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    • 4. 发明申请
    • PROCESS FOR PREPARING BEPOTASTINE AND INTERMEDIATES USED THEREIN
    • 用于制备BEPOTASTINE及其中间体的方法
    • WO2008153289A2
    • 2008-12-18
    • PCT/KR2008003161
    • 2008-06-05
    • HANMI PHARM IND CO LTDHA TAE HEEPARK CHANG HEEKIM WON JEOUNGCHO SOOHWAKIM HAN KYONGSUH KWEE HYUN
    • HA TAE HEEPARK CHANG HEEKIM WON JEOUNGCHO SOOHWAKIM HAN KYONGSUH KWEE HYUN
    • C07D401/12
    • C07D401/12
    • A process for stereospecific preparation of bepotastine of formula (I) and novel intermediates used therein having formulae (II) to (IV) are provided. The inventive process comprises subjecting (RS)-4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidine to a reaction with a 4-halobutanoic acid l-menthyl ester, halo being chloro, bromo or iodo, in an organic solvent in the presence of a base to produce (RS)-bepotastine l-menthyl ester of formula (II), conducting a reaction of the compound of formula (II) with N-benzyloxycarbonyl L-aspartic acid in an organic solvent to induce selective precipitation of bepotastine l-menthyl ester?N-benzyloxycarbonyl L-aspartate of formula (III), filtering the precipitates formed in step 2) to isolate the compound of formula (III), treating the compound of formula (III) with a base to liberate bepotastine l-menthyl ester of formula (IV), and hydrolyzing the compound of formula (IV) in the presence of a base. The inventive process can provide bepotastine having a high optical purity of not less than 99.5% in a high yield, and thus, is useful in the development of anti-histamines and anti-allergic agents.
    • 提供了式(I)的贝他辛汀的立体特异性制备方法和其中使用的具有式(II)至(IV)的新型中间体。 本发明的方法包括使(RS)-4 - [(4-氯苯基)(2-吡啶基)甲氧基]哌啶与4-卤代丁酸1-薄荷酯,卤素为氯,溴或碘的有机反应 溶剂在碱的存在下反应以制备式(II)的(RS) - 贝斯塔司汀l-薄荷酯,在有机溶剂中进行式(II)化合物与N-苄氧羰基L-天冬氨酸的反应,以诱导选择性 将式(III)的贝他辛汀1-薄荷酯β-苄氧羰基L-天冬氨酸的沉淀,过滤步骤2)中形成的沉淀物,以分离式(III)化合物,用碱将式(III)化合物 释放式(Ⅳ)的布他辛酯1-薄荷酯,并在碱的存在下水解式(Ⅳ)化合物。 本发明方法可以以高产率提供具有不低于99.5%的高光学纯度的贝他斯汀,因此可用于抗组胺和抗过敏剂的开发。