CN106749052B - 氯巴占的制备方法 - Google Patents
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Abstract
本发明提出了一种氯巴占的制备方法,包括以下步骤:包括以下步骤:1)以2‑硝基‑5‑氯二苯胺与丙二酸单乙酯酰氯为原料,在有机溶剂中回流反应,反应结束后,将反应体系中的有机溶剂减压蒸干,然后加入精制溶剂进行精制处理得到式II化合物:2)将式II化合物经锌粉还原,氨解环合生成Ⅲ化合物:3)将式III化合物在碱的醇溶液中与碘甲烷反应即可得到氯巴占,其中,所述碱为氢氧化钠、氢氧化锂与氢氧化钾中的一种或者多种。该方法制备得到的氯巴占杂质少,纯度高。
Description
技术领域
本发明属于1,5-苯二氮卓类衍生物制备技术领域,具体涉及一种氯巴占的制备方法。
背景技术
癫痫是一组由已知或未知病因所引起,脑部神经元高度同步化,且常具自限性的异常放电所导致,以反复发作性、短暂性、通常为刻板性的中枢神经系统功能失常为特征的综合征。据WHO统计,目前全球癫痫患者约有5000万人,其中80%在发展中国家。每年还出现200万新癫痫患者。发达国家、经济转轨国家、发展中国家和不发达国家的癫痫患病率分别为5.0‰、6.1‰、7.2‰、11.2‰。
数据显示,我国的癫痫患病率为7‰,与WHO报告的发展中国家7.2‰的发病率接近。而上世纪80年代初的一项调查显示,1983年我国癫痫患病率仅为4.4‰,比发达国家还要低。短短20年时间,我国癫痫患者人数已升至900万之多,且每年有将近40万的新发病人。在这些癫痫患者中,儿童和青少年仍是癫痫高发人群,0~9岁患者占38.5%,10~29岁患者占近40%。
目前市场上同类产品用于治疗癫痫的许多药物如苯妥英钠、苯巴比妥、卡马西平和丙戊酸钠等,但是它们有如下的缺陷:⑴在血药浓度达到充分控制发作的水平之前常需数日或数周之久;⑵每个药物具有其对癫痫的某种发作形式的显著作用,但不能对各种类型的癫痫都有作用;⑶对癫痫持续状态,不能迅速奏效。相对而言,苯二氮卓类药物则有三个优点:⑴控制抽搐的发作起效非常迅速(常在数小时或数天);⑵对各种类型的癫痫:小发作(失神或肌阵挛性)、全身性发作(原发或继发)及所有的部分性发作(单纯或复杂性)均有作用;⑶可口服治疗慢性癫痫或非经肠道给药治疗急性癫痫特别是癫痫持续状态。
氯巴占的中文化学名称为7-氯-1-甲基-5-苯基-1,5-二氮杂-2,4(3H)-二酮,是第一个应用于临床的1,5-苯二氮卓类衍生物。其作用机制为增强GABA (γ-氨基丁酸)能神经传递功能和突触抑制效应,还有增强GABA与GABAA受体相结合的作用。其药理活性与其他苯二氮卓类药物相似,具有抗焦虑和抗惊厥作用,抗电休克作用的ED50比地西泮小而比苯巴比妥、丙戊酸钠大。
氯巴占相关专利有US3984398与US3836653,其公开的氯巴占合成路线如下:
在制备氯巴占(I)时,上述专利采用强碱如氨基钠乙醇钠等,此类碱性较强,不仅能夺取N位上氢与碘甲烷生成氯巴占,而且能夺取化合物Ⅲ五元环上亚甲基上氢,形成碳负离子,从而与碘甲烷反应生成杂质Ⅳ,上述合成路线导致合成的氯巴占纯度不高,影响其药效发挥与应用。
发明内容
本发明提出一种氯巴占的制备方法,该方法制备得到的氯巴占杂质少,纯度高。
本发明的技术方案是这样实现的:
一种氯巴占的制备方法,包括以下步骤:
1)以2-硝基-5-氯二苯胺与丙二酸单乙酯酰氯为原料,在有机溶剂中回流反应,反应结束后,将反应体系中的有机溶剂减压蒸干,然后加入精制溶剂进行精制处理得到式II化合物:
2)将式II化合物经锌粉还原,氨解环合生成Ⅲ化合物:
3)将式III化合物在碱的醇溶液中与碘甲烷反应即可得到氯巴占,
其中,所述碱为氢氧化钠、氢氧化锂与氢氧化钾中的一种或者多种。
进一步,本发明优选实施例中,所述式II化合物与锌粉进行还原反应之前需要经过粉碎成粉末,加速溶解,促进还原反应的进行,提高了反应收率。
进一步,将式II化合物粉末过80目筛处理。
进一步,本发明优选实施例中,所述步骤1)有机溶剂为无水乙腈,所述精制溶剂为甲醇或乙醇,解决了传统氯巴占制备工艺采用苯(剧毒)作为反应溶剂导致后处理繁琐(需要多次碱洗与水洗)的问题。
进一步,加入精制溶剂进行精制处理得到式II化合物的具体步骤为:将精制溶剂加入到减压蒸干得到的固体化合物中,搅拌溶解,0~5℃冷却析晶,抽滤,烘干得式II化合物。
进一步,步骤3)中的醇为甲醇或者乙醇。
本发明有益效果:
本发明的氯巴占的制备方法在步骤3)采用碱性稍弱的氢氧化钠、氢氧化锂与氢氧化钾的醇溶液来替代氨基钠以及乙醇钠避免了杂质Ⅳ的产生,提高了产品的纯度。
具体实施方式
实施例
氯巴占的制备方法:
步骤1:化合物Ⅱ制备
