CN101142181B - 对映异构纯的4-吡咯烷子基苯基苄基醚衍生物的制备方法 - Google Patents
对映异构纯的4-吡咯烷子基苯基苄基醚衍生物的制备方法 Download PDFInfo
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- CN101142181B CN101142181B CN2006800082128A CN200680008212A CN101142181B CN 101142181 B CN101142181 B CN 101142181B CN 2006800082128 A CN2006800082128 A CN 2006800082128A CN 200680008212 A CN200680008212 A CN 200680008212A CN 101142181 B CN101142181 B CN 101142181B
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Abstract
本发明涉及对映异构纯的式(I)的4-吡咯烷子基苯基苄基醚衍生物的制备方法,其中R1、R21、R22、R23、R24和n如说明书和权利要求书中定义,以及涉及可用于本发明的方法的中间体和盐。
Description
本发明涉及对映异构纯的4-吡咯烷子基苯基苄基醚衍生物的制备方法。本发明还涉及可用于本发明的方法的中间体及其盐。
更具体而言,本发明涉及对映异构纯的式(I)的4-吡咯烷子基衍生物的制备方法:
所述方法包括如下步骤:使式(II)化合物
与(S)-N-(5-氧代-四氢呋喃-3-基)-乙酰胺反应,以获得式(III)化合物:
然后进行式(III)化合物的环化,以获得式(I)化合物;
其中:
R1是卤素、卤素-(C1-C6)-烷基、氰基、(C1-C6)-烷氧基或卤素-(C1-C6)-烷氧基;
R21、R22、R23和R24彼此独立地选自氢和卤素;且
n是0、1、2或3。
式(I)化合物的制备已公开在专利申请WO 2004/026825中,本申请人是其所有人。然而,该专利申请并未公开本发明的原创方法。此外,已经令人惊奇地发现本发明的原创方法能以高产率和高纯度获得式(I)化合物。
通式(I)化合物是选择性B型单胺氧化酶抑制剂。
单胺氧化酶(MAO,EC 1.4.3.4)是含黄素的酶,它负责内源性单胺神经递质如多巴胺、5-羟色胺、肾上腺素或去甲肾上腺素和痕量胺如苯乙胺以及多种胺外源物的氧化脱氨作用。该酶存在两种形式,MAO-A和MAO-B,它们由不同的基因编码[Bach等人,Proc.Natl.Acad.Sci.USA85:4934-4938(1988)],在组织分布、结构和底物特异性方面存在区别。MAO-A对5-羟色胺、章鱼胺、肾上腺素和去甲肾上腺素具有较高的亲和力;而MAO-B的天然底物是苯乙胺和酪胺。认为多巴胺能被这两种同工型氧化。MAO-B广泛分布于多个器官,包括脑[Cesura和Pletscher,Prog.Drug Research 38:171-297(1992)]。脑MAO-B的活性似乎随着年龄而增加。已把这种增加归因于与衰老有关的神经胶质增生[Fowler等人,J.Neural.Transm.49:1-20(1980)]。