CN1823047A - (S)-(+)和(R)-(-)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂䓬-5-甲酰胺及其旋光富集混合物的外消旋化方法 - Google Patents
(S)-(+)和(R)-(-)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂䓬-5-甲酰胺及其旋光富集混合物的外消旋化方法 Download PDFInfo
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Abstract
本文公开了使(S)-(+)-和(R)-(-)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂䓬-5-甲酰胺外消旋化的高收率方法和有用的中间体10-氯-10,11-二氢-5H-二苯并/b,f/氮杂䓬-5-甲酰胺(VII)。本文还公开了使旋光纯或旋光富集的(S)-(+)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂䓬-5-甲酰胺(I)与(R)-(-)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂䓬-5-甲酰胺(II)的混合物外消旋化成为外消旋(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂䓬-5-甲酰胺(III)的方法。
Description
本发明涉及将旋光纯或旋光富集的(S)-(+)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺和(R)-(-)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(式(I)和(II)的化合物)的混合物外消旋化的方法。
式(III)的外消旋(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺是一种已知物质,已证明其具有抗惊厥活性(Schutz,H.等人,Xenobiotica,16,769-778(1986)),并且已发现其是已知的抗癫痫药物奥卡西平(式IV)的主要代谢产物。除了其抗惊厥活性之外,外消旋醇(III)可以通过还原奥卡西平(IV)以高收率容易地合成,因此可以在两种最近公开的生物学性质有所改进的单个对映体抗癫痫药物即旋光纯(S)-(-)-10-乙酰氧基-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺(式V)和(R)-(+)-10-乙酰氧基-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺(式VI)的制备中作为有用的中间体(Benes,J.等,J.Med.Chem.,42,2582-2587(1999))。特别已证明(S)-(-)-对映体(V)显示很有利的抗惊厥特征。
(I),R=H (II),R=H (III) (IV)
(V),R=COCH3 (VI),R=COCH3
合成单个旋光纯乙酸酯(V)或(VI)的关键步骤涉及将外消旋(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(III)拆分为其单个旋光纯立体异构体即(S)-(+)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(I)和(R)-(-)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(II),它们在旋光纯乙酸酯(V)和(VI)的合成中是主要的中间体。最近公开了这种拆分的改进方法,其包括有效地分离外消旋(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(III)的非对映异构酒石酸半酯(Learmonth,D.,PCT/GB02/02176)。
如上所述,外消旋(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(III)可以通过使用例如金属氢化物在醇介质中简单地化学还原奥卡西平(IV)的苄型酮基来制备。但是,奥卡西平(IV)是极昂贵的物质,尽管该拆分程序效率很高(基于单个非对映异构约98%收率),但应注意比如说仅仅分离(S)-(-)-乙酸酯(V)就意味着损失约50%的极昂贵的材料。因此很期望有一种方法来重复利用可以从拆分混合物中回收出来的多余但极昂贵的(R)-(-)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(II)。这种重复利用可被设想为包括外消旋化过程,其中回收但多余的旋光富集的(R)-(-)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺对映体(II)被转化为外消旋(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(III)以重新引入拆分循环中。该外消旋化过程应该优选包括使用廉价而容易获得的溶剂和试剂,并且操作简单却以高收率获得纯的完全外消旋化的产物。但是,在醇(I)和(II)的情况下,在标准酸性或碱性条件下进行外消旋化通常很复杂,这主要是因为(I)和(II)的分子极易失水而导致只能产生在(V)和(VI)的合成中不太令人感兴趣的脱水烯属产物。
然而,现已令人惊奇地发现外消旋化可以通过简单的方法容易地实现,所述方法包括使旋光富集的(对映异构过量在1至99.5%之间)(R)-(-)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(II)或(S)-(+)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(I)与标准氯化剂在合适的取代条件下反应,所述条件提供中间体苯型氯化物10-氯-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺(式VII),其足够稳定且可以容易地分离,并且如果优选,可以通过标准技术进行纯化,或者不进行分离或纯化而直接使用。使用本发明的方法根据以下合成路线,该10-氯-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺(VII)在简单的反应条件下方便地进行水解,提供外消旋(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(III),收率高且纯度极好:
