氟比洛芬酯的合成

齐鲁药事●Qilu Pharmaceutial Affairs 2007 VoL 26 .No.9●557●Candidate Journal of Medicinal Chemistry,1992 ,35(6) :1049.toprazole and intrmediates therefore. W002/28852 Al, 2001 -[2]Sannders, D, Lawrise K. w. M The syathesis of pantoprazole-10-01. .An H+/ K+ ATP inhibitor. J Label Compd Radiopharm 1992,[5] Alberto Palomo Coll, Deborah Palomo, et al. Proces for the31 ,5,409.preparation ol pantopratole and intermediaterthere-[3]BEKHAZI, Michel et al Synthesis of Omeprarole- type pyridinefore. U5200/0049044 A1.2004-03-11.derivatives and Intermediates thereol. W097/29103. 1997- 02 -[6]Brennen J P, Turoer A. I. Chemical process for cthe production05.of sulphinyl derivtives by oxidation of the correspondiny co-de-[4]Palomo Coll, Alberto et al. A process for the preparation of pan-rivatives with perborates. W09947514.氟比洛芬酯的合成，国大亮,孙晋瑞' ,朱晓薇(天津中医药大学,天津300193;1. 山东省医药工业研究所,山东济南250100)摘要:目的考察氟比洛芬酯的合成工艺。 方法将四氢荼与液追反应，生成的澳化氢气体溶于无水乙酸,将此溶液与 .醋酸乙烯酯反应。生咸乙酸- -1- 涣乙酯，氟比洛芬与乙酸-1-涣乙酯缩合,生成氟比洛芬酯。结果及结论此合成工艺原料易得、操作简便,适于氟比洛芬酯的开发与生产。关键词:氟比洛芬酯镇痛合成中團分类号:T0460.31文献标识码:A 文章编号 :1672 - 7738{2007)09- 0557 -02Syntbesis of Flurbiprofen AxetilGUO Da-liang,SUN Jin-rui' ,ZHU Xiao wei(Tianjin University of Traditional Chinese Medicine, Tianjin.300193; 1. ShandongInstitute of Pharmaceutical Industry, Ji' nan,250100)ABSTRACT :OBJECTIVE To synthesice Flurbiprofen Axetil. METHODS Tetrahydronaphthalene was treated with bro-mine to produce hydrogen bromide. The hydrogen bromide was dissolved in anhydrous acetie acid, and this solution was reactedwith vinyl acetate to prepare 1- (acetoxy) ethyl bromide. Flurbiprofen Axetil was synthesized by esterfication of Flurbiprofenwith 1- (acetoxy) ethyI bromide. RESULIS and CONCLUSION Raw materiels are casily obtained. Synthesis route is simpleand suitable for development and manufacture.KEY WORDS:Flurbiprofen Axetil, analgesicsisynthesis氟比洛芬酯是非甾体抗炎药氟比洛芬的酯类前体药物,2实验部分采用静脉乳剂剂型,以卵磷酯包封成脂微球.镇痛效果迅速、2.1 无水乙酸的制备叨取冰醋酸 120mL,倒人干燥挠杯持久,对癌症性疼痛和术后疼痛临床疗效明显“1。本品由日中,冰水浴冷却,使冰醋酸冻结.倾倒到布氏滤斗中,抽滤掉本科研制药株式会社和绿十字制药株式会社联合开发,国内未冻结的液体,将剩余的固体转入250mL带有氯化钙干燥目前尚无氟比洛芬酯合成工艺的报道,我们查阅了有关文器的四颈瓶中,加入1. 5g五氧化二磷回流2b,常压蒸馏,收献,总结并设计了氟比袼芬酯的制备工艺路线。集117~118C的馏分,制得无水乙酸103mL。1合成路线2.2澳化氢-无水乙酸(3)的制备的 向带 有氯化钙干燥器的四颈瓶中加入四氢素(2) 40 g.铁粉a. 5g,冷水浴冷却.保持内温0~5C .搅拌下滴加液溴(104g) ,控制滴速,生成的气体经浓藐酸干燥后导人到96mL无水乙酸中,未吸收的尾气用浓氢氧化钾溶液中国煤化工达到145g为止(氢溴酸的浓鞍(3)。2.3乙YH. CNMHG上达漠化年一无水乙酸(3)溶液冷却,保持内温0~5C,在搅拌下慢慢加入醋酸乙烯酯(4>)43g(0.5mol) ,加完后继续搅拌1b,加入200mL●558●齐春药事Qiu Phamacuia Affairs 2007 Vol. 26.Na.9二氯甲烷稀释,将反应液倒入到300mL冰水混合物中,分出重要。乙酸-1-溴丙酯.