在20L反应瓶中,加入2.5kg2-硝基-5-氯二苯胺、16L无水乙腈、1.8kg丙二酸单乙酯酰氯搅拌,加热回流反应12小时。60℃减压蒸馏除乙腈,加入8L乙醇搅拌溶解,0~5℃冷却析晶,抽滤,60℃烘干得黄色结晶重3.3kg。熔点85-87℃,收率91%。
步骤2:化合物Ⅲ制备
在50L反应瓶中,加入粉碎的过80目筛的化合物Ⅱ3kg,30L乙醇搅拌,控温20℃以下滴加15L盐酸,滴完后,控温20-30℃分批加入2kg锌粉,约4小时加完,有白色固体析出,加完后继续搅拌4小时,抽滤,滤饼水洗至中性,乙醇洗,70℃烘干得白色晶体粉末1.2kg,收率50.7%。
步骤3:氯巴占制备
在50L反应瓶中,加入1.2kg化合物Ⅲ,185g氢氧化钠,36L乙醇室温搅拌,1小时后,加入600ml碘甲烷室温搅拌反应18小时,减压浓缩反应液体积至12L,0-5℃冷却析晶4小时,抽滤,滤饼用水洗,乙醇洗,烘干。所得固体用10L乙醇精制得白色晶体920g,熔点183-185℃,收率73%。纯度99.96%,不含杂质Ⅳ。
对比实施例,原研进口颗粒剂提取物纯度99.89%,含有0.04%杂质Ⅳ。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (1)
1.一种氯巴占的制备方法,其特征在于,包括以下步骤:
步骤1:化合物II制备
在20L反应瓶中,加入2.5kg 2-硝基-5-氯二苯胺、16L无水乙腈、1.8kg丙二酸单乙酯酰氯搅拌,加热回流反应12小时;60℃减压蒸馏除乙腈,加入8L乙醇搅拌溶解,0~5℃冷却析晶,抽滤,60℃烘干得黄色结晶;
步骤2:化合物III制备
在50L反应瓶中,加入粉碎的过80目筛的化合物II 3kg,30L乙醇搅拌,控温20℃以下滴加15L盐酸,滴完后,控温20-30℃分批加入2kg锌粉,4小时加完,有白色固体析出,加完后继续搅拌4小时,抽滤,滤饼水洗至中性,乙醇洗,70℃烘干得白色晶体粉末;
步骤3:氯巴占制备
在50L反应瓶中,加入1.2kg化合物III,185g氢氧化钠,36L乙醇室温搅拌,1小时后,加入600ml碘甲烷室温搅拌反应18小时,减压浓缩反应液体积至12L,0-5℃冷却析晶4小时,抽滤,滤饼用水洗,乙醇洗,烘干;所得固体用10L乙醇精制得白色晶体。
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US3984398A (en) * | 1966-12-14 | 1976-10-05 | Roussel-Uclaf | 1,5-Benzodiazepine-2,4-diones |
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WO2016193482A1 (en) * | 2015-06-05 | 2016-12-08 | Amneal Pharmaceuticals Company Gmbh | Process for preparing clobazam using novel intermediates |
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US3984398A (en) * | 1966-12-14 | 1976-10-05 | Roussel-Uclaf | 1,5-Benzodiazepine-2,4-diones |
WO2016193482A1 (en) * | 2015-06-05 | 2016-12-08 | Amneal Pharmaceuticals Company Gmbh | Process for preparing clobazam using novel intermediates |
CN105837522A (zh) * | 2016-06-14 | 2016-08-10 | 绍兴文理学院 | 一种1,5-苯并二氮卓酮衍生物的制备方法 |
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The synthesis of 7-chloro-5-pentadeuriophenyl-1-methyl-1H-1,5-benzodiazepine-2,4(3H,5H)dione([2H5]Clobazam);Anthony G. Borel et al;《 Journal of Labelled compounds and Radiopharmaceuticals》;19900731;第28卷(第7期);文献第781-782页 * |
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