另外,MAO-B的活性在患有阿尔茨海默病的患者脑中显著更高[Dostert等人,Biochem.Pharmacol.38:555-561(1989)],已发现它在老年斑附近的星形胶质细胞中大量表达[Saura等人,Neuroscience 70:755-774(1994)]。在本文中,由于MAO对伯单胺的氧化脱氨作用产生了NH3、醛类和H2O2,这些是具有确定毒性或潜在毒性的物质,因此提出用选择性MAO-B抑制剂治疗痴呆和帕金森病的理论。抑制MAO-B引起了多巴胺的酶灭活,从而延长了多巴胺能神经元中神经递质的供给。与年龄相关的变性过程和阿尔茨海默病和帕金森病也可归因于由于增加的MAO活性和随后由MAO-B带来的H2O2的形成增加而引起的氧化应激。因此,MAO-B抑制剂可通过减少氧原子团的形成和提高脑内单胺水平而起作用。
鉴于MAO-B在上述神经性紊乱中的作用,因此非常有兴趣获得能允许控制这种酶活性的有效且具有选择性的抑制剂。例如Bentué-Ferrer等人[CNS Drugs 6:217-236(1996)]讨论了一些已知的MAO-B抑制剂的药理学。然而对不可逆且非选择性的MAO抑制剂活性的主要限制是需要谨慎饮食,这是由于摄入饮食酪胺时有引起高血压危象的风险,以及由于与其它药物相互作用的可能性[Gardner等人,J.Clin.Psychiatry 57:99-104(1996)],这些不利事件在可逆且具有选择性的MAO抑制剂、尤其是MAO-B抑制剂中出现较少。因此,需要具有高选择性且不具有对酶选择性低的不可逆MAO抑制剂通常所具有的不利副作用的MAO-B抑制剂。
不论所讨论的术语单独出现或者组合出现,应用本文所用的一般术语的下列定义。必须注明的是,如说明书和所附的权利要求书中所用的单数形式“一个”、“一种”还包括复数形式,上下文另有明确规定除外。
在本文出现的结构式中,楔形键()表示取代基在纸平面之上。
本申请中所用的术语“(C1-C6)-烷基”表示具有1到6个碳原子的直链或支链饱和烃基,如甲基、乙基、正丙基、异丙基、正丁基、仲丁基和叔丁基等,优选具有1到3个碳原子。相应地,术语“(C1-C3)-烷基”指具有1到3个碳原子的直链或支链饱和烃基。
术语“卤素”表示氟、氯、溴和碘。
“卤素-(C1-C6)-烷基”或“卤素-(C1-C6)-烷氧基”指在任意位置上被本文定义的一个或多个卤素原子取代的分别如本文定义的低级烷基残基或低级烷氧基残基。卤素烷基残基的实例包括但不限于1,2-二氟丙基、1,2-二氯丙基、三氟甲基、2,2,2-三氟乙基、2,2,2-三氯乙基和1,1,1-三氟丙基等。“卤素烷氧基”包括三氟甲氧基。
“(C1-C6)-烷氧基”指-OR残基,其中R是本文定义的低级烷基残基。烷氧基的实例包括但不限于甲氧基、乙氧基和丙氧基等。
化合物的“可药用盐”指药学上可接受的盐,它通常是安全无毒的,既非生物学也非其它方面所不希望的,并且它具有所希望的母体化合物的药理学活性。这些盐衍生自无机或有机酸或碱。如果可能的话,式I化合物可转化成可药用盐。应当理解,可药用盐包括在本发明之内。
术语“对映异构纯”表示:所需对映异构体:不想要的对映异构体的对映异构体比例至少是95∶5,优选至少98∶2,更优选至少99.9∶0.1。对映异构体比例可以在手性柱上用HPLC测定。
可以在溶剂如四氢呋喃、特别是无水四氢呋喃中进行式(II)化合物与(S)-N-(5-氧代-四氢呋喃-3-基)-乙酰胺的反应以获得式(III)化合物。
另外可以使用碱,包括双(三甲基甲硅烷基)氨基锂或双(三甲基甲硅烷基)氨基钠,例如约1M溶液的形式,优选在溶剂如四氢呋喃中。