根据本发明,旋光纯或富集的(R)-(-)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(II)或(S)-(+)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(I)的苄型醇官能团通过与合适的氯化剂例如无机或有机酰卤包括亚硫酰氯、草酰氯、硫酰氯、五氯化磷、三氯化磷、磷酰氯等反应而进行氯取代。所使用的氯化剂与旋光富集的醇(I)或(II)的摩尔比是1.02-2,优选在1.05-1.2的范围内。该反应在溶剂中进行,所述溶剂在反应条件下是惰性的,例如二氯甲烷、氯仿、四氯化碳、氯苯等。该反应可以在从-78℃至所用溶剂的沸点的宽的温度范围内进行,优选在0℃-25℃的范围内。式(VII)的化合物可以通过本领域技术人员熟悉的方法从反应混合物中容易地分离出来,并且如果优选,可以通过调浆(slurrying)或从合适的溶剂如酯包括乙酸乙酯或酮包括丙酮和甲乙酮中重结晶来进一步纯化。
根据本发明,水解可以通过在纯水中搅拌式(VII)的中间体苄型氯衍生物来进行。该反应可以在5℃-100℃的宽的温度范围内进行,优选15℃-30℃。一旦反应完成,就可以经过滤或离心来方便地以良好的收率和高纯度回收外消旋产物(III)。外消旋产物(III)可以经手性HPLC分析法快速分析,并且发现其是(S)-(+)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺和(R)-(-)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺的严格外消旋(1∶1)混合物,即式(I)和(II)的化合物的等摩尔混合物。如果优选,式(III)的化合物的粗外消旋产物可以经调浆或在合适的溶剂如酯包括乙酸乙酯,酮包括丙酮和甲乙酮或低级脂族醇如甲醇、乙醇和异丙醇中重结晶来进一步纯化。
或者,如果优选,该反应可在具有增溶作用的、可与水混溶的溶剂如二噁烷、四氢呋喃、低级脂族醇包括甲醇、乙醇和异丙醇、N-甲基-2-吡咯烷酮、高分子量聚乙二醇、丙酮、乙腈、二甲基甲酰胺等的存在下进行。有机溶剂与水的体积比在1∶0.5至1∶50的范围内,并且该反应可在5℃-100℃的宽的温度范围内进行,优选20℃-60℃。一旦反应完成,外消旋产物可以经本领域技术人员熟悉的标准方法分离,并且如果优选可进一步纯化,并如上所述进行手性HPLC分析。
根据本发明的另一方面,提供了通式(VIII)的化合物的制备方法:
其中R1是氢、烷基、卤代烷基、芳烷基、环烷基、环烷基烷基、烷氧基、芳基或吡啶基;术语烷基意指含有1-18个碳原子的直链或支链烃链;术语卤素意指氟、氯、溴或碘;术语环烷基意指含有3-6个碳原子的脂环族饱和基团;而术语芳基意指未取代的苯基或被烷氧基、卤素或硝基取代的苯基,所述方法包括通过上述方法从旋光纯或旋光富集的(R)-(-)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(II)形成外消旋(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺,然后处理所述外消旋(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺,生成式(VIII)的化合物。
根据本发明的另一方面,提供了通式(IX)的化合物的制备方法:
其中R1是氢、烷基、卤代烷基、芳烷基、环烷基、环烷基烷基、烷氧基、芳基或吡啶基;术语烷基意指含有1-18个碳原子的直链或支链烃链;术语卤素意指氟、氯、溴或碘;术语环烷基意指含有3-6个碳原子的脂环族饱和基团;而术语芳基意指未取代的苯基或被烷氧基、卤素或硝基取代的苯基,所述方法包括通过上述方法从旋光纯或旋光富集的(S)-(+)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(II)形成外消旋(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺,然后处理所述外消旋(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺,生成式(IX)的化合物。
如我们的申请PCT/GB02/02176中更详细描述的,可以将回收的外消旋(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(III)拆分为其旋光纯的立体异构体(S)-(+)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(I)和(R)-(-)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(II)。我们的美国专利5753646中更详细地描述了式(VIII)和(IX)的化合物,该专利的内容引入本文作参考。该方法可用于制备US 5753646中公开的任一化合物。例如,如US 5753646的实施例4中所述,可以将乙酰氯(或乙酸酐)加至(S)-(+)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(I)和吡啶在二氯甲烷中的悬浮液中来制备(S)-(-)-10-乙酰氧基-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺(V)。
US 5753646的实施例4-17中描述的化合物可通过使用合适的酰氯或酸酐进行酰化来制备。实施例18-23中描述的化合物可使用合适的羧酸来制备。
因此,使用本发明的方法可以制备以下化合物:
