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公开(公告)号：US08791287B2
公开(公告)日：2014-07-29
申请号：US13807356
申请日：2011-06-20
IPC分类号： C07C69/76
CPC分类号： C07C229/38 , C07B57/00 , C07B2200/07 , C07C213/00 , C07C213/06 , C07C213/08 , C07C213/10 , C07C217/62 , C07C217/72 , C07C219/22 , C07C221/00 , C07C225/16 , C07C215/54
摘要： The object of the present invention is a new process for the synthesis of tapentadol, both as free base and in hydrochloride form, which comprises the step of alkylation of the ketone (VII) to yield the compound (VIII), as reported in Diagram 1, with high stereoselectivity due to the presence of the benzyl group as substituent of the amino group. It was surprisingly found that this substitution shifts the keto-enol equilibrium towards the desired enantiomer and amplifies the capacity of the stereocenter present in the compound (VII) to orient the nucleophilic addition of the organometallic compound at the carbonyl towards the desired stereoisomer. This substitution thus allows obtaining a considerable increase of the yields in this step, and consequently allows significantly increasing the overall yield of the entire tapentadol synthesis process.A further object of the present invention is constituted by the tapentadol free base in solid form, obtainable by means of the process of the invention.Still another object of the invention is represented by the crystalline forms I and II of the tapentadol free base.A further object of the present invention is the mixture of the crystalline forms I and II of the tapentadol free base.
摘要翻译： 本发明的目的是合成无论是游离碱还是盐酸盐形式的他喷他多的新方法，其包括将酮（Ⅶ）烷基化以产生化合物（Ⅷ）的步骤，如图1所示 由于存在苄基作为氨基的取代基而具有高立体选择性。 令人惊讶地发现，该取代将酮 - 烯醇平衡转移到期望的对映异构体，并放大化合物（VII）中存在的立体中心的能力，以使有机金属化合物在羰基处的亲核加成反应成所需的立体异构体。 因此，这种置换可以在该步骤中获得相当大的产率增加，因此允许显着增加整个他喷他多合成过程的总产率。 本发明的另一个目的是通过本发明方法获得的固体形式的他喷他多游离碱构成。 本发明的另一个目的是由他喷他多游离碱的结晶形式I和II表示。 本发明的另一个目的是使用他喷他多游离碱的结晶形式I和II的混合物。
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公开(公告)号：US20130178644A1
公开(公告)日：2013-07-11
申请号：US13807356
申请日：2011-06-20
IPC分类号： C07C229/38 , C07C217/62 , C07C217/72 , C07C213/08 , C07C225/16
CPC分类号： C07C229/38 , C07B57/00 , C07B2200/07 , C07C213/00 , C07C213/06 , C07C213/08 , C07C213/10 , C07C217/62 , C07C217/72 , C07C219/22 , C07C221/00 , C07C225/16 , C07C215/54
摘要： The object of the present invention is a new process for the synthesis of tapentadol, both as free base and in hydrochloride form, which comprises the step of alkylation of the ketone (VII) to yield the compound (VIII), as reported in Diagram 1, with high stereoselectivity due to the presence of the benzyl group as substituent of the amino group. It was surprisingly found that this substitution shifts the keto-enol equilibrium towards the desired enantiomer and amplifies the capacity of the stereocenter present in the compound (VII) to orient the nucleophilic addition of the organometallic compound at the carbonyl towards the desired stereoisomer. This substitution thus allows obtaining a considerable increase of the yields in this step, and consequently allows significantly increasing the overall yield of the entire tapentadol synthesis process.A further object of the present invention is constituted by the tapentadol free base in solid form, obtainable by means of the process of the invention.Still another object of the invention is represented by the crystalline forms I and II of the tapentadol free base.A further object of the present invention is the mixture of the crystalline forms I and II of the tapentadol free base.
摘要翻译： 本发明的目的是合成无论是游离碱还是盐酸盐形式的他喷他多的新方法，其包括将酮（Ⅶ）烷基化以产生化合物（Ⅷ）的步骤，如图1所示 由于存在苄基作为氨基的取代基而具有高立体选择性。 令人惊讶地发现，该取代将酮 - 烯醇平衡转移到期望的对映异构体，并放大化合物（VII）中存在的立体中心的能力，以使有机金属化合物在羰基处的亲核加成反应成所需的立体异构体。 因此，这种置换可以在该步骤中获得相当大的产率增加，因此允许显着增加整个他喷他多合成过程的总产率。 本发明的另一个目的是通过本发明方法获得的固体形式的他喷他多游离碱构成。 本发明的另一个目的是由他喷他多游离碱的结晶形式I和II表示。 本发明的另一个目的是使用他喷他多游离碱的结晶形式I和II的混合物。
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