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    NOVEL CRYSTALLINE CILASTATIN AMMONIUM SALTS AND PREPARATION METHOD THEREOF
    8.
    发明申请
    NOVEL CRYSTALLINE CILASTATIN AMMONIUM SALTS AND PREPARATION METHOD THEREOF 审中-公开
    新型结晶氯化酪氨酸铵盐及其制备方法

    公开(公告)号：WO2010005175A3

    公开(公告)日：2010-03-11

    申请号：PCT/KR2009003046

    申请日：2009-06-08

    申请人： HIGH TECH PHARM CO LTD ,  KIM YOUNG HOON ,  KIM JEONG SOO ,  GOO YOUNG SAM

    发明人： KIM YOUNG HOON ,  KIM JEONG SOO ,  GOO YOUNG SAM

    IPC分类号： C07C231/24

    CPC分类号： C07C323/59 ,  C07C319/14 ,  C07C2601/02

    摘要： The present invention relates to a preparation method for novel crystalline cilastatin ammonium salts of chemical formula (1) which is used in the preparation of cilastatin sodium salts with high purity and the crystalline cilastatin ammonium salts prepared thereby. More specifically, the preparation method for crystalline cilastatin ammonium salts of the following chemical formula (1) comprises: (i) reacting, in (a) the solution of sodium hydroxide or potassium hydroxide, (b) (Z)-7-chloro-[[[(S)-2,2-dimethylcyclopropyl]carbonyl]amino]-2-heptanoic acid of chemical formula (2) or its salts with (c) cilastatin of chemical formula (3) or its salts, in nitrogen gas at 50~80? for 3-15 hours so that an equivalent ratio of (a):(b):(c) is 1:1:1~1:3:5 to prepare cilastatin, wherein water, at least one organic solvent, or a mixture of water and the organic solvent are used as a solvent, and sodium bromide, potassium bromide, or sodium iodide are used as a catalyst, wherein the organic solvent is selected from the group consisting of C1-C4 alcohol, acetonitrile, and acetone, which can be mixed with water; (ii) controlling the pH of cilastatin prepared in step (i) to 1.0 ~ 5.0 by strong acids, adsorbing the cilastatin to a neutral adsorption resin, washing the cilastatin with water, eluting the cilastatin with ammonia water and concentrating the cilastatin to prepare cilastatin ammonium salts; and (iii) dissolving the cilastatin ammonium salts prepared in step (ii) in water, ammonia water, or a mixed solution of water and ammonia water, stirring the cilastatin ammonium salts: water, ammonia water, or their mixed solution: organic solvent in an equivalent ratio of 1:20:40(W/V/V) ~ 1:0.5:40(W/V/V) in at least one organic solvent at 5~50? for 2-5 hours, to create crystals, wherein the organic solvent is selected from the group consisting of C1-C4 alcohol, acetonitrile, and acetone.

    摘要翻译： 本发明涉及用于制备高纯度西司他丁钠盐的化学式（1）的新型结晶西司他丁铵盐的制备方法及由其制备的结晶西司他丁铵盐。 更具体地，下列化学式（1）的结晶西司他丁铵盐的制备方法包括：（i）在（a）氢氧化钠或氢氧化钾溶液中，（b）（Z）-7-氯-3- 化学式（2）的[[（S）-2,2-二甲基环丙基]羰基]氨基] -2-庚酸或其与（c）化学式（3）的西司他丁或其盐的盐在 50〜80？ （a）：（b）:( c）的当量比为1：1：1〜1：3：5，以制备西司他丁，其中水，至少一种有机溶剂或混合物 的水和有机溶剂作为溶剂，并且使用溴化钠，溴化钾或碘化钠作为催化剂，其中有机溶剂选自由C 1 -C 4醇，乙腈和丙酮组成的组，其中 可以与水混合; （ii）通过强酸将步骤（i）中制备的西司他丁的pH控制在1.0〜5.0，将西司他丁吸附到中性吸附树脂上，用水洗涤西司他汀，用氨水洗脱西司他丁，浓缩西司他丁以制备西司他丁 铵盐; （iii）将步骤（ii）中制备的西司他汀铵盐溶解于水，氨水或水和氨水的混合溶液中，将西司他丁铵盐：水，氨水或它们的混合溶液：有机溶剂在 （W / V / V）〜1：0.5：40（W / V / V）的当量比在至少一种有机溶剂中在5〜50？ 保持2-5小时以产生晶体，其中有机溶剂选自C 1 -C 4醇，乙腈和丙酮。