中國醫(yī)藥工業(yè)雜志 Chinese journal of pharmaceuticals2012,43(10)》》》》》》》》》》》》》》》》》》》化學藥物與合成技術《《《《《《《《《《《《《《《《《《《舍吲哚的合成張瑾,黃雷,李建其*〔中國醫(yī)藥工業(yè)研究總院上海醫(yī)藥工業(yè)硏究院,上海藥物合成工藝過程工程技術硏究中心,上海200437)摘要:1-(2-氯乙基)-2·咪唑啉酮和哌啶酮鹽酸鹽縮合得1-[2-(2-氧代咪唑晽)乙基]哌啶-4-酮,再和-(4-氟苯基)-5-氯吲哚(3)縮合得!-[2-「4-「5-氯-1-(4-氟苯基)-lH-吲哚-3-基]-1,2,3,6-四氫-1-吡啶η乙基]-2-咪唑晽酮,最后經(jīng)還原制得舍吲哚,總收率約63%(以3計)關鍵詞:舍吲哚;非典型抗精神病藥;合成中圖分類號:R97141文獻標志碼:A文章編號:10018255(2012)100801-03Synthesis of sertindoleZHANG Jin, HUANG Lei, LI Jianqi*( Shanghai Engineering Research Center of pharmaceutical Process, Shanghai Institute of pharmaceutical Industry,China state Institute of pharmaceutical Industry, Shanghai 200437)ABSTRACT: Sertindole was synthesized from 4-piperidone hydrochloride hydrate by substitution with1-(2-chloroethy1)-2-imidazolidinone to give 1-[2-(2-oxoimidazoline) ethyl]-4-piperidone, which was subjected tocondensation with 1-(4-fluoropheny1)-5-chloro-1H-indole (3)and followed by reduction with an overall yield of about63%(based on compound 3Key Words: sertindole; atypical antipsychotic drug; synthesis舍吲哚( sertindole,1),化學名為l-[2-[4-[5-收率為41.8%。②3依次與哌啶酮鹽酸鹽、1-(2氯-1-(4-氟苯基)-1H吲哚-3-基]-1-哌啶基]乙氯乙基)-2-咪唑啉酮縮合,再經(jīng)PtO2催化還原基-2-咪唑啉酮,由丹麥 Lundbeck公司研發(fā),1996與酒石酸成鹽、堿化制得18,總收率為558%年首次在英國上市2。本品屬強效中樞性多巴胺以上路線均以直線型方法制備目標產(chǎn)物,且都采用D2和5-HT受體拮抗劑3,為非典型的抗精神了價格昂貴的PO2作為還原催化劑,反應中伴有分裂癥藥物脫氯副產(chǎn)物的生成。1的合成路線主要有以下兩條:①1-(4-氟苯本研究參考文獻.1013,以1-(2-氯乙基)-2基)-5-氯吲哚(3)與哌啶酮縮合后經(jīng)PO2催化還原,咪唑啉酮0為原料,首先和哌啶酮鹽酸鹽一水合再與1-(2-氯乙基)-2-咪唑啉酮縮合制得16,總物縮合制得1-[2-(2-氧代咪唑啉)乙基]哌啶酮(2),2與3縮合制得1-[2-[4-[5-氯-1-(4-氟苯收稿日期:2012-06-01作者簡介:張瑾(1966-),女,工程師,從事藥物合成研究基)-1H-吲哚-3-基]-1,2,3,6-四氫-1-吡啶基]乙Tel:021-55514600×210基]-2-咪唑啉酮(4)32,4經(jīng)硼氫化鈉還原制得1。E-mail;zhangjinyw(163.com通信聯(lián)系人:李建其(1957),男,研究員,博士生導師,從事藥該路線未見文獻報道,其中2為新化合物;用硼氫物化學的研究與教學。化鈉還原可避免使用貴重試劑PO2,減少脫氯副Tel:021-55514600×288E-mail:lijq@sipi.com.cn物的生成。