为控制氯氮平的质量，本研究基于其合成工艺，合成了6 个有关物质，分别为8- 氯-5,10- 二氢-11H- 二苯并[b,e]- [1,4] 二氮杂?-11- 酮( 有关物质A)、11,11'-(1,4- 哌嗪二基) 双(8- 氯-5H- 二苯并[b,e][1,4] 二氮杂?)( 有关物质B)、 8- 氯-11-(1- 哌嗪基)-5H- 二苯并[b,e][1,4] 二氮杂?( 有关物质C)、2-(2- 氨基-4- 氯苯基) 氨基苯基-1-(4- 甲基哌嗪基)- 甲酮( 有关物质D)、8- 氯-11-(4- 甲基哌嗪基)-5H- 二苯并[b,e][1,4] 二氮杂?· 氮氧化物( 有关物质E) 和11-(4- 甲基哌嗪基)-5H- 二苯并[b,e][1,4] 二氮杂?( 有关物质F)。其中，该有关物质F 的合成方法尚未见文献报道。上述有关物质的结构均经ESI-HRMS 和1H NMR 确证。
Abstract
In order to control the quality of clozapine, six related substances, namely 8-chloro-5,10-dihydro-11Hdibenzo[ b,e][1,4]diazepin-11-one(related substance A), 11,11'-(piperazin-1,4-diyl)bis(8-chloro-5H-dibenzo[b,e][1,4]- diazepine)(related substance B), 8-chloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine(related substance C), [2-[(2-amino-4-chlorophenyl)amino]phenyl](4-methylpiperazin-1-yl)methanone(related substance D), 8-chloro-11- (4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine-1-oxide(related substance E) and 11-(4-methylpiperazin-1- yl)-5H-dibenzo[b,e][1,4]diazepine(related substance F), were synthesized based on the synthetic process of clozapine. Among them, the synthetic method of related substance F has not been found in literature. The structures of the above related substances were confirmed by ESI-HRMS and 1H NMR.
关键词
氯氮平 /
抗精神病药 /
有关物质 /
合成
{{custom_keyword}} /
Key words
clozapine /
antipsychotic drug /
related substance /
synthesis
{{custom_keyword}} /
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
[1] 于立国, 金晓峰，王 兵，等．氯氮平的合成工艺改进[J]．中国医药工业杂志, 2020, 51(10): 1259-1261．
[2] 徐开堃, 段士道, 程玲云, 等．有机药物合成手册(补编)[M]．上海: 上海医药工业研究院, 1983: 144-145．
[3] RUEGER C, ROHNERT H, LOHMANN D．New derivatives of 5,10-dihydro-11H-dibenzo[b,e][1,4]-diazepine-11-ones with anticholinergic activity [J]．Pharmazie, 1990, 45(8): 555-559．
[4] SCHNEIDER J．Process for making 11-piperazinodiazepines,oxazepines, thiazepines and azepines: US,3962248 [P]．1976-06-08．
[5] 王福祥, 彭振云．氯氮平的合成[J]．中国医药工业杂志,2013, 44(10): 969-971．
[6] 陈 爽, 陈 悦, 邵 鹏, 等．《中国药典》氯氮平片有关物质检测方法问题探讨[J]．中国药品标准, 2018, 19(1): 12-15．
[7] 范亚刚, 左文松, 秦 立．氯氮平有关物质研究[J]．中国药师, 2014, 17(12): 2159-2161．
[8] GARIPELLI N, REDDY B M, JITHAN A V．Synthesis and evaluation of clozapine and its related compounds [J]．Int J Pharm Sci Nanotechnol, 2010, 2(4): 762-767．
[9] 周 佳, 李方林, 肖海新．氯氮平杂质、该杂质的制备方法及其应用: 中国, 108129347A [P]．2018-06-08．
[10] 罗先金, 修乃云, 阎建民．含卤素取代基中间体的还原工艺[J]．化学工业与工程, 2008, 25(1): 92-94．
[11] 闫福林, 曹 轲, 闫建伟, 等．一种二苯并氮?类化合物及其制备方法与应用: 中国, 108586364A [P]．2017-12-28．
[12] CAPUANO B．8-Chloro-11-[4-(8-chloro-5H-dibenzo[b,e]-[1,4]diazepin-11-yl)piperazino]-5H-dibenzo[b,e][1,4]-diazepine [J]．Molecules, 1999, 4(4): 329-332．
[13] TRYNISZEWSKI M, BUJOK R, CMOCH P, et al．Direct reductive cyclocondensation of the nitro group with the amido group: key role of the iminophosphorane intermediate in the synthesis of 1,4-dibenzodiazepine derivatives [J]．J Org Chem, 2019, 84(4): 2277-2286．
{{custom_fnGroup.title_cn}}
脚注
{{custom_fn.content}}
基金
江苏省重点国别产业技术研发合作项目(BZ2018035)
{{custom_fund}}
PDF(1807 KB)
