雌酮的合成工藝

474中國醫藥工業(yè)雜志 Chinese journal of pharmaceuticals2002,33(10)674-676L5]徐鳴夏,周?chē)?楊艷,等.取代芳甲酰哌嗪新衍生物L(fēng)4 Silvia ZT, Cesare C, Franco DM, et al. Hydroxyimi的合成及其藥理活性[J].化學(xué)研究與應用,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文章編號:1001-8255(2002)10-0474-02雌酮的合成工藝劉巍,姚詠梅南藥業(yè)公司,湖南長(cháng)沙410005)摘要:以雄甾-1,4-二烯-3,17-二酮為原料,經(jīng)縮酮化、芳構化和水解三步反應合成雌酮,并對此工藝進(jìn)行中試放大總收率可達53.3%關(guān)鍵詞:合成;雌酮;中試中圖分類(lèi)號:O629.8文獻標識碼:A雌酮(Ⅰ)是合成雌二醇、雌三醇、炔雌醇、炔雌醚試規模以雄甾-1,4-二烯-3,1-二酮(ADD,2)為原等雌甾藥物及炔諾酮等19-去甲甾體化合物的關(guān)鍵料,經(jīng)縮酮化、芳構化和水解反應制得1。操作簡(jiǎn)中間體?，F行生產(chǎn)路線(xiàn)系以瞽芋皂素為起始原料,經(jīng)便,總收率53.3%(τ/)。2可由天然甾醇經(jīng)微生物開(kāi)環(huán)、乙?；?、氧化、水解、消除等反應制得醋酸妊娠發(fā)酵,再切除17-位邊鏈制得雙烯醇酮,再經(jīng)肟化、重排、水解、加成、環(huán)氧、水解、反應式如下:氧化、消除、還原、開(kāi)環(huán)、氧化等反應制得。本文在中中國煤化工CNMHG實(shí)驗部分收稿日期:2001-12-04作者簡(jiǎn)介:劉巍(1967),男,工程師,從事藥品研發(fā)及生產(chǎn)工17-環(huán)次乙二氧基雄甾-1,4二烯3酮(3)Tel:0731-2232900在200L反應罐中加入2(3.0kg,10.55mol)中國醫藥工業(yè)雜志 Chinese Journal of Pharmaceuticals2002.33(10)和苯(150L),回流分水20min,滴加乙二醇(2.04體,自然晾干過(guò)夜。次日,將上述固體投入50L反應L,36.58mol),加畢后繼續反應1.5h。稍冷,迅速罐中,加石油醚(60kg)并回流1h,趁熱過(guò)濾,濾餅加入對甲基苯磺酸(0.15kg),回流4h,其間毎隔用少量石油醚洗滌,抽干,干燥,得淺黃色固體粉末。0.5h通過(guò)反應罐底閥返料一次。冷至8C,用飽和將上述粉末及乙醇(56.4kg)投入反應罐中,加碳酸鈉溶液洗除對甲基苯磺酸,無(wú)水硫酸鈉干燥,先熱回流εmin使溶,稍冷·加入活性炭(.13kg)回常壓后減壓蒸至盡可能干,冷卻后析岀類(lèi)白色晶體流ω.5h,熱濾,濃縮,冷卻析晶,用少量乙醇洗滌,3(2.82kg,94.0%),mp169.5~172C(文獻:抽干,干燥,得微黃色晶體1(1.6kg,56.7%),mp172~174C)258~260C(文獻:254.5~256C)。雌酮(1)在50L反應罐中依次加入聯(lián)苯(3.70kg,參考文獻:25.49mol)、二苯甲烷(2.06kg,12.24mol)及四氫1 Webber GM, Dryden Jr HI. Process for reducing呋喃(23.6kg),夾套通冷水,攪拌使溶。通N2保護nethyl-1, 4-dien-3-ones to corresponding 19-nor-3迅速加入切成小塊的金屬鋰(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)新鮮溶液,滴畢繼21do0nM, Ridge P, Twit RO.a.l- Acylthiosubstitution products of 3, 17-dioxygenated androstane續攪拌回流20min。先水浴后冰鹽浴冷至15C,緩derivatives [ P].US:2875215,1959-02-24.(CA1959慢加入甲醇(22.3kg),再加入2mol/L鹽酸(3353:13214e)kg),回流2h,減壓蒸干有機溶劑,冷至室溫,加入[3 Merck Index, 10th ed [z] Whitehouse Station, N J石油醚(5kg),攪拌約1h得固化物,濾出,濾出物Merck& Co., No. 3655先用水再用少許石油醚浸泡洗滌,抽干,得黃色固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《中成藥》雜志歡迎投稿,歡迎訂閱,歡迎刊登廣告《中成藥》雜志是經(jīng)國家科委和國家新聞出版署批準的,由國家藥品監督管理局信息中心中成藥信息站主辦,已有24年歷史的國內外公開(kāi)發(fā)行的有關(guān)中成藥、中藥飲片生產(chǎn)、科研和應用的國家級專(zhuān)業(yè)學(xué)術(shù)性刊物,已被列為中國中文核心期刊、中國自然科學(xué)核心期刊,并已編入《中國學(xué)術(shù)期刊(光盤(pán)版)》,標準刊號:ISsN1001-1528,統一刊號:CN31-1368/R《中成藥》雜志主要介紹中國中藥成藥的制劑工藝、質(zhì)量標準、古方研究、藥理和臨床運用的現狀和發(fā)展。文章側重反映中《中成藥孫志是第一批由國家批準能刊登醫藥廣告的雜志、歡過(guò)米電,,CNM藥現代化的理論和方法創(chuàng )新。發(fā)行對象為從事中成藥科研生產(chǎn)的科研人員生產(chǎn)人員管理人員銷(xiāo)售人員及醫生等歡迎來(lái)稿和在當地郵局訂閱(郵發(fā)代號:4-249)或直接向《中成中國煤化工介仍為10元,全年訂價(jià)120地址:上海市漢口路239號129~131室電話(huà):021-63213275傳真:021-63213363銀行匯款:國家醫藥管理局中成藥信息中心站1001234609014413684022346-黃浦支行延分(工商銀行)沔窮數據網(wǎng)址http://www.cherb.com.cn