头孢拉定合成工艺的优化
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摘要
7-ADCA与四甲基胍反应形成胍盐,再与苯酐氨酸邓钠盐的混合酸酐缩合,经水解得到头孢拉定,收率>94%。此工艺优化了反应条件,找到了可行的检测方法来监控反应终点,省去了炭脱色步骤,采用抽除二氯甲烷的方法稳定晶型,还可以从母液中回收复盐并套用,易于工业化生产。
The cefradine is synthesized by hydrolysis from the condensation products of guanidine salt, which is the combination of 7-Aminodesacetoxycephalosporanic acid with an overall yield of more than 94%. It is easy to realize industrial mass production by optimizing reaction conditions and finding a feasible detection method to monitor the ending point of the reactions. It is also feasible to take several other measures to realize industrial mass production, including eliminating carbon decoloring process, adopting the method of pumping methylene chloride to stablize crystal structure and recycling double salts to reuse.
The cefradine is synthesized by hydrolysis from the condensation products of guanidine salt, which is the combination of 7-Aminodesacetoxycephalosporanic acid with an overall yield of more than 94%. It is easy to realize industrial mass production by optimizing reaction conditions and finding a feasible detection method to monitor the ending point of the reactions. It is also feasible to take several other measures to realize industrial mass production, including eliminating carbon decoloring process, adopting the method of pumping methylene chloride to stablize crystal structure and recycling double salts to reuse.
引文
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[2]陈新谦,金有豫,汤光.新编药物学[M].17版.北京:人民卫生出版社,2011:49-50.
[3]中国药物大全编辑委员会.中国药物大全(西药卷)[M].第2版.北京:人民卫生出版社,1998:34.
[4]中国药典编委.中国药典[M].北京:化学工业出版社,2015:267.
[5]中国药物大全编辑委员会.中国药物大全(西药卷)[M].第2版.北京:人民卫生出版社,1998:347.
[6]Takahashi T,Yamazaki Y,Kato K.et al.Enzymatic synthesis of cephalosporins[J].Am Chem Soc,1972,94(11):4036-4037.
[7]Schreiber FG,Park HJ.Method for the production of 3-methyl cephem derivative:US,5034522[P].1991-07-23.
[8]吴薇萍.头孢拉定生产工艺[J].化工技术经济,2002,6(1):48-51.
[9]Joseph ED,Harold EA,Bach G.et al.A new class of semisynthetic penicillins and cephalosporins derived from D-2-(1,4-cy-clohexa-dienyl)glycine[J].Med Chem,1971,14(2):105-108.
[10]Schreiber FG.Method for the production of 3-methyl caphem derivative:US,5034522[P].1991-07-23.
[11]Gerardus J.Kemperman,Jie Z,et al.Synthesis of cephalosporin-type antibiotics by coupling of theirβ-lactam nucleus and racemic amino acid side chains using a clathration-induced asymmetric transformation[J].Eur JOrg Chem,2001,1817-1820.
[12]Gerardner J P.Improved process for preparing cephalosporins:EP,0567323[P].1993-10-27.
[13]Palomo-Coll A,Cabre-Castellvi J,Palomo-Coll AL.Salts of amino-beta-lactamic acids and process for the preparation thereof:US,4659814[P].1987-04-21.