所得式(III)化合物可采用常规方法和设备(如萃取、沉淀等)进行分离和纯化。
可以采用常规的Mitsunobu试剂如可以选自偶氮二甲酸二叔丁酯(DBAD)、偶氮二甲酸二乙酯(DEAD)、偶氮二甲酸二异丙酯(DIAD)或1,1′-(偶氮二羰基)二哌啶的偶氮二甲酸酯联合三正丁基膦将式(III)化合物环化为本发明的式(I)化合物。在环化中可以适宜地使用溶剂,包括四氢呋喃。
按照Mitsunobu方法进行的适宜环化的描述例如在I.M.Bell等人,Tetrahedron.Lett.2000,41,1141中给出。
或者,可以通过将式(III)化合物转化为磺酸酯、例如采用甲磺酰氯(MsCl)在三乙胺(Et3N)中按照M.P.Heitz,L. E.Overman,J.Org.Chem.1989,54,2591来将式(III)化合物环化为本发明的式(I)化合物。
式(III)化合物可如专利申请WO 2004/026825中所述来制备,本申请人是其所有人,其公开内容引入本文作为参考。
(S)-N-(5-氧代-四氢呋喃-3-基)-乙酰胺可以以市售材料为原料如Q.-Z.Liu等人,Youji Huaxue,2004,24,637和G.Calvisi等人,Synlett 1997,71中所述来制备。在实施例B中以N-乙酰基-L-天冬氨酸酐为原料描述了一种可能的制备(S)-N-(5-氧代-四氢呋喃-3-基)-乙酰胺的途径,其中N-乙酰基-L-天冬氨酸酐的制备在实施例A中有描述。
在本发明的方法的某些实施方案中,式(II)化合物是4-(3-氟-苄氧基)-苯胺,式(III)化合物是(S)-3-乙酰氨基-N-[4-(3-氟-苄氧基)-苯基]-4-羟基-丁酰胺,且式(I)化合物是(S)-N-{1-[4-(3-氟-苄氧基)-苯基]-5-氧代-吡咯烷-3-基}-乙酰胺。
本发明还囊括式(III)中间体化合物:
其中:
R1是卤素、卤素-(C1-C6)-烷基、氰基、(C1-C6)-烷氧基或卤素-(C1-C6)-烷氧基;
R21、R22、R23和R24彼此独立地选自氢和卤素;且
n是0、1、2或3。
如上文所提及的,在本发明的某些实施方案中,式(III)化合物是(S)-3-乙酰氨基-N-[4-(3-氟-苄氧基)-苯基]-4-羟基-丁酰胺。
式(I)化合物,如上文已经提及的,是B型单胺氧化酶抑制剂,可以用于治疗或预防其中MAO-B抑制剂可能会有益的疾病。这些疾病包括急性和慢性神经障碍、认知障碍和记忆缺失。可治疗的神经障碍是例如神经系统的创伤性或慢性变性过程,如阿尔茨海默病、其它类型的痴呆、轻微的认知缺陷或帕金森病。其它适应症包括精神病,如抑郁、焦虑、惊恐发作、社交恐怖、精神分裂症,饮食和代谢障碍,如肥胖症,以及预防和治疗由滥用酒精、尼古丁和其它成瘾性药物引起的戒断综合征。其它可治疗的适应症可为由癌症化疗引起的周围神经病(WO 97/33,572)、奖励缺乏综合征(WO 01/34,172)或治疗多发性硬化(WO 96/40,095),和其它神经炎性疾病。
式(I)化合物对于治疗和预防阿尔茨海默病和老年痴呆特别有用。
用下列方法测试化合物的药理学活性:
用Schlaeger和Christensen[Cytotechnology 15:1-13(1998)]描述的方法将编码人MAO-A和MAO-B的cDNA瞬时转染到EBNA细胞中。转染后,通过Polytron均浆器在含0.5mM EGTA和0.5mM苯基甲磺酰氟的pH 8.0的20mM Tris HCl缓冲液中均质处理细胞。以45,000×g离心获得细胞膜,经过用含0.5mM EGTA的pH8.0的20mM Tris HCl缓冲液进行的两个冲洗步骤后,将细胞膜最终重新混悬在以上缓冲液中,将等分试样在-80℃下保存备用。
