舍吲哚的合成

中国医药工业杂志 Chinese journal of pharmaceuticals2012,43(10)》》》》》》》》》》》》》》》》》》》化学药物与合成技术《《《《《《《《《《《《《《《《《《《舍吲哚的合成张瑾,黄雷,李建其*〔中国医药工业研究总院上海医药工业硏究院,上海药物合成工艺过程工程技术硏究中心,上海200437)摘要:1-(2-氯乙基)-2·咪唑啉酮和哌啶酮盐酸盐缩合得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)缩合得!-[2-「4-「5-氯-1-(4-氟苯基)-lH-吲哚-3-基]-1,2,3,6-四氢-1-吡啶η乙基]-2-咪唑晽酮,最后经还原制得舍吲哚,总收率约63%(以3计)关键词:舍吲哚;非典型抗精神病药;合成中图分类号:R97141文献标志码:A文章编号: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),化学名为l-[2-[4-[5-收率为41.8%。②3依次与哌啶酮盐酸盐、1-(2氯-1-(4-氟苯基)-1H吲哚-3-基]-1-哌啶基]乙氯乙基)-2-咪唑啉酮缩合,再经PtO2催化还原基-2-咪唑啉酮,由丹麦 Lundbeck公司研发,1996与酒石酸成盐、碱化制得18,总收率为558%年首次在英国上市2。本品属强效中枢性多巴胺以上路线均以直线型方法制备目标产物,且都采用D2和5-HT受体拮抗剂3,为非典型的抗精神了价格昂贵的PO2作为还原催化剂,反应中伴有分裂症药物脱氯副产物的生成。1的合成路线主要有以下两条:①1-(4-氟苯本研究参考文献.1013,以1-(2-氯乙基)-2基)-5-氯吲哚(3)与哌啶酮缩合后经PO2催化还原,咪唑啉酮0为原料,首先和哌啶酮盐酸盐一水合再与1-(2-氯乙基)-2-咪唑啉酮缩合制得16,总物缩合制得1-[2-(2-氧代咪唑啉)乙基]哌啶酮(2),2与3缩合制得1-[2-[4-[5-氯-1-(4-氟苯收稿日期:2012-06-01作者简介:张瑾(1966-),女,工程师,从事药物合成研究基)-1H-吲哚-3-基]-1,2,3,6-四氢-1-吡啶基]乙Tel:021-55514600×210基]-2-咪唑啉酮(4)32,4经硼氢化钠还原制得1。E-mail;zhangjinyw(163.com通信联系人:李建其(1957),男,研究员,博士生导师,从事药该路线未见文献报道,其中2为新化合物;用硼氢物化学的研究与教学。化钠还原可避免使用贵重试剂PO2,减少脱氯副Tel:021-55514600×288E-mail:lijq@sipi.com.cn物的生成。该汇聚式合成路线反应步骤少,操作简中国医药工业杂志 Chinese journal of pharmaceuticals2012,43(10)HCL·H2NaHCO3/MIBK0NHNaBH4/THFNH图11的合成路线便,成本低,产品纯度高,有利于工业化生产,总(CDCl3)8:2.59(brs,2H),267(t,J=68Hz,2H)收率为62.8%(以3计)。1的合成路线见图1。279(t,J=56Hz,2H),328(s,2H),3.38~343(m实验部分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将1-(2-氯乙基)-2-咪唑啉酮(按文献自制,舍吲哚(1)212g,1.43mo)、哌啶酮盐酸盐ˉ水合物(l57g,将4(60g,0.14mol)和THF(1000ml)置1.02mo1)、碳酸氢钠(258g,3.07moU)和甲基反应瓶中,搅拌均匀,室温加入硼氢化钠(30g,异丁酮(l000m)置反应瓶中,于90~95℃反0.79mol),滴加冰乙酸(5ml),室温搅拌3h,应24h,过滤,滤液蒸干,剩余物用乙醚-乙酸向反应液中慢慢滴加37%盐酸(150ml),搅拌乙酯(1:1,200m)打浆洗涤,得淡黄色固体30min,加水(800ml),减压蒸除THF,加30%2(137g,63.4%),mp112~14℃。