該匯聚式合成路線反應步驟少,操作簡中國醫(yī)藥工業(yè)雜志 Chinese journal of pharmaceuticals2012,43(10)HCL·H2NaHCO3/MIBK0NHNaBH4/THFNH圖11的合成路線便,成本低,產(chǎn)品純度高,有利于工業(yè)化生產(chǎn),總(CDCl3)8:2.59(brs,2H),267(t,J=68Hz,2H)收率為62.8%(以3計)。1的合成路線見圖1。279(t,J=56Hz,2H),328(s,2H),3.38~343(m實驗部分4H),353~3.56(m,2H),4.78(brs,lH),6.16(s,1-[2-(2-氧代咪唑啉)乙基]哌啶-4酮(2)1H),714~7.40(m,7H),7.88(d,J=72Hz,1H將1-(2-氯乙基)-2-咪唑啉酮(按文獻自制,舍吲哚(1)212g,1.43mo)、哌啶酮鹽酸鹽ˉ水合物(l57g,將4(60g,0.14mol)和THF(1000ml)置1.02mo1)、碳酸氫鈉(258g,3.07moU)和甲基反應瓶中,攪拌均勻,室溫加入硼氫化鈉(30g,異丁酮(l000m)置反應瓶中,于90~95℃反0.79mol),滴加冰乙酸(5ml),室溫攪拌3h,應24h,過濾,濾液蒸干,剩余物用乙醚-乙酸向反應液中慢慢滴加37%鹽酸(150ml),攪拌乙酯(1:1,200m)打漿洗滌,得淡黃色固體30min,加水(800ml),減壓蒸除THF,加30%2(137g,63.4%),mp112~14℃。MS(m/z):氫氧化鈉溶液(約200ml)調至約pH12,用二氯212M+H];HNMR(400MHz,CDC13)8:241(t,甲烷(400m1×3)萃取,合并有機層,經(jīng)飽和氯化6.0Hz,4H),2.61(t,J=6.4Hz,2H),2.78(t,J=鈉溶液(300m)洗滌,經(jīng)無水硫酸鈉干燥后過濾,52Hz,4H),332(t,J=6.0Hz,2H),3.36~3.38(m,濾液減壓蒸于,剩余物用丙酮重結晶,得白色結2H),347~3.51(m,2H),511(s,H)晶1(43g,71.3%),mp153~154℃(文獻61-[2-[4-[5-氯-1-(4氟苯基)-1H吲哚3-154-155℃)。純度98.8%[HPLC歸一化法:基]-12,3,6-四氫-1-吡啶基]乙基]-2-咪唑啉酮(4)色譜柱 Sepa GP-C8柱(4.6mmx250mm,5μm)將2(100g,0.47mol)、濃鹽酸(320m)和流動相磷酸鹽緩沖液(pH7.2)-乙腈·THF(50冰乙酸(320ml)置反應瓶中,加熱至回流,滴43:7);檢測波長230nm;柱溫40℃;流速加3(按文獻8自制,80g,0.33mol)的冰乙酸1ml/min]。MS(m/z):44[M+H]+;HNMR(480m1)溶液,繼續(xù)回流1h,冷卻至室溫,加(400MHz,CDCl2)8:1.77~1.87(m,2H),205(d,入丙酮(300ml),過濾,加至20%氫氧化鈉溶液J=7.6Hz,2H),2.27(t,J=6.4Hz,2H),2.62(t,J(100ml)中,用乙酸乙酯(200ml×3)提取,合并64Hz,2H),2.82(m,1H),3.13(d,J=7.6Hz,2H有機層,經(jīng)無水硫酸鈉干燥后過濾,濾液減壓蒸干,3.38~3.44(m,4H),353~3.57(m,2H),4.66(s,得類白色固體4(126g,88.1%),mpl45~147℃1H),7.07(s,1H),7.3~7.21(m,3H),7.32(d,J文獻:146℃)。MS(m2):439[M+H]t;HNMR88Hz,1H),7.38~745(m,2H),7.63(d,≠=2.0Hz,中國醫(yī)藥工業(yè)雜志 Chinese Journal of pharmaceuticals20l2,43(10)8031H)。l092-1101刁李雯,王宇,娗璐蕗,等.以烷基咪唑型離子液體為溶參考文獻:劑制備舍吲哚的方法:中國,101899036[P].2010-12-01[1] Murdoch D, Keating GM. 