用与Zhou和Panchuk-Voloshina描述的方法相适应的分光光度法,在96孔板中分析MAO-A和MAO-B酶活性[Analytical Biochemistry253:169-174(1997)]。简言之,在37℃下,在含不同浓度化合物的pH 7.4的0.1M磷酸钾缓冲液中培养细胞膜的等分试样30分钟。在此阶段之后,通过加入MAO底物酪氨连同1U/ml辣根过氧化物酶(Roche Biochemicals)和80μM N-乙酰基-3,7-二羟基吩嗪(Amplex Red,Molecular Probes)启动酶反应。在37℃下,以200μl的最终体积进一步培养样品30分钟,然后用SpectraMax平板读数器(Molecular Devices)以570nm的波长测定吸收度。在10μM氯吉兰的存在下测定MAO-A的背景(非特异)吸收度,或在10μM L-丙炔苯丙胺的存在下测定MAO-B的背景(非特异)吸收度。从抑制曲线测量IC50值,该抑制曲线采用9个抑制剂浓度一式两份、通过采用计算机程序将数据拟合成四参数逻辑方程而获得。
本发明化合物是特异性MAO-B抑制剂。在上述测试中测量的优选式(I)化合物的IC50值为1μM或更小,通常是0.1μM或更小,理想地是0.02μM或更小。
式(I)化合物可以用作药物,例如以药物制剂的形式。药物制剂可以口服施用,例如以片剂、包衣片、锭剂、硬和软明胶胶囊、溶液剂、乳剂或混悬剂的形式。然而,也可以经直肠给药,例如以栓剂的形式,或经胃肠道外给药,例如以注射溶液的形式。
式(I)化合物可以与药学惰性的无机或有机载体一起加工制成药物制剂。可以使用乳糖、玉米淀粉或其衍生物、滑石粉、硬脂酸或其盐等,例如用于片剂、包衣片、锭剂、硬和软明胶胶囊的载体。适于软明胶胶囊的载体是例如植物油、蜡、脂肪、半固体和液体多元醇等;然而根据活性物质的性质,软明胶胶囊通常不需要载体。适于生产溶液剂和糖浆剂的载体是例如水、多元醇、蔗糖、转化糖、葡萄糖等。诸如乙醇、多元醇、甘油、植物油等的辅剂可以用于式I化合物的水溶性盐的注射水溶液,但通常不是必需的。适于栓剂的载体是例如天然油或硬化油、蜡、脂肪、半固体或液体多元醇等。
另外,药物制剂可以含有防腐剂、增溶剂、稳定剂、润湿剂、乳化剂、甜味剂、着色剂、调味剂、调节渗透压的盐、缓冲剂、掩蔽剂或抗氧化剂。它们也可含有其它在治疗方面有价值的物质。
如先前提到的,包含式(I)化合物和治疗惰性赋形剂的药物也是本发明的目的,如同生产该药物的方法那样,所述方法包括将一种或多种式I化合物以及如果需要的话和一种或多种其它在治疗方面有价值的物质连同一种或多种治疗惰性的载体一起制成盖仑制剂的形式。
剂量可以在很大范围内改变,当然要符合各特定情况的个体需要。一般来说,口服或胃肠道外给药的有效剂量是0.01-20mg/kg/天,对于所述的所有适应症而言,0.1-10mg/kg/天的剂量是优选的。体重70kg的成人的日剂量相应地为0.7-1400mg/天,优选7-700mg/天。
提供下列实施例用于解释本发明。不应当认为它们限制了本发明的范围,而仅仅是示例本发明。缩写“RT”表示“室温”。
原料的合成
实施例A
N-乙酰基-L-天冬氨酸酐的制备
