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    Bicyclic tetrahydroxypyrrolizidine
    7.
    发明授权
    Bicyclic tetrahydroxypyrrolizidine 失效
    双环四羟基吡咯烷啶

    公开(公告)号：US5068243A

    公开(公告)日：1991-11-26

    申请号：US564009

    申请日：1990-08-07

    申请人： George W. J. Fleet

    发明人： George W. J. Fleet

    IPC分类号： C07D317/10 ,  C07D487/04 ,  C07D491/04 ,  C07D491/22 ,  C07D493/04 ,  C07F7/18

    CPC分类号： C07D487/04 ,  C07D317/10 ,  C07D491/04 ,  C07D493/04 ,  C07F7/1856 ,  Y02P20/55

    摘要： Novel bicyclic tetrahydroxylated pyrrolizidines are disclosed which are inhibitors of glycosidase enzymes. A preferred inhibitor is (1S,2R,6R,7S)-1,2,6,7-tetrahydroxypyrrolizidine. It is synthesized from D-glycero-D-talo-heptono-1,4-lactone and utilizes the novel intermediate compounds, 7-O-tert-butyldiphenylsilyl-2,3:5,6-di-O-isopropylidene-D- glycero-D-talo-heptono-1,4-lactone and (1S,2R,6R,7S)-1,2:6,7-di-O-isopropylidene-1,2,6,7-tetrahydroxypyrrolizidine, as follows:a) reacting D-glycero-D-talo-heptono-1,4-lactone with 2,2-dimethoxypropane to provide a fully protected lactone,b) selectively removing the acetonide group at C-6,7 to give a C-2,3 protected heptonolactone,c) reacting the C-2,3 protected lactone with a silyl blocking agent to protect the primary hydroxyl group and give a C-2,3,7 protected lactone,d) reacting the protected lactone with 2,2-dimethoxypropane to provide a fully protected lactone,e) reacting the fully protected lactone with fluoride ion to cleave at C7 and thereby provide access to nitrogen in the ring and give a primary alcohol,f) esterifying the primary alcohol with triflic anhydride to afford a triflate,g) reacting the triflate with azide ion to give an azidolactone,h) reducing the azidolactone to give an azidodiol,i) reacting the azidodiol with methanesulfonyl chloride to provide an axidodimesylate,j) catalytically hydrogenating the azidodimesylate in ethanol at ambient temperature,k) heating the resulting product in ethanol in the presence of sodium acetate to give a tetracyclic pyrrolizidine, andl) removing the acetonide protecting groups of the tetracyclic pyrrolizidine by acid hydrolysis to give (1S,2R,6R,7S)-1,2,6,7-tetrahydroxypyrrolizidine.

    摘要翻译： 公开了作为糖苷酶的抑制剂的新型二环四羟甲基化的吡咯烷子。 优选的抑制剂是（1S，2R，6R，7S）-1,2,6,7-四羟基吡咯烷啶。 由D-甘油基-D-庚内酰-1,4-内酯合成并利用新的中间体化合物7-O-叔丁基二苯基甲硅烷基-2,3：5,6-二-O-异亚丙基-D- 甘油基-D-庚内酰-1,4-内酯和（1S，2R，6R，7S）-1,2：6,7-二-O-异亚丙基-1,2,6,7-四羟基吡咯烷脒，为 如下：a）使D-甘油基-D-庚内酰-1,4-内酯与2,2-二甲氧基丙烷反应，得到完全保护的内酯，b）选择性地除去C-6,7上的丙酮化合物，得到C -2,3保护的庚内酯，c）使C-2,3保护的内酯与甲硅烷基封闭剂反应以保护伯羟基并得到C-2,3,7保护的内酯，d）使保护的内酯与2 的2-二甲氧基丙烷，以提供完全保护的内酯，e）使完全保护的内酯与氟离子反应以在C7处裂解，从而提供进入环中的氮并获得伯醇，f）用三氟甲磺酸酯化伯醇 得到三氟甲磺酸酯，g）使三氟甲磺酸酯反应 用叠氮化物离子，得到叠氮内酯，h）还原叠氮内酯得到叠氮基二醇，i）叠氮二醇与甲磺酰氯反应，得到二硫代二季铵盐，j）在环境温度下催化氢化叠氮二季戊酸酯在乙醇中，k）加热得到的产物 在乙酸乙酯中，在乙酸钠存在下反应，得到四环吡咯烷啶，并且l）通过酸水解除去四环吡咯烷子酮的丙酮化合物保护基，得到（1S，2R，6R，7S）-1,2,6,7-四羟基吡咯烷 。