【作者】 白雪；

【导师】 杜玉民；

【作者基本信息】 河北医科大学 ， 药物化学， 2015， 硕士

【摘要】 精神分裂症(Schizophrenia)是一种常见的精神疾病,据世卫组织估计,全球精神分裂症的终身患病率大概为3.8~8.4‰,美国研究显示该病终生患病率达13‰,据2002年我国卫生部的通报,我国精神分裂症患病率达6.2‰,该病病因复杂,到目前为止仍未完全阐明其原因。经调查青壮年多患此病,通常表现为思维、情感、感知、意志行为等多方面的障碍,精神活动与内心体验和周围环境不协调,脱离现实。一般存在无意识障碍和明显的智能障碍,可有注意、工作记忆、抽象思维和信息整合等方面认知功能损害,病程多迁延,反复发作,部分患者发生精神活动衰退和不同程度社会功能缺损[1-2]。药物治疗仍然是目前首选的治疗措施,盐酸鲁拉西酮与安慰剂相比,对于精神分裂症患者有明显疗效。盐酸鲁拉西酮在治疗精神分裂症方面不存在性别、年龄、人种的差异,且治疗效果显著。而对于双相情感障碍,盐酸鲁拉西酮组单药治疗时,与安慰剂相比具有显著差异性;作为锂或丙戊酸钠的辅助药物治疗双相情感障碍时,虽然数据未进行统计分析,但相关报道已证明其有效性,盐酸鲁拉西酮受到临床的青睐,本品的开发具有广阔的前景[3]。盐酸鲁拉西酮是新的分子实体,是由日本住友制药公司开发的一种非典型抗精神病药物,已于2010年10月在美国上市销售[4]。日本住友制药有限公司最先以消旋1,2-双(甲磺酰基氧基甲基)环己烷(消旋体)、(3a R,4S,7R,7a S)-7-亚甲基-1H-异吲哚-1,3(2H)-二酮和3-(1-哌嗪基)-1,2-苯并异噻唑为主要原料,经过三步亲核取代反应得到消旋的鲁拉西酮,然后进行手性拆分得到光学纯的鲁拉西酮[5]。基于日本住友制药有限公司有关手性合成和拆分的研究,2011年天津药物研究院申请的专利CN102731512A[6]报道了鲁拉西酮中间体及鲁拉西酮的制备方法,同时印度兰伯西实验室有限公司(Ranbaxy Laboratories Limited)2012年也申请了相关的专利WO2012107890A2[7],但都在鲁拉西酮阶段进行手性拆分,得到光学纯的鲁拉西酮。2001年日本住友制药有限公司在1,2-环己烷二甲醇阶段进行手性拆分,得到(1R,2R)-环己烷二甲醇,避免了手性拆分收率低,溶剂消耗大等缺点。用化学拆分的方法获得光学纯的鲁拉西酮有很多缺点,正如专利US5532372所述,最高收率仅达到50%,收率较低;拆分试剂消耗大,成本较高。因此以手性(1R,2R)-环己烷二甲醇为起始原料合成盐酸鲁拉西酮,是一条简易可行的合成路线。本论文采用光学纯度的(1R,2R)-1,2-环己烷二甲醇为起始原料,按照自行设计的合成路线,进行盐酸鲁拉西酮的合成。目的:采用手性原料合成盐酸鲁拉西酮,有效控制光学异构体的含量,优化合成工艺,得到高纯度的盐酸鲁拉西酮,利用熔点,红外,质谱,核磁,单晶衍射手段对盐酸鲁拉西酮结构进行确认。方法:鲁拉西酮可以分割成片段1,片段2和片段3。片段1可以由(3a R,4S,7R,7a S)-7-亚甲基-1H-异吲哚-1,3-(2H)-二酮得到;片段2可以由1,2-环己烷二甲醇的衍生物引入到鲁拉西酮中;片段3是杂环物3-(1-哌嗪基)-1,2-苯并异噻唑。通过化学反应把片段1、2和3组合起来,得到鲁拉西酮,与盐酸成盐得到盐酸鲁拉西酮。采取的技术路线:光学纯的(1R,2R)-1,2-环己烷二甲醇(SM1)经由甲基磺酰氯进行磺酰化反应得到(1R,2R)-1,2-双(甲磺酰基氧基甲基)环己烷(INT1)。INT1与3-(1-哌嗪基)-1,2-苯并异噻唑(SM2)可以发生两次亲核取代反应,得到(3a R,7a R)-4’-(1,2-苯并异噻唑-3-基)八氢螺[2H-异吲哚-2,1’-哌嗪]甲磺酸盐(INT1)。再与(3a R,4SR,7a S)-7-亚甲基-1H-异吲哚-1,3(2H)-二酮(SM3)反应得到鲁拉西酮,最后与盐酸成盐得到盐酸鲁拉西酮。结果:1熔点:265℃~275℃2红外吸收光谱(IR),IR cm-1:3064.99,1562.39,1504.53,777.34,740.69,证明了分子中有苯环存在。IR cm-1:2258.72,证明了分子以盐酸盐存在。3高分辨质谱数据M+H峰:493.26318,与盐酸鲁拉西酮分子量吻合。4核磁共振氢谱(1H-NMR)中有16组峰,与盐酸鲁拉西酮结构中36个质子相对应;核磁共振碳谱(13C-NMR)证明了盐酸鲁拉西酮分子中的28个碳原子,其中仲碳15个,叔碳8个,季碳5个,每个碳原子的归属与盐酸鲁拉西酮分子中各个碳相吻合。5单晶X-衍射图谱证明盐酸鲁拉西酮的分子中含有6个手性中心,确证了其绝对构型,同时证明了鲁拉西酮分子与HCl按1:1摩尔比成盐。结论:优化出最佳合成工艺,制备出了高纯度的盐酸鲁拉西酮,通过熔点,红外,质谱,核磁,单晶衍射手段确认了盐酸鲁拉西酮结构。更多还原

【Abstract】 Schizophrenia is a common mental illness, according to WHO estimates that lifetime prevalence of schizophrenia was about 3.8-8.4‰ in a word, US studies have shown that the lifetime prevalence rate of the disease is 13‰.According to the 2002 Ministry of Health informed of schizophrenia prevalence rate of 6.2‰. The disease causes complex, has not been fully elucidated. Multi-onset in young adults, showed perception, thinking, emotion,will conduct, and many other disorders, mental activity and the surrounding environment and inner experience uncoordinated, divorced from reality.General disorders and obviously unconscious mental retardation, may have