将N-乙酰基-L-天冬氨酸(35.0g,199.9mmol)在乙酸酐(100mL,1.06mol)中的搅拌的混悬液于80℃加热约1小时直至所有固体材料溶解。移去加热浴,将反应混合物于环境温度搅拌4小时。过滤收集产物,用叔丁基甲基醚洗涤,得到N-乙酰基-L-天冬氨酸酐(27.8g,88%),为白色晶体,[α]D-49.0°(c=2.5,Ac2O)。
实施例B
(S)-N-(5-氧代-四氢呋喃-3-基)-乙酰胺的制备
于0℃历经1小时向硼氢化钠(1.264g,33.41mmol)在四氢呋喃(100mL)中的搅拌的混悬液中分5批加入N-乙酰基-L-天冬氨酸酐(5.0g,31.82mmol,如实施例A中制备)。将白色混悬液温热至室温,搅拌3小时,再次冷却至0℃。向搅拌的混合物中缓慢加入冷水(约50ml),同时使温度达到15℃。于室温搅拌过夜后,真空蒸发四氢呋喃。将残余的水性溶液用水稀释至100mL,过Dowex 50X8离子交换柱(100g)。将离子交换柱用水冲洗(3×100mL)。将所得水性溶液真空浓缩,将残余物加入甲苯(30mL)和甲醇(70mL)的混合物中。真空蒸发溶剂。另外重复该操作(即,将残余物加入甲苯-甲醇中并再次浓缩)三次。将剩余的无色油状物(5.4g,由羟基酸和内酯的混合物组成)溶于乙酸(54mL)中。加入甲苯(54mL),将溶液于110℃搅拌2.5小时。此后,根据已经被浓缩和硅烷基化的反应物样品的GC分析,所有羟基酸被环化为所需的内酯。真空浓缩反应混合物。重复将残余物加入甲苯并浓缩的操作三次,得到粗品(4.2g),为白色固体。对于纯化,将粗品溶于乙腈(30mL)中。向溶液中加入甲苯(60mL),从混合物中真空除去部分乙腈直至产物开始结晶。过滤收集产物,用甲苯和叔丁基甲基醚洗涤,真空干燥,得到(S)-N-(5-氧代-四氢呋喃-3-基)-乙酰胺(3.8g,83%,基于N-乙酰基-L-天冬氨酸酐),为白色晶体。化合物结构通过1H-NMR、MS、IR和元素分析确定。
式(III)中间体的制备
实施例C
采用LiHMDS作为碱制备(S)-3-乙酰氨基-N-[4-(3-氟-苄氧基)-苯基]-4-羟基
-丁酰胺
于0℃,历经15分钟向(S)-N-(5-氧代-四氢呋喃-3-基)-乙酰胺(1.0g,6.99mmol,如实施例B所述制备)和4-(3-氟-苄氧基)-苯胺(1.366g,6.29mmol)在无水四氢呋喃中的搅拌的溶液中滴加双(三甲基甲硅烷基)氨基锂在四氢呋喃中的1M溶液(17.47mL,17.47mmol)。移去冷却浴,于环境温度继续搅拌。总共3.5小时反应时间后,滴加10%氯化铵水溶液(10mL),然后加入二氯甲烷(20mL)。过滤收集所沉淀的产物,真空干燥后得到(S)-3-乙酰氨基-N-[4-(3-氟-苄氧基)-苯基]-4-羟基-丁酰胺(2.0g,79%),为白色晶体,纯度为96.9%(HPLC面积)。化合物的结构通过1H-NMR、MS和IR确定。
实施例D
采用NaHMDS作为碱制备(S)-3-乙酰氨基-N-[4-(3-氟-苄氧基)-苯基]-4-羟基
-丁酰胺
如实施例C所述进行反应。但是,双(三甲基甲硅烷基)氨基锂在四氢呋喃中的1M溶液用双(三甲基甲硅烷基)氨基锂在四氢呋喃中的2M溶液(8.73mL,17.47mmol)代替。反应时间为4.5小时,分离产物后得到(S)-3-乙酰氨基-N-[4-(3-氟-苄氧基)-苯基]-4-羟基-丁酰胺(1.45g,58%),为白色晶体,纯度为95.4%(HPLC面积)。
式(I)化合物的制备
(S)-N-{1-[4-(3-氟-苄氧基)-苯基]-氧代-吡咯烷-3-基}-乙酰胺的制备
