄色固体粉末。0.5h通过反应罐底阀返料一次。冷至8C,用饱和将上述粉末及乙醇(56.4kg)投入反应罐中,加碳酸钠溶液洗除对甲基苯磺酸,无水硫酸钠干燥,先热回流εmin使溶,稍冷·加入活性炭(.13kg)回常压后减压蒸至尽可能干,冷却后析岀类白色晶体流ω.5h,热滤,浓缩,冷却析晶,用少量乙醇洗涤,3(2.82kg,94.0%),mp169.5~172C(文献:抽干,干燥,得微黄色晶体1(1.6kg,56.7%),mp172~174C)258~260C(文献:254.5~256C)。雌酮(1)在50L反应罐中依次加入联苯(3.70kg,参考文献:25.49mol)、二苯甲烷(2.06kg,12.24mol)及四氢1 Webber GM, Dryden Jr HI. Process for reducing呋喃(23.6kg),夹套通冷水,搅拌使溶。通N2保护nethyl-1, 4-dien-3-ones to corresponding 19-nor-3迅速加入切成小块的金属锂(0.39kg,56.06mol)oxy-1,3,5(10)- trienes[P].US:3274182,1966-09-20(CA1967,66:11131)8.59mo1)的四呋喃(26.7kg)新鲜溶液,滴毕继21do0nM, Ridge P, Twit RO.a.l- Acylthiosubstitution products of 3, 17-dioxygenated androstane续搅拌回流20min。先水浴后冰盐浴冷至15C,缓derivatives [ P].US:2875215,1959-02-24.(CA1959慢加入甲醇(22.3kg),再加入2mol/L盐酸(3353:13214e)kg),回流2h,减压蒸干有机溶剂,冷至室温,加入[3 Merck Index, 10th ed [z] Whitehouse Station, N J石油醚(5kg),搅拌约1h得固化物,滤出,滤出物Merck& Co., No. 3655先用水再用少许石油醚浸泡洗涤,抽干,得黄色固Synthesis of estroneLIU Wei, YAO Yong-Me(Hunan Pharmaceutical Company, Changsha 410005)ABSTRACT: Estrone was synthesized from andro-1, 4-dien-3, 17-dione by three steps including ketaformation, aromatization and hydrolysis. The new synthetic method of estrone was verified by amplifyingand the overall yield of its amplification was 53. 3 %(w/w)Key words: estrone; synthesis; amplify《中成药》杂志欢迎投稿,欢迎订阅,欢迎刊登广告《中成药》杂志是经国家科委和国家新闻出版署批准的,由国家药品监督管理局信息中心中成药信息站主办,已有24年历史的国内外公开发行的有关中成药、中药饮片生产、科研和应用的国家级专业学术性刊物,已被列为中国中文核心期刊、中国自然科学核心期刊,并已编入《中国学术期刊(光盘版)》,标准刊号:ISsN1001-1528,统一刊号:CN31-1368/R《中成药》杂志主要介绍中国中药成药的制剂工艺、质量标准、古方研究、药理和临床运用的现状和发展。文章侧重反映中《中成药孙志是第一批由国家批准能刊登医药广告的杂志、欢过米电,,CNM药现代化的理论和方法创新。发行对象为从事中成药科研生产的科研人员生产人员管理人员销售人员及医生等欢迎来稿和在当地邮局订阅(邮发代号:4-249)或直接向《中成中国煤化工介仍为10元,全年订价120地址:上海市汉口路239号129~131室电话:021-63213275传真:021-63213363银行汇款:国家医药管理局中成药信息中心站1001234609014413684022346-黄浦支行延分(工商银行)沔穷數据网址http://www.cherb.com.cn