伊潘立酮原料药合成新工艺研究
发布时间：2019-03-28 08:19
【摘要】：伊潘立酮是一种非典型抗精神病药物，属于苯并异VA唑类衍生物，与5-羟色胺和多巴胺D2、D3受体具有较高的亲和性，能很好的控制精神分裂症状。 论文对目前伊潘立酮合成路线进行优化，设计并通过试验获得一条操作简便，路线短，收率高，产品质量高，且污染物排放少，适合工业化生产的工艺路线，即以2,4-二氟苯基-4-哌啶基甲酮盐酸盐为起始原料，经立体选择性反应获得(Z)-2,4-二氟苯基-4-哌啶基甲酮肟(2)，，纯度在99.9%以上；香草酮和1,3-二溴丙烷反应获得中间体4-(3-溴丙基氧基)-3-甲氧基苯乙酮(6)，纯度在99.0%以上。在IV类溶剂(甲基异丙基甲酮，MIPK)中经分子间N-烃代反应和分子内环合反应获得目标产物，所得伊潘立酮经HPLC检测纯度达到99.9%以上，总收率为65%。 论文分别合成了该原料药中所含有的6种有关物质，即：4-[3-[4-(6-氟-1,2-苯并异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-苯并异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-双[氧代(3-甲氧基-4,1-亚苯基)]]双-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-苯并异VA唑-3-基)-1-哌啶基]丙氧基]-3-甲氧基苯基]乙酮(C)、1-(3-(4-乙酰基-2-甲氧基苯氧基)丙基)-4-(6-氟-1,2-苯并异VA唑-3-基)哌啶-N-氧化物(D)，6种有关物质结构经红外谱图、核磁共振氢谱、碳谱及质谱确证。 采用13种不同溶剂对伊潘立酮进行重结晶，所得晶体通过粉末衍射及DSC-TGA验证为同一晶型，在2θ值约为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等的位置对应有吸收峰；采用单晶衍射法证明：伊潘立酮分子中含氮六元环呈椅式构象，其他环近平面构象，分子不具有旋光活性。晶态下分子以范德华力维系其在空间的稳定排列。
[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-伪-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.
【学位授予单位】：河北科技大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914
本文编号：2448695
[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-伪-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.
【学位授予单位】：河北科技大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914
【参考文献】
相关期刊论文 前10条
1 赵迎春;陈生弟;;药物引起的锥体外系不良反应[J];世界临床药物;2009年07期
2 何安阳;陈惠龙;;氟哌啶醇的不良反应[J];海峡药学;2009年10期
3 赵静;;辛伐他汀片的处方工艺优化[J];河北工业科技;2011年01期
4 黄继忠,张明园;非典型抗精神病药治疗精神分裂症的评价(二)[J];上海精神医学;2005年05期
5 王传跃;;精神分裂症研究的进展[J];上海精神医学;2011年04期
6 傅学民;马学军;;氯普噻吨中毒致癫痫大发作临床机制[J];临床荟萃;2009年19期
7 李园园;李华芳;;新型非典型抗精神病药:伊潘立酮[J];中国临床药学杂志;2011年05期
8 谢根生;项爱萍;;第二代抗精神病药在精神分裂症治疗中的应用[J];现代中西医结合杂志;2008年24期
9 宋丽;臧志和;廖洪利;谢静;曹丽萍;王静;;药物中有关物质检查方法研究进展[J];西南国防医药;2007年06期
10 蔡飒,陈一岳;抗精神病药物治疗的进展[J];广东药学;2004年01期
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