CN1102143C - 生产(9α,13α,14α)-1-(3-甲氧基吗啡喃-17-基)烷酮的方法 - Google Patents

生产(9α,13α,14α)-1-(3-甲氧基吗啡喃-17-基)烷酮的方法 Download PDF

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CN1102143C
CN1102143C CN97119635A CN97119635A CN1102143C CN 1102143 C CN1102143 C CN 1102143C CN 97119635 A CN97119635 A CN 97119635A CN 97119635 A CN97119635 A CN 97119635A CN 1102143 C CN1102143 C CN 1102143C
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克里斯托弗·韦尔利
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    • C07D221/00Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
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Abstract

通式I的(9α,13α,14α)-1-(3-甲氧基吗啡喃-17-基)烷酮是一种有价值的生产式III的右甲吗喃的中间体。该中间体可以在约5-50℃,但高于所用的烷基磺酸或烷基磺酸混合物的熔点温度下,用烷基磺酸或烷基磺酸混合物环化式II的(R)或(S)-1-[1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢-异喹啉-2-基]烷酮来生产,它们可通过分裂残基R和N-甲基化以公知的方式转化成右甲吗喃。

Description

生产(9α,13α,14α)-1- (3-甲氧基吗啡喃-17 -基)烷酮的方法
本发明涉及一种通式I的(9α,13α,14α)-1-(3-甲氧基吗啡喃-17-基)烷酮[(9α,13α,14α)-1-(3-methoxymorphinan-17-yl)(alkanones)]的生产方法
Figure C9711963500041
其中,R为低级烷酰基,
该方法用烷基磺酸使下式的(R)或(S)-1-[1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢-异喹啉-2-基]烷酮环化,其中,R定义如前。
本文所用术语“低级烷酰基”是指具有2-4个碳原子的脂族羧酸的直链或支链残基,如乙酰基、丙酰基、丁酰基等,优选乙酰基。
上式I的(9α,13α,14α)-1-(3-甲氧基吗啡喃-17-基)烷酮为生产下式右甲吗喃的重要原料
按照如德国专利2,311,881所述类似的公知方法,可将式I化合物转化成右甲吗喃,即,使残基R分裂及N-甲基化。(9α,13α,14α)-1-(3-甲氧基吗啡喃-17-基)烷酮生产右甲吗喃中的应用也是本发明的一个目的。
已经公知有多种生产右甲吗喃的方法。方法之一在Helv.Chim.Acta  33,1437(1950)中有述,按照该公知方法,相应于上述式II的衍生物,但其中R代表甲基,即(R)或(S)-1-[1-(4-甲氧基苄基)-2-甲基-1,2,3,4,5,6,7,8-八氢-异喹啉,用磷酸环化,产率为66%。在最后步骤中的低产率是这种方法的缺点。
另一种起始原料即相应于上式II的衍生物,但其中R为甲酰基,即(R)或(S)-1-[1-(4-甲氧基苄基)-2-甲酰基-1,2,3,4,5,6,7,8-八氢-异喹啉,可被转化成右甲吗喃,见Tetrahedron Letters(1987), 28,4829及日本专利公告01034964,尽管其未详细描述产率。这一点并不重要,因为这种转化并不是特别有吸引力的。其原因在于,(R)或(S)-1-[1-(4-甲氧基苄基)-2-甲酰基-1,2,3,4,5,6,7,8-八氢-异喹啉必须通过下述方法生产:对消旋(rac.)的1-[1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢-异喹啉进行外消旋物拆开(产率≤50%),随后进行N-甲酰化,或者按照如上的两篇文献对仅以复合方式使用的(Z)-1-[1-(4-甲氧基亚苄基)-1,2,3,4,5,6,7,8,-八氢-异喹啉-2-基]甲酮进行不对称氢化。对映选择性(enantioselective)氢化(Z)-1-[1-(4-甲氧基亚苄基)-1,2,3,4,5,6,7,8,-八氢-异喹啉-2-基]烷酮的发展拓宽了生产(R)或(S)-1-[1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢-异喹啉-2-基]烷酮的简单方法而无须外消旋物拆开,如参见US 4,857,648。
本发明的目的是提供一种通式I的(9α,13α,14α)-1-(3-甲氧基吗啡喃-17-基)烷酮的生产方法,该方法通过环化上述式II的(R)或(S)-1-[1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢-异喹啉-2-基]烷酮而完成,该方法也以高产率对易于得到的(R)或(S)-1-[1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢-异喹啉-2-基]烷酮进行环化。
在下面将详述的特定条件下,用烷基磺酸或烷基磺酸的混合物进行环化可实现本发明的目的。
相应地,本发明涉及一种通式I的(9α,13α,14α)-1-(3-甲氧基吗啡喃-17-基)烷酮的生产方法,该方法包括在约5-50℃,但高于所用的烷基磺酸或烷基磺酸混合物的熔点温度,优选在约10℃至室温下,用烷基磺酸或烷基磺酸混合物环化上述式II的(R)或(S)-1-[1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢-异喹啉-2-基]烷酮。
(R)或(S)-1-[1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢-异喹啉-2-基]烷酮的环化可以公知的方式在所用的酸中进行,所用的酸同时也起溶剂的作用。烷基磺酸或烷基磺酸混合物,特别是甲磺酸、乙磺酸和丙磺酸,尤其是甲磺酸适用于本发明。当各种烷基磺酸在优选的反应温度约10℃至室温下为固体,且它们不能同时用作溶剂时,必须通过加入0-4%,优选0-2%的水或者通过与另一种烷基磺酸混合来降低酸的熔点,从而使反应可以在高于酸或酸混合物的熔点温度下进行。当加入的水>1%时,离析物反应的速度会有些降低,尽管使用更长的反应时间产率可保持一定。
有利地,将(R)或(S)-1-[1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢-异喹啉-2-基]烷酮以熔化的形式(约85℃)加入冷酸中。(9α,13α,14α)-1-(3-甲氧基吗啡喃-17-基)烷酮在60-65℃下通过加入水直接从酸中结晶,或者用反应条件下惰性的有机溶剂进行萃取,如甲苯或二氯甲烷,优选甲苯。
下述由(R)或(S)-1-[1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢-异喹啉-2-基]乙酮生产(9α,13α,14α)-1-(3-甲氧基吗啡喃-17-基)乙酮的实施例用于说明本发明的优选实施方案,但其并不是对本发明的限定。所有的温度均为℃。
实施例1
在惰性气氛下,将200g的无水甲磺酸置于750ml备有温度计及搅拌棒的四颈烧瓶中,用2ml的水处理。在30分钟内,在约10-15℃下,分四次将30.40g(100mmol)熔化(加热至约85℃)的(R)或(S)-1-[1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢-异喹啉-2-基]乙酮(含量:约98%)加入该溶液中。在水浴中搅拌反应混合物。在3小时后,(R)或(S)-1-[1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢-异喹啉-2-基]乙酮完全溶解。在10-21℃下将棕色溶液搅拌6天。通过气相色谱对反应过程进行检测。
  反应时间[h]     温度[℃]   转化率[%]
   0    10     0
   24    12     25
   48    14     55
   72    17     78
   96    20     89
   120    21     98
   144    21     99.5
实施例2
向实施例1的棕色溶液中加入400ml的甲苯及一次加入150g的冰和330ml的水的混合物。搅拌5分钟后,混合物用2×100ml的甲苯萃取。甲苯相连续用2×100ml的水洗涤。合并水相,回收甲磺酸。合并甲苯相并在水夹套真空器中蒸发。得到30.25g(92%)的粗产物(9α,13α,14α)-1-(3-甲氧基吗啡喃-17-基)乙酮,按照GC含量为91%。
实施例3
在60℃下,在约1小时内,边搅拌边向实施例1的棕色溶液中加入600ml的水。将得到的结晶悬浮液冷却至室温。对固体抽滤,压制,并用100ml的水淋洗。滤饼在35℃的水夹套真空器中干燥18小时。得到27.81g(88%)的(9α,13α,14α)-1-(3-甲氧基吗啡喃-17-基)乙酮,按照GC含量为95%。

