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[1]吴丕业,赖小燕,汤清华,等.磷酸奥司他韦中相关杂质的合成[J].武汉工程大学学报,2014,(10):13-16.[doi:103969/jissn167428692014010003]
　WU Pi ye,LAI Xiao yan,TANG Qing hua,et al.Synthesis of related impurities in Oseltamivir phosphate[J].Journal of Wuhan Institute of Technology,2014,(10):13-16.[doi:103969/jissn167428692014010003]
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磷酸奥司他韦中相关杂质的合成(/HTML)
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《武汉工程大学学报》[ISSN:1674-2869/CN:42-1779/TQ]

卷:
期数:
2014年10期
页码:
13-16
栏目:
化学与化学工程
出版日期:
2014-10-30

文章信息/Info

Title:
Synthesis of related impurities in Oseltamivir phosphate
文章编号:
16742869(2014)010001304
作者:
吴丕业1;  赖小燕2 ; 汤清华2 ; 戴鹏2 ; 查高峰2*
1．武汉工程大学材料科学与工程学院，湖北 武汉430200；2武汉理工大学化学化工与生命科学学院，湖北武汉 430070
Author(s):
WU Piye1; LAI Xiaoyan2; TANG Qinghua2; DAI Peng2; ZHA Gaofeng2
1.Materials Science and Engineering, Wuhan Institute of Technology Wuhan 430200,China;2.School of Chemistry , Chemical Engineering and Life Science,WuhanUniversity of Technology,Wuhan 430070,China
关键词:
磷酸奥司他韦; 杂质合成; 结构表征
Keywords:
Oseltamivir phosphate;  impurity synthesis;  structure identification
分类号:
TQ460.6
DOI:
103969/jissn167428692014010003
文献标志码:
A
摘要:
磷酸奥司他韦作为选择性的流感病毒神经氨酸酶抑制剂，是治疗禽流感最有效的药物.美国药典38 版收载了磷酸奥司他韦中的两个杂质.杂质 (3R，4R，5S)3(1乙基丙氧基)4乙酰胺5氨基1环己烯1羧酸(A)是原料药在精制和存储过程中发生微量水解产生的.对合成条件进行了优化，采用了常规分离手段得到了杂质A ,合成收率达到86.6%.杂质3羟基4乙酰氨基苯甲酸乙酯(B)是美国药典38 版所载磷酸奥司他韦中的另一个杂质，目前没有合成方面的报道.设计了杂质B的合成路线，以3羟基4氨基苯甲酸为原料，用乙酸酐作为酰化试剂对原料进行乙酰化，然后加入氢氧化钠和盐酸，调节pH，发生水解，最后用溴乙烷作为烃化剂得到了目标产物，合成收率达到52.1%.整条合成路线操作简单、反应条件温和、没有环境污染，对磷酸奥司他韦的生产检验和贮存均具有现实意义.
Abstract:
Oseltamivir phosphate as a potent selective neuraminidase inhibitor is the most effective treatment of avian influenza now. There are two related substances of Oseltamivir phosphate recorded in USP38. Impurity (3R,4R,5S)4acetamido5amino3 (1ethylpropoxy) 1cyclohexene1 carboxylic acid（A） is produced during the refining and storage of the raw material medicine. We optimized the synthesis process of A and got it with a 86.6% yield by conventional separation methods .Impurity 4Acetylamino 3hydroxybenzoic acid ethyl ester（B）is the other related substance recorded, and there is no report about synthetic route of it so far. After exploring the references related to B, we proposed a synthesis process, using 3 hydroxy 4 amino benzoic acid as raw material and acetic anhydride as acylation reagent, then adding sodium hydroxide and hydrochloric acid to regulate pH, sequently hydrolysis occurring. Finally we got B with a 52.1% yield by bromoethane as alkylating agent .The entire synthetic route has the advantages of simple operation, mild reaction condition and no environmental pollution, which has practical significance for the production, inspection and storage of Oseltamivir phosphate.

参考文献/References:

［1］HAYDEN F G，TREANOR J J，FRITZ R S . Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza randomized controlled trials for prevention and treatment［J］. JAMA，1999，282: 12401246.［2］TREANOR J J，HAYDEN F G，VROOMAN P S. Efficacy and safety of the oral neuraminidase inhibitor Oseltamivir in treating acute influenza［J］. JAMA，2000，283: 10161024.［3］王孟昭,孙武装,王亚梅，等. 磷酸奥司他韦治疗流行性感冒的临床疗效和安全性研究［J］.中华传染病杂志,2003,21:114117. WANG Mengzhao, SUN Wuzhuang, WANG Yamei, et al. Clinical efficacy and safety study on Oseltamivir phosphate for influenza［J］. Chinese Journal of Infectious Diseases, 2003, 21:114117.［4］陈晓红，祝亚非，关山越，等. 抗流感药物奥司他韦的结构确证［J］.广州化工，2006(6)：3435.CHEN Xiaohong, ZHU Yafei, GUAN Shanyue, et al. The structure confirmation of the anti flu drug  Oseltamivir［J］. Guangzhou Chemical Industry, 2006(6):3435.［5］FUJIKO K, TAKUYA A, ZHANG M R. Radiosyntheses of two positron emission tomography probes:［11C］Oseltamivir and its active metabolite ［11C］Ro 640802［J］.Bioorganic & Medicinal Chemistry Letters,2008,18: 12601263.［6］BISCHOFBERGER, NORBERT W. Compounds containing sixmembered rings processes for their preparation and their use as medicaments:WO,9914185［P］.19990325.［7］LUO M, KONISHI W J. Inhibitors of influenza virus neuraminidase and methods of making and using the same:WO,5453533［P］.19951026. ［8］LUO M, BIRMINGHAM A. Methods of inhibition bacterial sialidase：US, 5985859［P］. 19990607. ［9］GUO W, LI J F, FAN N J, et al. A simple and effective method for chemisetiove esterification of phenolicacids ［J］.Synthetic Conmunications,2005 , 35:145152.

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备注/Memo

备注/Memo:
收稿日期：20140917作者简介：吴丕业（1987），男，湖北孝感人，硕士.研究方向：不对称合成和药物工艺.﹡通信联系人
更新日期/Last Update: 2014-11-20