attention, working memory, abstract thinking, and information integration and other aspects of cognitive impairment, duration and more persistent, recurrent,and some patients with varying degrees of mental activity and social functions of recession defects.Drug treatment is still the preferred treatment, Lurasidone hydrochloride compared with placebo for patients with schizophrenia have significant effects.Lurasidone hydrochloride does not exist in the treatment of schizophrenia gender differences in age, race, and the significant treatment effect. For bipolar disorder, when lurasidone hydrochloride monotherapy group,compared with placebo was significant difference. Lithium or valproate as an adjunct to the treatment of bipolar disorder, although the statistical analysis is not carried out,but reports have proven their effectiveness. Lurasidone hydrochloride by clinical favored the development of this product has broad prospects.Lurasidone hydrochloride is a new molecular entity, developed by Japan’s Sumitomo Pharmaceuticals, an atypical antipsychotic, has been marketed in the United States.Sumitomo Pharmaceutical Co., Ltd. first racemic 1,2-bis(methylsulfonyloxy) cyclohexane(racemate),(3a R,4S,7R,7a S)-7-methylene-1H- isoindole-1,3(2H)- dione and 3-(1-piperazinyl)-1,2-benzisothiazole racemic get through a three-step as the main raw material nucleophilic substitution reaction lurasidone followed by chiral resolution to give optically pure lurasidone. Sumitomo Corporation of Japan and then conducted a series of studies on chiral synthesis and split, research-based Sumitomo Pharma Co.,Tianjin Institute of Pharmaceutical patents CN102731512 A reported lurasidone lurasidone intermediates and preparation methods in 2011, while India’s Ranbaxy Laboratories Limited(Ranbaxy Laboratories Limited) also applied for patents related WO2012107890A2 in 2012,but all were in lurasidone chiral separation stage to obtain optically pure lurasidone, in 2001 Sumitomo pharmaceutical Co.,Ltd. in the 1,2-cyclohexanedimethanol phase chiral resolution to give(1R, 2R)- cyclohexane dimethanol, avoiding low yield chiral resolution, solvent consumption and other shortcomings.Obtain optically pure chemical lurasidone split method has many drawbacks,as patent US5532372, the highest closing rate reached 50%, a lower yield; resolving reagent consumption, the higher the cost. Therefore chiral(1R, 2R)- cyclohexanedimethanol as a starting material to synthesize lurasidone hydrochloride, is a simple and feasible synthetic route,while isomer introduced from the starting materials and ease of tracking control.In this thesis, the optical purity of(1R, 2R)-1,2- cyclohexanedimethanol as a starting material, since the proposed synthetic route, synthesis performed