向偶氮二甲酸二叔丁酯(958mg,4.16mmol)在四氢呋喃(8mL)中的搅拌的溶液中加入三正丁基膦(886mg,4.16mmol)。将所得溶液于室温搅拌5分钟,冷却至0℃。在该温度下,历经5分钟分数批加入(S)-3-乙酰氨基-N-[4-(3-氟-苄氧基)-苯基]-4-羟基-丁酰胺(1.0g,2.77mmol,如实施例C所述制备)固体。采用四氢呋喃(4mL)进行冲洗。移去冷却浴,于室温继续搅拌。总共3小时反应时间后,将反应混合物用饱和碳酸氢钠水溶液(30mL)和二氯甲烷(40mL)萃取。分离有机相,用水洗涤。将水相用新鲜二氯甲烷萃取一次。合并二氯甲烷相,经硫酸钠干燥,真空浓缩,得到粗品。采用含有4%甲醇的二氯甲烷进行硅胶(90g)色谱法,得到白色固体(620mg),将其溶于温热丙酮(25mL)中。将溶液经真空浓缩至体积为约3mL。产物开始结晶,加入叔丁基甲基醚(10mL)。将混悬液于室温放置过夜,过滤收集晶体,真空干燥,得到(S)-N-{1-[4-(3-氟-苄氧基)-苯基]-5-氧代-吡咯烷-3-基}-乙酰胺(570mg,60%),纯度为98.4%(HPLC面积)。产品的对映异构纯度为er(S)/(R)>99.9∶0.1。
Claims (12)
2.根据权利要求1的方法,其中式(II)化合物与(S)-N-(5-氧代-四氢呋喃-3-基)-乙酰胺的反应在选自双(三甲基甲硅烷基)氨基锂或双(三甲基甲硅烷基)氨基钠的碱的存在下进行。
3.根据权利要求2的方法,其中式(II)化合物与(S)-N-(5-氧代-四氢呋喃-3-基)-乙酰胺的反应在四氢呋喃存在下进行。
4.根据权利要求1至3任一项的方法,其中式(III)化合物的环化在偶氮二甲酸酯联合三正丁基膦的存在下进行。
5.根据权利要求4的方法,其中偶氮二甲酸酯选自偶氮二甲酸二叔丁酯、偶氮二甲酸二乙酯、偶氮二甲酸二异丙酯或1,1′-(偶氮二羰基)二哌啶。
6.根据权利要求1至3任一项的方法,其中式(III)化合物的环化通过将式(III)化合物转化为磺酸酯来进行。
7.根据权利要求6的方法,其中式(III)化合物的环化采用甲磺酰氯在三乙胺中进行。
8.根据权利要求1至3、5和7任一项的方法,其中式(II)化合物是4-(3-氟-苄氧基)-苯胺,式(III)化合物是(S)-3-乙酰氨基-N-[4-(3-氟-苄氧基)-苯基]-4-羟基-丁酰胺,且式(I)化合物是(S)-N-{1-[4-(3-氟-苄氧基)-苯基]-5-氧代-吡咯烷-3-基}-乙酰胺。
9.根据权利要求4的方法,其中式(II)化合物是4-(3-氟-苄氧基)-苯胺,式(III)化合物是(S)-3-乙酰氨基-N-[4-(3-氟-苄氧基)-苯基]-4-羟基-丁酰胺,且式(I)化合物是(S)-N-{1-[4-(3-氟-苄氧基)-苯基]-5-氧代-吡咯烷-3-基}-乙酰胺。
10.根据权利要求6的方法,其中式(II)化合物是4-(3-氟-苄氧基)-苯胺,式(III)化合物是(S)-3-乙酰氨基-N-[4-(3-氟-苄氧基)-苯基]-4-羟基-丁酰胺,且式(I)化合物是(S)-N-{1-[4-(3-氟-苄氧基)-苯基]-5-氧代-吡咯烷-3-基}-乙酰胺。
12.根据权利要求11的式(III)中间体化合物,其为(S)-3-乙酰氨基-N-[4-(3-氟-苄氧基)-苯基]-4-羟基-丁酰胺。
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