METHOD OF SYNTHESIZING TETRAHYDROBIOPTERIN
    5.
    发明申请
    METHOD OF SYNTHESIZING TETRAHYDROBIOPTERIN 有权
    合成四氢生物素的方法

    公开(公告)号:US20090198055A1

    公开(公告)日:2009-08-06

    申请号:US12349479

    申请日:2009-01-06

    IPC分类号: C07D475/04

    CPC分类号: C07D487/04

    摘要: The present disclosure provides a method that efficiently produces (6R)-tetrahydrobiopterin in high yield and purity. The method includes the step of hydrolyzing diacetylbiopterin to biopterin under basic conditions in a biphasic mixture comprising an organic phase and an aqueous phase. After substantially complete hydrolysis of diacetylbiopterin, the aqueous phase containing biopterin can be separated from the organic phase containing most of the organic impurities, which avoids the time-consuming step of isolating biopterin as a solid. The aqueous solution containing biopterin is stereoselectively hydrogenated to (6R)-tetrahydrobiopterin under basic conditions and high hydrogen pressure in the presence of a metal catalyst (e.g., a platinum catalyst). To improve the purification of an acid addition salt of (6R)-tetrahydrobiopterin (e.g., (6R)-tetrahydrobiopterin dihydrochloride), any residual salts (e.g., sodium salts) in the aqueous solution after the hydrogenation reaction can be removed by contacting the aqueous solution with an ion (e.g., cation) exchange resin or column. Alternatively, removal of residual salts from the aqueous solution can be omitted if an organic amine (e.g., diethylamine or triethylamine) rather than an inorganic base is used in the hydrolysis and/or hydrogenation reactions.

    摘要翻译: 本公开提供了以高产率和纯度有效生产(6R) - 四氢生物蝶呤的方法。 该方法包括在碱性条件下在包含有机相和水相的两相混合物中将二乙酰生物蝶呤水解成生物蝶呤的步骤。 在二乙酰生物蝶呤基本上完全水解后,含有生物蝶呤的水相可以从含有大部分有机杂质的有机相中分离出来,这避免了将生物蝶呤分离成固体的耗时的步骤。 含有生物蝶呤的水溶液在碱性条件下,在金属催化剂(如铂催化剂)存在下,氢压高,立体选择氢化为(6R) - 四氢生物喋呤。 为了改善(6R) - 四氢生物蝶呤(例如(6R) - 四氢生物喋呤二盐酸盐)的酸加成盐的纯化,氢化反应后的水溶液中的任何残留盐(例如钠盐)可以通过使水溶液 溶液与离子(如阳离子)交换树脂或色谱柱。 或者,如果在水解和/或氢化反应中使用有机胺(例如二乙胺或三乙胺)而不是无机碱,则可以从水溶液中除去残留的盐。

    Method of synthesizing tetrahydrobiopterin
    6.
    发明授权
    Method of synthesizing tetrahydrobiopterin 有权
    合成四氢生物喋呤的方法

    公开(公告)号:US08178670B2

    公开(公告)日:2012-05-15

    申请号:US12349479

    申请日:2009-01-06

    IPC分类号: C07D475/00

    CPC分类号: C07D487/04

    摘要: The present disclosure provides a method that efficiently produces (6R)-tetrahydrobiopterin of Formula I in high yield and purity. The method includes the step of hydrolyzing diacetylbiopterin to biopterin under basic conditions in a biphasic mixture comprising an organic phase and an aqueous phase. After substantially complete hydrolysis of diacetylbiopterin, the aqueous phase containing biopterin can be separated from the organic phase containing most of the organic impurities, which avoids the time-consuming step of isolating biopterin as a solid. The aqueous solution containing biopterin is stereoselectively hydrogenated to (6R)-tetrahydrobiopterin under basic conditions and high hydrogen pressure in the presence of a metal catalyst (e.g., a platinum catalyst). To improve the purification of an acid addition salt of (6R)-tetrahydrobiopterin (e.g., (6R)-tetrahydrobiopterin dihydrochloride), any residual salts (e.g., sodium salts) in the aqueous solution after the hydrogenation reaction can be removed by contacting the aqueous solution with an ion (e.g., cation) exchange resin or column. Alternatively, removal of residual salts from the aqueous solution can be omitted if an organic amine (e.g., diethylamine or triethylamine) rather than an inorganic base is used in the hydrolysis and/or hydrogenation reactions.

    摘要翻译: 本公开提供了以高产率和纯度有效生产式I的(6R) - 四氢生物喋呤的方法。 该方法包括在碱性条件下在包含有机相和水相的两相混合物中将二乙酰生物蝶呤水解成生物蝶呤的步骤。 在二乙酰生物蝶呤基本上完全水解后,含有生物蝶呤的水相可以从含有大部分有机杂质的有机相中分离出来,这避免了将生物蝶呤分离成固体的耗时的步骤。 含有生物蝶呤的水溶液在碱性条件下,在金属催化剂(如铂催化剂)存在下,氢压高,立体选择氢化为(6R) - 四氢生物喋呤。 为了改善(6R) - 四氢生物蝶呤(例如(6R) - 四氢生物喋呤二盐酸盐)的酸加成盐的纯化,氢化反应后的水溶液中的任何残留盐(例如钠盐)可以通过使水溶液 溶液与离子(如阳离子)交换树脂或色谱柱。 或者,如果在水解和/或氢化反应中使用有机胺(例如二乙胺或三乙胺)而不是无机碱,则可以从水溶液中除去残留的盐。