lurasidone hydrochloride.Objective: The source control, by controlling the optical purity of the starting material to synthesize lurasidone hydrochloride, effectively control the content of an optical isomer, optimize the best synthesis process to obtain high purity lurasidone hydrochloride, and lurasidone hydrochloride structure melting point, IR, MS, NMR diffraction means to confirm.Methods: lurasidone can be divided into segments 1, fragment 2 and fragment 3. Fragment 1 may be made of(3a R, 4S, 7R, 7a S)-7- methylene-1H- isoindole-1,3-(2H)-dione obtained; fragment 2 may be made of1,2-cyclohexanedicarboxylic derivative of methanol is introduced into lurasidone in; fragment 3 is heterocycles 3-(1-piperazinyl)-1,2-benzisothiazole. By suitable chemical reaction to fragment 1,2 and 3 combined to obtain a lurasidone, by salt formation with hydrochloric acid lurasidone hydrochloride.Take the technical route is as follows:Optically pure(1R,2R)-1,2-cyclohexane dimethanol(SM1) were sulfonylation reaction to give(1R,2R)-1,2-bis(methanesulfonyloxy methyl via methanesulfonyl chlorideyl) cyclohexane(INT1); INT1 and 3-(1-piperazinyl)-1,2-benzisothiazole(SM2) can occur twice a nucleophilic substitution reaction, to give(3a R, 7a R)-4’-(1,2-benzisothiazol-3-yl) octahydro-spiro [2Hisoindole-2,1’-piperazinyl] methanesulfonate(INT1); then with(3a R,4SR, 7a S)-7-methylene-1H-isoindole-1,3(2H)-dione(SM3) substituted lurasidone obtained; finally lurasidone hydrochloride to give the hydrochloride salt.The result:Melting point: 265 ℃~275 ℃2 The infrared absorption spectrum(IR), IR cm-1: 3064.99, 1562.39,1504.53, 777.34, 740.69, demonstrated the presence of a benzene molecule. IR cm-1: 2258.72, proved the existence of the hydrochloride salt molecules.3 The high resolution mass spectrometry data M + H peak(493.26318).4 The proton nuclear magnetic resonance spectroscopy(1H-NMR) in a total of 16 sets of peaks corresponding hydrochloride lurasidone structure 36 protons, is consistent with lurasidone hydrochloride number of protons in the molecule; Carbon NMR spectra(13C-NMR) proved lurasidone HCl molecule has 28 carbon atoms, where secondary carbon 15, carbon eight tertiary,quaternary carbon 5, in the 13C-NMR spectrum, each carbon attribution lurasidone hydrochloride individual carbon molecules coincide.5 The single crystal X-diffractogram proved lurasidone hydrochloride molecule contains six chiral centers, the absolute configuration was confirmed,and proves the sample molecules with HCl salt, the ratio of 1: 1.Conclusion: The optimal synthesis process optimization, prepared with high purity hydrochloric acid lurasidone, by melting point, IR, MS, NMR,single crystal diffraction means confirmed lurasidone hydrochloride structure.更多还原