(1)10-乙酰氧基-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(2)10-苯甲酰氧基-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(3)10-(4-甲氧基苯甲酰氧基)-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(4)10-(3-甲氧基苯甲酰氧基)-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(5)10-(2-甲氧基苯甲酰氧基)-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(6)10-(4-硝基苯甲酰氧基)-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(7)10-(3-硝基苯甲酰氧基)-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(8)10-(2-硝基苯甲酰氧基)-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(9)10-(4-氯苯甲酰氧基)-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(10)10-(3-氯苯甲酰氧基)-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(11)10-(2-乙酰氧基苯甲酰氧基)-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(12)10-丙酰氧基-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(13)10-丁酰氧基-10,1-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(14)10-新戊酰氧基-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(15)10-(2-丙基)戊酰氧基]-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(16)10-[(2-乙基)己酰氧基]-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(17)10-硬脂酰氧基-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(18)10-环戊酰氧基-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(19)10-环己酰氧基-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(20)10-苯基乙酰氧基-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(21)10-(4-甲氧基苯基)乙酰氧基-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(22)10-(3-甲氧基苯基)乙酰氧基-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(23)10-(4-硝基苯基)乙酰氧基-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(24)10-(3-硝基苯基)乙酰氧基-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(25)10-烟酰氧基-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(26)10-异烟酰氧基-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(27)10-氯乙酰氧基-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(28)10-溴乙酰氧基-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(29)10-甲酰氧基-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(30)10-乙氧羰氧基-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
(31)10-(2-氯丙酰氧基-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺
如已经提到的,可以将回收的(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(III)拆分为其旋光纯的(R)-(+)-和(S)-(-)-立体异构体(II)和(I),从而可制备上述所有化合物的期望的(R)-(+)-和(S)-(-)-立体异构体。
这些化合物或其药学可接受的衍生物(如盐)可以用于制备药物组合物,所述药物组合物包含该化合物本身或该衍生物以及药学可接受的载体。这种组合物具有抗惊厥性质并且可用于治疗一些中枢及外周神经系统疾病,如癫痫。
本文公开的发明由以下制备实施例例示。要理解本发明不限于确切的操作细节,因为明显的修饰和等价物对于本领域技术人员来说将是清楚的。
实施例1.10-氯-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺(VII)
向冷却至0-5℃的(R)-(-)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(II)(100g,393.7mmol)(手性HPLC分析得到的旋光纯度为98.67%)在二氯甲烷(1000mL)中的搅拌悬浮液中滴加亚硫酰氯(56.2g,472.4mmol)。加入快结束时反应混合物变为溶液,将该溶液再搅拌10分钟。在搅拌下加入少量活性炭,然后将反应混合物滤过短硅藻土(Celite)垫。然后将滤液蒸发(40℃,水泵压力)至少量残余物体积。加入甲苯(500mL),再次将混合物蒸发(40℃,水泵压力)至得到固体。加入乙酸乙酯(300mL),并将所得浆液在室温下搅拌1小时,此时通过过滤移出固体并用少量冷乙酸乙酯洗涤。干燥至恒重后,得到10-氯-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺(VII),为米色固体(97.48g,91%),熔点156-157℃。
实施例2.10-氯-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺(VII)
