摘要
富马酸福莫特罗作为特效哮喘治疗药物被临床广泛应用,本文对其合成工艺进行了研究并对重要中间体的合成工艺进行了优化。以4-羟基-3-硝基-苯乙酮为原料,经苄基化、溴代、还原、环氧化四步反应得到重要中间体4-苄氧基-3-硝基苯基环氧乙烷(3)。在制备中间体3时,采用一锅法,简化了反应步骤,同时在反应中加入了缚酸剂碳酸钾,加快了反应速率并提高了收率。此外,以对甲氧基苯基丙酮为原料,经过还原胺化反应一步生成另一个重要中间体1-(4-甲氧基苯基-2-甲基乙基)苄胺(4)。中间体3和4经偶合生成化合物5,在制备5时,采用微波合成,大大缩短了反应时间。中间体5再经硝基还原、甲酰化、去保护、成盐得到富马酸福莫特罗。该工艺操作简单,适合工业化生产,总收率达7. 46%。
Formoterol fumarate is widely used as a therapeutic agent in the treatment of asthma. In this work,the synthesis process for preparation of formoterol fumarate was optimized and improved. 4-Benzyloxy-3-nitrophenyloxirane( Intermediate 3), one of the important intermediates, was obtained from 4-hydroxy-3-nitroacetophenone by benzylation, bromination, reduction and epoxidation reactions. During the preparing of intermediate 3,a one-pot method was adopted to simplify the processing. Potassium carbonate as an acid-binding agent was added in the reaction to accelerate the reaction rate and increase the yield. Another important intermediate,1-( 4-methoxyphenyl-2-methylethyl) benzylamine( Intermediate 4) was prepared from p-methoxyphenylacetone by a one-step reductive amination reaction. 3 and 4 were coupled to obtain intermediate 5 under microwave condition in a considerably short period. After nitro reduction,formylation,deprotection and salification,formoterol fumarate was obtained. This optimized method is simple and suitable for industrial production of formoterol fumarate with total yield of 7. 46 %.
作者
吕海军
靳根根
刘磊
王子卉
卢世贤
王婷婷
Lv Haijun;Jin Gengen;Liu Lei;Wang Zihui;Lu Shixian;Wang Tingting(Hebei Research Center of Pharmaceutical and Chemical Engineering,College of Chemical and Pharmaceutical Engineering,Hebei University of Science and Technology,Shijiazhuang 050018;Hebei Key Laboratory of Molecular Chemistry for Drug,Shijiazhuang 050018)
出处
《化学通报》
CAS
CSCD
北大核心
2019年第2期133-137,97,共6页
Chemistry
基金
河北省优秀专家出国培训项目
河北省自然科学基金项目(B2014208121)
河北省教育厅项目(Z2013001)
河北科技大学五大平台开放基金(2015PT37)资助
关键词
富马酸福莫特罗
微波合成
催化加氢
工艺优化
还原反应
Formoterol fumarate
Microwave synthesis
Catalytic hydrogenation
Improved synthesis
Reduction reaction