Claims (9)

1、一种生产通式I的(9α,13α,14α)-1-(3-甲氧基吗啡喃-17-基)烷酮的方法
Figure C9711963500021
其中,R为直链或支链的具有2-4个碳原子的脂族羧酸形成的烷酰基,
该方法包括在5-50℃,但高于所用的烷基磺酸或烷基磺酸混合物的熔点温度下,用烷基磺酸或烷基磺酸混合物环化式II的(R)或(S)-1-[1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢-异喹啉-2-基]烷酮,
Figure C9711963500022
其中,R定义如前。
2、根据权利要求1的方法,其中使用甲磺酸、乙磺酸或丙磺酸。
3、根据权利要求1的方法,其中使用甲磺酸。
4、根据权利要求1或2的方法,其中环化反应在10℃至室温下进行。
5、根据权利要求1-3任一项的方法,其中通过加入0-4%的水或者通过与另一种烷基磺酸混合来降低烷基磺酸的熔点。
6、根据权利要求1-3任一项的方法,其中通过加入0-2%的水或者通过与另一种烷基磺酸混合来降低烷基磺酸的熔点。
7、根据权利要求1-3任一项的方法,其中将(R)或(S)-1-[1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢-异喹啉-2-基]烷酮以熔化的形式加入冷酸中。
8、根据权利要求1-3任一项的方法,其中R为乙酰基、丙酰基、丁酰基。
9、一种生产通式III的右甲吗喃的方法,
该方法包括在5-50℃,但高于所用的烷基磺酸或烷基磺酸混合物的熔点温度下,用烷基磺酸或烷基磺酸混合物环化式II的(R)或(S)-1-[1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢-异喹啉-2-基]烷酮,并将形成的式I(9α,13α,14α)-1-(3-甲氧基吗啡喃-17-基)烷酮通过分裂残基R和N-甲基化以公知的方式转化成右甲吗喃
Figure C9711963500032
其中,R定义如前,
Figure C9711963500033
其中,R定义如前。
CN97119635A 1996-10-02 1997-09-24 生产(9α,13α,14α)-1-(3-甲氧基吗啡喃-17-基)烷酮的方法 Expired - Fee Related CN1102143C (zh)

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CN104761496A (zh) * 2015-04-02 2015-07-08 华东理工大学 一种右美沙芬中间体的合成方法

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US20040204862A1 (en) * 2003-04-11 2004-10-14 Wainer Irving W. Computer-based model for identification and characterization for non-competitive inhibitors of nicotinic acetylcholine receptors and related ligand-gated ion channel receptors
CN103044327B (zh) * 2013-01-07 2014-12-17 苏州立新制药有限公司 一种右美沙芬的制备方法
CN103265489B (zh) * 2013-06-17 2015-03-25 苏州立新制药有限公司 ent-(14S)-3-甲氧基-17-甲基吗喃的制备方法

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FR1584396A (zh) * 1967-08-25 1969-12-19
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CN104761496A (zh) * 2015-04-02 2015-07-08 华东理工大学 一种右美沙芬中间体的合成方法

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