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    • 33. 发明专利
    • Pipertdone compound
    • PIPERTDONE化合物
    • JPH11276187A
    • 1999-10-12
    • JP36217698
    • 1998-12-21
    • Eli Lilly & Coイーライ・リリー・アンド・カンパニー
    • BARNETT CHARLES JWILSON THOMAS M
    • C12P7/62C07B53/00C07C69/007C07C69/16C07C69/28C07C237/30C07C247/10C07C247/12C07C255/67C07D211/76C07D211/78C07D295/192C07D471/04C12P7/02C12P13/00
    • C07D471/04C07C69/007C07C247/10C07D211/78Y02P20/55
    • PROBLEM TO BE SOLVED: To obtain either the 6R- or 6S-form of protected 5,10- dideaza-5,6,7,8-tetrahydrofolic acid derivative as an anticancer agent, by acylating a specific diol in an asymmetrically synthetic way and by proceeding the reaction via a new piperidone compound and the like.
      SOLUTION: A dial with E
      2 being Br, Cl, I, carboxyl or the like is first acylated in an asymmetrically synthetic way using swine pancreatic lipase as catalyst to form an intermediate of R-configuration with E
      6 being a 1-3C alkyl. Secondly, the above intermediate is converted into a new intermediate of R-configuration, which, in turn, is further converted into an intermediate of S-configuration with E
      5 being a bis(alkoxycarbonyl)methyl or (alkoxycarbonyl) (cyano)methyl, based on the desired E-group (hydroxy or amino) in the final product; subsequently, the above intermediate is converted, via a new piperidone of S-configuration (E
      3 is a 1-3C alkoxycarbonyl or the like), into a compound of S-configuration of formula II (E
      1 is OH or the like), which is then converted to the aimed medicinal agent of formula III (E
      8 is a carboxyl-protecting group; (n) is 0 or 1) using an L-glutamate.
      COPYRIGHT: (C)1999,JPO
    • 要解决的问题:为了获得6R或6S形式的受保护的5,10-二氮杂-5,6,7,8-四氢叶酸衍生物作为抗癌剂,通过以不对称合成的方式酰化特定的二醇,以及 通过新的哌啶酮化合物等进行反应。 解决方案:首先用不对称合成的方式,用猪胰脂肪酶作为催化剂将具有E 2的Br,Cl,I,羧基等的表盘酰化形成R构型的中间体,其中E 6为1 -3C烷基。 其次,将上述中间体转化为R-构型的新中间体,其又进一步转化为S-构型的中间体,其中E 5为双(烷氧基羰基)甲基或(烷氧基羰基)(氰基) 甲基,基于最终产物中所需的E基(羟基或氨基); 随后,通过S-构型的新的哌啶酮(E 3是1-3C烷氧基羰基等)将上述中间体转化成式II的S-构型的化合物(E 1是OH或 等),然后将其转化为式III的目标药剂(E 8为羧基保护基;(n)为0或1),使用L-谷氨酸。