MS(m/z):氢氧化钠溶液(约200ml)调至约pH12,用二氯212M+H];HNMR(400MHz,CDC13)8:241(t,甲烷(400m1×3)萃取,合并有机层,经饱和氯化6.0Hz,4H),2.61(t,J=6.4Hz,2H),2.78(t,J=钠溶液(300m)洗涤,经无水硫酸钠干燥后过滤,52Hz,4H),332(t,J=6.0Hz,2H),3.36~3.38(m,滤液减压蒸于,剩余物用丙酮重结晶,得白色结2H),347~3.51(m,2H),511(s,H)晶1(43g,71.3%),mp153~154℃(文献61-[2-[4-[5-氯-1-(4氟苯基)-1H吲哚3-154-155℃)。纯度98.8%[HPLC归一化法:基]-12,3,6-四氢-1-吡啶基]乙基]-2-咪唑啉酮(4)色谱柱 Sepa GP-C8柱(4.6mmx250mm,5μm)将2(100g,0.47mol)、浓盐酸(320m)和流动相磷酸盐缓冲液(pH7.2)-乙腈·THF(50冰乙酸(320ml)置反应瓶中,加热至回流,滴43:7);检测波长230nm;柱温40℃;流速加3(按文献8自制,80g,0.33mol)的冰乙酸1ml/min]。MS(m/z):44[M+H]+;HNMR(480m1)溶液,继续回流1h,冷却至室温,加(400MHz,CDCl2)8:1.77~1.87(m,2H),205(d,入丙酮(300ml),过滤,加至20%氢氧化钠溶液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有机层,经无水硫酸钠干燥后过滤,滤液减压蒸干,3.38~3.44(m,4H),353~3.57(m,2H),4.66(s,得类白色固体4(126g,88.1%),mpl45~147℃1H),7.07(s,1H),7.3~7.21(m,3H),7.32(d,J文献:146℃)。MS(m2):439[M+H]t;HNMR88Hz,1H),7.38~745(m,2H),7.63(d,≠=2.0Hz,中国医药工业杂志 Chinese Journal of pharmaceuticals20l2,43(10)8031H)。l092-1101刁李雯,王宇,娗璐蕗,等.以烷基咪唑型离子液体为溶参考文献:剂制备舍吲哚的方法:中国,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》征订启事2013年《世界临床药物》征订信息《世界临床药物》原名《国外医药——合成药、生化药、制剂分册》,由上海医药工业研究院主管主办,1980年创刊,为中国科技核心期刊,中国科技论文统计源期刊,中国学术期刊综合评价数据库来源期刊中国生物医学期刊数据库入选期刊,中文科技资料目录—医药卫生入选期刊被国内外多家权威数据库(如CNKI和美国CA等)收录;全国各大医药学院校图书馆均有收录,30余年坚持不懈倡导安全用药、合理用药理念,积极推进国内临床用药水平的提高,在国内医药、医疗卫生企事业单位颇兵影响本刊关注全球医药研发进展、涵盖临床各科用药,是一本服务临床医师、药师,面向医药行业及医疗卫生从业人员的综合性药学学术期刊。本刊聚焦药物临床应用、研发进展和市场管理等各个环节,精心组织临床热点专题综述,兼具学术性、权威性和时效性。主要栏目:医药专论,研究论文,综述评论,信息。读者对象:临床医师、药师;制药企事业单位从业人员;髙等院校医药专业师生本刊为月刊,每月10日出版,定价:26元,全年312元。邮发代号:4302联系人:施厚权;Tel:021-62896800,13391235955;E-mai:shih@pharmadl.com。把握世界药物研发趋势,探讨临床用药焦点问题,请看《世界临床药物》!