氟马西尼的合成工艺改进
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摘要
对氟马西尼的合成工艺进行研究.以2-氨基-5-氟苯甲酸为起始原料,经过缩合、闭环等一系列步骤得到关键桥环中间体6-氟靛红酸酐(3)和7-氟-3,4二氢-4-甲基-2H-1,4苯并二氮杂卓-2,5(1H)-二酮(4),通过3步反应得到氟马西尼.结果:大范围改进现有氟马西尼的制备工艺,工艺总收率为21. 6%,纯度大于99. 9%.结论:该工艺操作简便,稳定性好,收率高,适用于工业化生产.
The objective is to improve the synthesis of flumazenil. The methods are: starting from 2-Amino-5-Fluor benzoic acid,the key intermediate 6-Fluoroisatoic? anhydride( 3) and 7-Fluoro-3,4-dihydro-4-methyl-1 H-1,4-Benzodiazepine-2,5-dione( 4) was obtained via such procedures as condensation reaction and ring closure reaction. Through 3-step reaction,flumazenil was prepared. The results show that the existing preparation process of flumazenil was modified greatly and the total yield of the whole process reached21.6%,and its purity was more than 99. 9%. The conclusion is that this improved process is simple,stable,productive and suitable for the industrial production.
The objective is to improve the synthesis of flumazenil. The methods are: starting from 2-Amino-5-Fluor benzoic acid,the key intermediate 6-Fluoroisatoic? anhydride( 3) and 7-Fluoro-3,4-dihydro-4-methyl-1 H-1,4-Benzodiazepine-2,5-dione( 4) was obtained via such procedures as condensation reaction and ring closure reaction. Through 3-step reaction,flumazenil was prepared. The results show that the existing preparation process of flumazenil was modified greatly and the total yield of the whole process reached21.6%,and its purity was more than 99. 9%. The conclusion is that this improved process is simple,stable,productive and suitable for the industrial production.
引文
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[13]Broggini G,Molteni G,Terraneo A,et al.A facile synthesis of flumazenil analogues[J].Tetrahedron,1999,55(51):14803-14806.
[14]Cheng Z G,Li-Wei L I,Xue-Gong M A,et al.Separation,synthesis and identification of the main impurity of flumazenil[J].Journal of China Pharmaceutical University,2007,38(2):184-185.
[15]Rogers-Evans M,Spurr P,Hennig M.The isolation and use of a benzodiazepine iminochloride for the efficient construction of flumazenil[J].Tetrahedron Letters,2003,44(11):2425-2428.
[2]Broggini G,Molteni G,Terraneo A,et al.A facile synthesis of flumazenil analogues[J].Tetrahedron,1999,55(51):14803-14806.
[3]Ondo W G,Silay Y S.Intravenous flumazenil for Parkinson's disease:a single dose,double blind,placebo controlled,cross-over trial.[J].Movement Disorders,2006,21(10):1614-1617.
[4]Sivilotti M L.Flumazenil,naloxone and the'coma cocktail'[J].Br J Clin Pharmacol,2016,81(3):428-436.
[5]Templeton L,Barker A,Wesnes K,et al.A double-blind,placebo-controlled single dose trial of intravenous flumazenil in Alzheimer's disease[J].Human Psychopharmacology Clinical&Experimental,2015,14(4):239-245.
[6]Pajoumand A,Hassanianmoghaddam H,Zamani N.Response to:Adverse Events Associated with Flumazenil Treatment for the Management of Suspected Benzodiazepine Intoxication-A Systematic Review with Meta-Analyses of Randomized Trials.[J].Basic&Clinical Pharmacology&Toxicology,2016,118(5):323.
[7]彭震云,祁超.氟马西尼的合成[J].中国医药工业杂志,1994,(1):3-4.
[8]F,Watjen,R,Baker,M,Engelstoff,et al.Novel benzodiazepine receptor partial agonists:oxadiazolylimidazobenzodiazepines[J].Journal of medicinal chemistry,1989,32(10):2282-91.
[9]徐金峰,许煦,沈永嘉.靛红酸酐的合成与应用[J].化工科技市场,2003,(1):6-9.
[10]Cleij M C,Clark J C,Baron J C,et al.Rapid preparation of[11C]flumazenil:captive solvent synthesis combined with purification by analytical sized columns[J].Journal of Labelled Compounds&Radiopharmaceuticals,2007,50(1):19-24.
[11]Pan L,Wen X,Sha Y,et al.Synthesis of impurity B of Flumazenil[J].中国药学(英文版),2015,24(2):133-136.
[12]Donohue S R,Dannals R F.A concise and efficient synthesis of flumazenil and its precursor for radiolabeling with fluorine-18[J].Tetrahedron Letters,2009,50(52):7271-7273.
[13]Broggini G,Molteni G,Terraneo A,et al.A facile synthesis of flumazenil analogues[J].Tetrahedron,1999,55(51):14803-14806.
[14]Cheng Z G,Li-Wei L I,Xue-Gong M A,et al.Separation,synthesis and identification of the main impurity of flumazenil[J].Journal of China Pharmaceutical University,2007,38(2):184-185.
[15]Rogers-Evans M,Spurr P,Hennig M.The isolation and use of a benzodiazepine iminochloride for the efficient construction of flumazenil[J].Tetrahedron Letters,2003,44(11):2425-2428.