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The acute effect ofSect B,1982,21B(10):928-940sertindole on brain 5-HT2, D2 and alpha one receptors(ex vivo [ 11] Jacopo Z, Marco V, Francesco C Method for manufacture ofradioreceptor binding studies)[J]. J Neural Transm, 1992sertindole:WO,2003080597[P].203-10-02.(CA2003,89(1-2):6!-69139:276901)[5] Arnt J, Skarsfeldt T Do novel antipsychotics have similar [12] Frederick H Copper catalyzed arylation WO, 2004 013072harmacological characteristics? A review of the evidence [Jy[P].200402-12.(CA2004,140:181322)europsychopharmacology, 1998, 18(2): 63-101[13 Borghesea a, antoine L, Stephenson g. novel[] Perregaard J, Ant J, Boegesoc KP, et al. Noncataleptogenicchemoselective reduction of the tetrahydro-4-pyridyl versuscentrally acting dopamine d, and serotonin 5-HTindole moiety governed by electron donation: first X-rayantagonists within a series of 3-substituted 1-(4evidence for indolopiperidyl-borane complexation [J1fluorophenyl)-1H-indoles [J].J Med Chem, 1992, 35(6)Tetrahedron letl,2002,43(45):8087-8090哈嗡哈嗡嗡呱吼嗡嗡吼哈嗡嗡嗡嗡哈少》》)》》》》2》征訂啟事2013年《世界臨床藥物》征訂信息《世界臨床藥物》原名《國外醫(yī)藥——合成藥、生化藥、制劑分冊》,由上海醫(yī)藥工業(yè)研究院主管主辦,1980年創(chuàng)刊,為中國科技核心期刊,中國科技論文統(tǒng)計源期刊,中國學術期刊綜合評價數(shù)據(jù)庫來源期刊中國生物醫(yī)學期刊數(shù)據(jù)庫入選期刊,中文科技資料目錄—醫(yī)藥衛(wèi)生入選期刊被國內外多家權威數(shù)據(jù)庫(如CNKI和美國CA等)收錄;全國各大醫(yī)藥學院校圖書館均有收錄,30余年堅持不懈倡導安全用藥、合理用藥理念,積極推進國內臨床用藥水平的提高,在國內醫(yī)藥、醫(yī)療衛(wèi)生企事業(yè)單位頗兵影響本刊關注全球醫(yī)藥研發(fā)進展、涵蓋臨床各科用藥,是一本服務臨床醫(yī)師、藥師,面向醫(yī)藥行業(yè)及醫(yī)療衛(wèi)生從業(yè)人員的綜合性藥學學術期刊。本刊聚焦藥物臨床應用、研發(fā)進展和市場管理等各個環(huán)節(jié),精心組織臨床熱點專題綜述,兼具學術性、權威性和時效性。主要欄目:醫(yī)藥專論,研究論文,綜述評論,信息。讀者對象:臨床醫(yī)師、藥師;制藥企事業(yè)單位從業(yè)人員;髙等院校醫(yī)藥專業(yè)師生本刊為月刊,每月10日出版,定價:26元,全年312元。郵發(fā)代號:4302聯(lián)系人:施厚權;Tel:021-62896800,13391235955;E-mai:shih@pharmadl.com。把握世界藥物研發(fā)趨勢,探討臨床用藥焦點問題,請看《世界臨床藥物》!