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【摘要】：伊潘立酮是一種非典型抗精神病藥物，屬于苯并異VA唑類衍生物，與5-羥色胺和多巴胺D2、D3受體具有較高的親和性，能很好的控制精神分裂癥狀。 論文對目前伊潘立酮合成路線進行優(yōu)化，設計并通過試驗獲得一條操作簡便，路線短，收率高，產品質量高，且污染物排放少，適合工業(yè)化生產的工藝路線，即以2,4-二氟苯基-4-哌啶基甲酮鹽酸鹽為起始原料，經立體選擇性反應獲得(Z)-2,4-二氟苯基-4-哌啶基甲酮肟(2)，，純度在99.9%以上；香草酮和1,3-二溴丙烷反應獲得中間體4-(3-溴丙基氧基)-3-甲氧基苯乙酮(6)，純度在99.0%以上。在IV類溶劑(甲基異丙基甲酮，MIPK)中經分子間N-烴代反應和分子內環(huán)合反應獲得目標產物，所得伊潘立酮經HPLC檢測純度達到99.9%以上，總收率為65%。 論文分別合成了該原料藥中所含有的6種有關物質，即：4-[3-[4-(6-氟-1,2-苯并異VA唑-3-基)-1-哌啶基]丙氧基]-3-甲氧基-α-甲基苯甲醇(P88)、4-[3-[4-(6-氟-1,2-苯并異VA唑-3-基)-1-哌啶基]丙氧基]-3-甲氧基苯甲酸(P95)、1,1'-[1,3-丙二基-雙[氧代(3-甲氧基-4,1-亞苯基)]]雙-乙酮(A)、(E)-2,4-二氟苯基-4-哌啶基甲酮肟(B)、1-[4-[3-[4-(6-乙氧基-1,2-苯并異VA唑-3-基)-1-哌啶基]丙氧基]-3-甲氧基苯基]乙酮(C)、1-(3-(4-乙�；�-2-甲氧基苯氧基)丙基)-4-(6-氟-1,2-苯并異VA唑-3-基)哌啶-N-氧化物(D)，6種有關物質結構經紅外譜圖、核磁共振氫譜、碳譜及質譜確證。 采用13種不同溶劑對伊潘立酮進行重結晶，所得晶體通過粉末衍射及DSC-TGA驗證為同一晶型，在2θ值約為7.1o,10.1o,11.8o,12.6o,14.2o,17.2o,17.4o,18.2o,19.0o,19.3o,19.9o,20.3o,21.5o,22.0o,23.8o,26.3o,28.9o,30.7o,31.7o,34.1o等的位置對應有吸收峰；采用單晶衍射法證明：伊潘立酮分子中含氮六元環(huán)呈椅式構象，其他環(huán)近平面構象，分子不具有旋光活性。晶態(tài)下分子以范德華力維系其在空間的穩(wěn)定排列。
[Abstract]:Imperidone is an atypical antipsychotic drug, which belongs to benzo-isobarbazole derivatives. It has high affinity with 5-hydroxytryptamine and dopamine D _ 2, D _ 3 receptor, and can well control the symptoms of schizophrenia. In this paper, the synthesis route of Ipensone is optimized, and a simple route, short route, high yield, high quality of product and less pollutant emission is obtained by experiment, which is suitable for industrial production. (Z)-2,4-difluorophenyl-4-piperidine methoxime (2) was synthesized from 2,4-difluorophenyl-4-piperidine methyl ketone hydrochloride by stereoselective reaction, the purity of which was more than 99.9%. The intermediate 4-(3-bromopropyl)-3-methoxyacetophenone (6) was synthesized by the reaction of vanilone with 1,3-dibromopropane, the purity of which was more than 99.0%. The target product was obtained by intermolecular N-alkylation and intramolecular cyclization in IV solvent (methyl isopropyl ketone, MIPK). The purity of Ipensone was over 99.9% by HPLC, and the overall yield was 65%. In this paper, six related substances contained in the drug were synthesized. That is, 4-[3-[3-[4-(6-fluoro-1,2-benzo-isoVA-3-yl)-1-piperidyl] propyl]-3-methoxy-偽-methylbenzyl alcohol (P88), 4-[3-[4-(6-fluoro-1,2-benzo-isoVA-3-yl)-1-piperidyl] propyl]-3-methoxybenzoic acid (P95), 1,1-[1,3-propyl-bis [oxo (3-methoxy-4,1-phenylene)] bis-acetophenone (A), (E)-2,4-difluorophenyl-4-piperidine methanone oxime (B), 1-[4-[3-[4-(6-ethoxy-1,2-benzisoVA-3-yl)-1-piperidyl] propyl]-3-methoxyphenyl] ethyl ketone (C), The structures of 1-(3-(4-acetyl-2-methoxyphenoxy) propyl)-4-(6-fluoro-1,2-benzo-isoVA-3-yl) piperidine-N-oxide (D), were characterized by IR, 1H NMR, Carbon spectrum and mass spectrometry. The crystals were recrystallized with 13 different solvents, and the obtained crystals were confirmed to be the same crystal form by powder diffraction and DSC-TGA. The values of 2 胃 were about 7.1o, 10.1o, 11.8o, 12.6o, 14.2o, 17.2o, 17.4o, respectively. 18.2o, 19.0o, 19.3o, 19.9o, 20.3o, 21.5o, 22.0o, 23.8o, 26.3o, 28.9o, 30.7o, 31.7o, 34.1o, etc. It is proved by single crystal diffraction that the six-membered ring containing nitrogen is chair conformation and the other ring conformation is near-plane. The molecule has no optical activity. The molecules in crystalline state maintain their stable arrangement in space by van der Waals force.
【學位授予單位】：河北科技大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R914

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