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2. 发明申请

WO2009023191A2 AN IMPROVED PROCESS FOR THE PREPARATION OF CLARITHROMYCIN 审中-公开
标题翻译：改进氯雷他定的制备方法
公开(公告)号：WO2009023191A2
公开(公告)日：2009-02-19
申请号：PCT/US2008/009633
申请日：2008-08-11
申请人： TEVA PHARMACEUTICAL INDUSTRIES LTD. , TEVA PHARMACEUTICALS USA, INC. , KANSAL, Vinod, Kumar , MISTRY, Dhirenkumar, N. , GANDHI, Mitesh , PATEL, Rakesh
发明人： KANSAL, Vinod, Kumar , MISTRY, Dhirenkumar, N. , GANDHI, Mitesh , PATEL, Rakesh
CPC分类号： C07H17/08 , C07H1/00
摘要： The present invention includes a process involving a one-pot reaction for preparing erythromycin 9-oxime salt comprising: (a) reacting erythromycin thiocyanate with an ammonium source to obtain erythromycin free base; (b) oximating the C-9 carbonyl of the erythromycin free base by reacting the erythromycin free base with triethylamine and hydroxyl amine hydrochloride to form erythromycin oxime; and (c) reacting the erythromycin oxime obtained in step (b) with an ammonium source to obtain the erythromycin 9-oxime salt. The present invention is also drawn to a one-pot reaction for preparing clarithromycin starting with the one-pot reaction for preparing erythromycin 9-oxime salt, further comprising after step (c): (d) silylating the hydroxy groups at the oxime group, and the 2" and 4> λ positions of the erythromycin 9-oxime salt to obtain a silylated derivative; (e) methylating the hydroxy group at the 6 position of the silylated derivative using at least one methylating agent in the presence of at least one inorganic base to obtain SMOP, wherein SMOP is 6-O-methyl-2', 4"-bis(trimethylsilyl)- erythromycin A 9-O-(2-methoxyprop-2-yl)oxime; and (f) converting the SMOP into clarithromycin using at least one deoximating agent in the presence of aqueous ethanol.
摘要翻译：本发明包括一种用于制备红霉素9-肟盐的一锅反应的方法，包括：（a）将红霉素硫氰酸盐与铵源反应以获得游离红霉素的碱; （b）通过使红霉素游离碱与三乙胺和羟胺盐酸盐反应，使红霉素游离碱的C-9羰基肟化，形成红霉素肟; 和（c）使步骤（b）中获得的红霉素肟与铵源反应，得到红霉素9-肟盐。本发明还涉及从用于制备红霉素9-肟盐的一锅反应开始制备克拉霉素的一锅反应，还包括在步骤（c）之后：（d）使肟基上的羟基甲硅烷基化，和红霉素9-肟盐的2“和4”→位置，以获得甲硅烷基化衍生物;（e）使用至少一种甲基化试剂在甲硅烷基化衍生物的6位甲基化存在下，无机碱以获得SMOP，其中SMOP为6-O-甲基-2'，4“ - 双（三甲基甲硅烷基） - 红霉素A 9-O-（2-甲氧基丙-2-基）肟; 和（f）在含水乙醇的存在下使用至少一种去肟剂将SMOP转化成克拉霉素。

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