乙酸-1-氯乙酯和亚乙基二乙酸有机层,蒸馏水洗涤(2X 200mL),分取二氯甲烷层,无水硫酯中的离去基团分别为Br.Cl和0C0CH,这三个基团的碱酸钠干燥,减压浓缩除去溶剂,将剩余物臧压蒸馏,收集122性顺序为Br>CI>0C0CH ,Br原子最易离去,所以乙酸一~125C/738mmHg馏分,得乙酸一1- 溴乙酯(5)无色液体1-溴丙酯的反应活性最佳。5lg,收率61%。4结论2. 4氟比洛芬酯(1)的合成的向 250mL四颈瓶加入氟比洛本文将四氢荼与液溴反应,生成的溴化氢气体溶于无水芬12. 2g(0.05mol) ,碳酸氢铆8g,搅拌下加人丙酮110mL,乙酸,将此榕液与醋酸乙烯酯反应,生成乙酸一1一溴乙酯，滴加乙酸-1-溴乙酯(5)13.4g(0. 08mol),室温反应5h,加氟比路芬与乙酸- -1-溴乙酯缩合,生成氟比洛芬酯。反应入200mL乙酸乙酯稀释,将反应液转入分液漏斗中,用3%条件温和,每步收率良好,工艺稳定.碳酸钠詵涤(2X 200mL),分取有机层,无水硫酸钠干燥,过参考文献滤除去干燥剂，加人活性炭回流脱色20min,过滤除去活性[1]Liposomal Flurbiprofen Axtil. Drugs of the Future 1992,17(9),炎,将滤液常压浓缩至无液体馏出,将剩余物减压蒸馏，收集788~790.173~175C /0. 8mmHg馏分,得无色液体13. 8g,氟比洛芬[2]李述文,范如霖。实用有机化学手册。上学科学技术出版社.1981年12月第1版,552.酯收率83.7%.[3]李长寿,尹鲁生,范俊源,等。漠化氬- -冰乙酸制备方法的改进.3讨论化学试剂,992,14(3)188此缩合反应的底物除乙酸-1-溴丙酯外.还可以使用[4]Hong You Wha, Shin Yaung Chul. A proces for the preparaion乙酸-1-氯乙酯和亚乙基二乙酸酯。反应历程为氟比洛芬of 1- bromnoethylacethyl acetate. WO9855445.分子中羧基上的一0H进攻此三者连有卤原子或乙酰氧基[5]Mimura Misuo,Uchida Katsuhiro, Production of 1- actoxethr的碳原子,而卤原子或乙酰氧基离去.属于Snz历程的亲核yI- 2- (2iluoro- 4- biphenylyl)propionate. . JP1211550.取代反应,所以离去基团的碱性对反应速度和反应条件至关医药中间体茄尼醇的体外抗菌活性研究陈保汉，张君'，余荷秀,胡庆利”(浙江永宁制药厂，浙江黄岩318020; 1杭州奥默医药技术有限公司。浙江杭州30011;2临邑县医药公司,山东临邑251500)摘要:目的研究从废弃的烟草叶申提取纯化后的医药中间体茄尼醇,对莘兰阴性和革 兰阳性菌的体外抗菌活性。方法采用琼脂扩歉法和两倍稀释法考察茄尼醇对多种标准菌株和临床分离菌株的抗菌活性。结果与绪论茄尼醇对被测菌株中的革兰阴性菌(大肠埃希氏菌和铜缥假单胞酋)和革兰阳性菌(金黄色葡萄球菌和苹分枝杆菌)具有显著的抗菌活性,而对枯草杆菌和环状芽孢杆蓠活性较弱。关键词:茄尼醇抗菌活性 烟草叶(茄科烟草属)中图分类号:R965.2文献标识码:A 文章编号 :1672- 7738(2007)09 - 0558- 02In Vitro Study on the Antibacterial Activities of a Medicinal Intermediate , SolanesolCHEN Bao-han, ZHANG Jun' , YU He xiu, HU Qingli(Zhejiang Yongning Pharmaceutical Factory, Huangyan 318020;L. Hangzhou Aome Medical Teechnology CompanyLimited, Hangzhou 310011;2. linyi county medicine company,Linyi 25150)ABSTRACT:OBJECTIVE Solanesol, purified from abandoned tobacco leaf, is an important medicinal intermediate. Ouraim of this study was to observe the antibacterial effect of solanesol against the gram- negative and gram - positive bacteri-a. METHODS Two classic methods, broth dilution and two- fold dilution. were employed to examine the activities of solane-sol on several standard strains and those collected from clinical patientclanesol demonstratedsignificant antibacterial activities ageinst all of the gram- negative (Esc中国煤化工。uginosa) and most ofthe gram- positive bacteria (Staphylococcus aureus and Mycobacterium:YHCNMHGteswereshownforthe two strains , Baillus subilis and Bacillus circulans.KEY WORDS:Solanesol,antibacterial activity ; tobacco leaves (Nicotiana tabacum L)