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    • 7. 发明申请
    • A PROCESS FOR THE SYNTHESIS OF RAMELTEON AND ITS INTERMEDIATES
    • 一个合成中间体及其中间体的方法
    • WO2009056993A3
    • 2009-07-02
    • PCT/IB2008003894
    • 2008-11-03
    • TEVA PHARMATEVA PHARMAKANSAL VINOD KUMARMISTRY DHIRENKUMAR NVASOYA SNJAY LPATEL RAKESHJADAV ARPAN M
    • KANSAL VINOD KUMARMISTRY DHIRENKUMAR NVASOYA SNJAY LPATEL RAKESHJADAV ARPAN M
    • C07D307/93
    • C07D307/93
    • A process f or the preparation of ramelteon including the steps a) - c) a intermediates useful in the process. The process suitable for industrial provides increased yield and/or greater purity with f ewer process steps. a) hydrolysis of a compound of formula 11 to produce the compound of formula III : wherein R1 is selected from the group consisting of C1 to C4 (or C1 to C6) straight or branched alkyl, b) condensation of the compound of formula Hl with a chiral compound to yield a compound of formula IV: wherein R2, R3, R4 and R5 can be hydrogen, C1-C6 alkyl (preferably C1-C-4 alkyl), C6-C12 aryl or arylalkyl (wherein the alkyl group contains 1-4 carbon atoms, and the aryl group contains 6-12 carbon atoms), c) hydrogenarion of the alkene bond of the compound of formula IV to yield a compound of formula VIl: wherein R2, R3, R4 and R5, can be hydrogen, C1-C6 alkyl (preferably C1-C4 alkyl), C6-C12 aryl, or arylalkyl (wherein the alkyl group contains 1-4 carbon atoms, and the aryl group contains 6-12 carbon atoms).
    • 方法f或制备拉面包括步骤a)c)在该方法中有用的中间体。 适用于工业的工艺通过加工步骤提高了产量和/或更高的纯度。 a)水解式11的化合物以产生式III化合物:其中R 1选自C 1至C 4(或C 1至C 6)直链或支链烷基,b)式II化合物与 产生式IV化合物的手性化合物:其中R 2,R 3,R 4和R 5可以是氢,C 1 -C 6烷基(优选C 1 -C 4烷基),C 6 -C 12芳基或芳烷基(其中烷基含有1 -4个碳原子,并且芳基含有6-12个碳原子),c)式IV化合物的烯键的氢键化,得到式VI1化合物:其中R2,R3,R4和R5可以是氢 ,C 1 -C 6烷基(优选C 1 -C 4烷基),C 6 -C 12芳基或芳烷基(其中烷基含有1-4个碳原子,芳基含有6-12个碳原子)。
    • 8. 发明申请
    • AN IMPROVED PROCESS FOR THE PREPARATION OF CLARITHROMYCIN
    • 一种改进的克拉霉素制备方法
    • WO2009023191A3
    • 2009-04-23
    • PCT/US2008009633
    • 2008-08-11
    • TEVA PHARMATEVA PHARMAKANSAL VINOD KUMARMISTRY DHIRENKUMAR NGANDHI MITESHPATEL RAKESH
    • KANSAL VINOD KUMARMISTRY DHIRENKUMAR NGANDHI MITESHPATEL RAKESH
    • C07H1/00A61K31/7048A61P31/04C07H17/08
    • C07H17/08C07H1/00
    • 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> ? 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.
    • 本发明包括涉及制备红霉素9-肟盐的一锅法反应的方法,其包括:(a)使硫氰酸红霉素与铵源反应以获得红霉素游离碱; (b)通过使红霉素游离碱与三乙胺和羟胺盐酸盐反应形成红霉素肟来肟化红霉素游离碱的C-9羰基; 和(c)使步骤(b)中得到的红霉素肟与铵源反应得到红霉素9-肟盐。 本发明还涉及用制备红霉素9-肟盐的一锅法反应制备克拉霉素的一锅法反应,在步骤(c)之后进一步包括:(d)将肟基上的羟基甲硅烷基化, 和红霉素9-肟盐的2'和4''位以获得甲硅烷基化衍生物;(e)使用至少一种甲基化试剂,在至少一种存在下甲基化甲硅烷基化衍生物的6位上的羟基 SMOP是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)使用至少一种脱氧剂在含水乙醇存在下将SMOP转化为克拉霉素。