向冷却至0-5℃的(R)-(-)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(II)(4.29g,16.89mmol)(手性HPLC分析得到的旋光纯度为99.2%)在二氯甲烷(50mL)中的搅拌悬浮液中滴加亚硫酰氯(2.22g,18.58mmol)。加入快结束时反应混合物变为溶液,将该溶液再搅拌10分钟,此时加入冰/水。分离各相,并用少量二氯甲烷萃取水相。用水和盐水洗涤合并的有机层,然后用无水硫酸镁干燥,过滤并蒸发(40℃,水泵压力)至得到白色固体。加入乙酸乙酯(20mL),并将浆液在室温下搅拌1小时。通过过滤移出固体,并干燥至恒重,得到10-氯-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺(VI1),为白色固体(4.22g,92%),熔点156.3-156.6℃。
实施例3.(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(III)
将10-氯-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺(VII)(50.0g,183.5mmol)在去离子水(900mL)中的悬浮液在室温下搅拌48小时。通过过滤移出固体并用去离子水(100mL)洗涤。在50℃和高真空下用五氧化二磷干燥至恒重后,得到外消旋(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(III),为米色固体(42.12g,90%),熔点186-188℃。
该产物的手性HPLC分析(LiChroCART 250-4HPLC CartridgeChiraDex 5μm,(Merck),流速:0.8mL/min,流动相:水/甲醇8∶2,进样20μL,样品是每毫升流动相中溶解0.2mg分析物的溶液,在210/254nm处进行UV检测)显示完全外消旋化((S)-(+)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(I)和(R)-(-)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(II)的1∶1混合物,(R)-(-)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(II)的保留时间是8.39分钟,而(S)-(+)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(I)的保留时间是9.1分钟)。
实施例4.(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(III)
将10-氯-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺(VII)(7.68g,28.16mmol)在二噁烷(40mL)和水(40mL)中的搅拌悬浮液在50℃下搅拌40分钟。然后通过蒸发(40℃,水泵压力)除去有机溶剂,并向残余物中加入水(40mL),然后用10%异丙醇/二氯甲烷溶剂混合物萃取。用水和盐水洗涤合并的有机萃取液,然后用无水硫酸镁干燥,过滤并蒸发(40℃,水泵压力)至得到微黄色泡沫状物。从二氯甲烷/异丙醇混合物中重结晶,得到外消旋(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(III),为白色晶体(4.92g,69%),熔点186.5-188℃。
该产物的手性HPLC分析(LiChroCART 250-4 HPLC CartridgeChiraDex5μm,(Merck),流速:0.8mL/min,流动相:水/甲醇8∶2,进样20μL,样品是每毫升流动相中溶解0.2mg分析物的溶液,在210/254nm处进行UV检测)显示完全外消旋化((S)-(+)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(I)和(R)-(-)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(II)的1∶1混合物,(R)-(-)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(II)的保留时间是8.39分钟,而(S)-(+)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(I)的保留时间是9.1分钟)。
实施例5.10-氯-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺(VII)
向冷却至0-5℃的(S)-(+)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(II)(10g,39.37mmol)(手性HPLC分析得到的旋光纯度为87%)在二氯甲烷(100mL)中的搅拌悬浮液中滴加亚硫酰氯(5.62g,47.24mmol)。加入快结束时反应混合物变为溶液,将该溶液再搅拌10分钟,此时加入冰/水。分离各相,用少量二氯甲烷萃取水相。用水和盐水洗涤合并的有机层,然后用无水硫酸镁干燥,然后过滤并蒸发(40℃,水泵压力)至得到白色固体。加入乙酸乙酯(50mL),并将浆液在室温下搅拌1小时。通过过滤移出固体,干燥至恒重,得到10-氯-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺(VII),为白色固体(9.98g,93%),熔点155-157℃。
如实施例3所述水解该中间体,经手性HPLC分析判定得到完全外消旋产物(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(III)。
应理解可以对以上描述的本发明进行修改。
Claims (16)
2.权利要求1的化合物(VII)的制备方法,其包括使旋光纯或旋光富集的(R)-(-)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(II)或者旋光纯或旋光富集的(S)-(+)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(I)与氯化剂在基本上惰性的溶剂中反应,生成式(VII)的化合物。
3.使旋光纯或旋光富集的(R)-(-)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(II)外消旋化的方法,其包括:
a)使旋光纯或旋光富集的(R)-(-)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(II)与氯化剂在基本上惰性的溶剂中反应,生成式(VII)的中间体,和
b)水解所得的式(VII)的中间体,生成外消旋(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(III)。
4.使旋光纯或旋光富集的(S)-(+)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(I)外消旋化的方法,其包括:
a)使旋光纯或旋光富集的(S)-(+)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(I)与氯化剂在基本上惰性的溶剂中反应,生成式(VII)的中间体,和
b)水解所得的式(VII)的中间体,生成外消旋(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(III)。
5.权利要求2、3或4的方法,其中所述氯化剂选自于亚硫酰氯、草酰氯、硫酰氯、五氯化磷、三氯化磷或磷酰氯。
6.权利要求2、3、4或5的方法,其中所述基本上惰性的溶剂是氯代脂族或芳香烃溶剂。
7.权利要求2-6之任一项的方法,其中所述中间体(VII)的水解在纯水中进行。
8.权利要求2-6之任一项的方法,其中所述中间体(VII)的水解在水/可与水混溶的溶剂混合物中进行。
9.权利要求7的方法,其中所述可与水混溶的溶剂选自于二噁烷、四氢呋喃、甲醇、乙醇、异丙醇、N-甲基-2-吡咯烷酮、高分子量聚乙二醇、丙酮、乙腈和二甲基甲酰胺。
10.通式(VIII)的化合物的制备方法:
其中R1是氢、烷基、卤代烷基、芳烷基、环烷基、环烷基烷基、烷氧基、芳基或吡啶基;术语烷基意指含有1-18个碳原子的直链或支链烃链;术语卤素意指氟、氯、溴或碘;术语环烷基意指含有3-6个碳原子的脂环族饱和基团;而术语芳基意指未取代的苯基或被烷氧基、卤素或硝基取代的苯基,所述方法包括:
a)通过权利要求3的方法从旋光纯或旋光富集的(R)-(-)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(II)形成外消旋(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺,或
b)通过权利要求4的方法从旋光纯或旋光富集的(S)-(+)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(I)形成外消旋(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺,
然后,在步骤(a)或(b)之后:
c)处理所述外消旋(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺,生成式(VIII)的化合物。
11.权利要求10的方法,其中对外消旋(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺的所述处理包括拆分步骤以分离(S)-(+)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(I),然后将分离的对映体酰化,生成式(VIII)的化合物。
12.通式(IX)的化合物的制备方法:
其中R1是氢、烷基、卤代烷基、芳烷基、环烷基、环烷基烷基、烷氧基、芳基或吡啶基;术语烷基意指含有1-18个碳原子的直链或支链烃链;术语卤素意指氟、氯、溴或碘;术语环烷基意指含有3-6个碳原子的脂环族饱和基团;而术语芳基意指未取代的苯基或被烷氧基、卤素或硝基取代的苯基,所述方法包括:
a)通过权利要求3的方法从旋光纯或旋光富集的(R)-(-)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(II)形成外消旋(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺,或
b)通过权利要求4的方法从旋光纯或旋光富集的(S)-(+)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(I)形成外消旋(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺,
然后,在步骤(a)或(b)之后:
c)处理所述外消旋(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺,生成式(IX)的化合物。
13.权利要求12的方法,其中对外消旋(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺的所述处理包括拆分步骤以分离(R)-(-)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(II),然后将分离的对映体酰化,生成式(IX)的化合物。
14.(S)-(-)-乙酰氧基-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺(V)的制备方法,其包括通过权利要求3的方法从旋光纯或旋光富集的(R)-(-)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(II)形成外消旋(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(III),然后拆分并酰化(S)-(+)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(I)。
15.(R)-(+)-乙酰氧基-10,11-二氢-5H-二苯并/b,f/氮杂-5-甲酰胺(VI)的制备方法,其包括通过权利要求4的方法从旋光纯或旋光富集的(S)-(+)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(I)形成外消旋(±)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺,然后拆分并酰化(R)-(-)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂-5-甲酰胺(II)。
16.权利要求11、13、14或15之任一项的方法,其中所述酰化步骤在吡啶的存在下在二氯甲烷中进行。
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