CN1050840C - 咪唑脂氧合酶抑制剂 - Google Patents
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Abstract
能够抑制脂氧合酶并具有式(Ⅰ)的某些新的咪唑衍生物,其中Y是氢、C1-C8烷基、卤代C1-C4烷基、苯基、取代苯基、C7-C14苯基烷基、C7-C14(取代苯基)烷基、吡啶基、取代吡啶基、C6-C13吡啶基烷基或C6-C13(取代吡啶基)烷基,其中每个取代基独立地为卤素、硝基、氰基、C1-C4烷基、C1-C4烷氧基,卤代C1-C4烷基、卤代C1-C4烷氧基、NR4R5、CO2R4或CONR4R5,其中R4和R5各自独立地为氢或C1-C6烷基;Ar1和Ar2各自独立地为亚苯基、一取代的亚苯基或二取代的亚苯基,其中取代基独立地为卤素、C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷基或卤代C1-C4烷氧基;X和X1各自独立地为O、S、SO或SO2;R1是氢或C1-C4烷基;和R2和R3各自独立地为亚甲基、亚乙基或亚丙基。这些化合物适用于治疗哺乳动物的疾病例如支气管哮喘、皮肤病和关节炎,并且适合用作治疗这些疾病的药物组合物中的活性成分。
Description
技术领域
本发明涉及新的咪唑化合物。本发明的化合物抑制脂氧合酶的作用,并且适用于治疗或减轻哺乳动物、特别是人的炎性疾病、变应性疾病和心血管疾病。本发明还涉及含有这些化合物的药物组合物。
发明背景
已知花生四烯酸是几组生物活性内源性代谢物的生物前体。花生四烯酸代谢的第一步是通过磷脂酶A2的作用从膜磷脂中释放。然后花生四烯酸通过环氧合酶代谢,产生前列腺素包括前列环素和血栓烷,或者通过脂氧合酶代谢,产生氢过氧化脂肪酸,后者进一步转化为白三烯。
白三烯是非常有效的物质,它通常可以在毫微摩尔至微微摩尔的浓度范围内引起多种生物效应。肽白三烯(LTC4、LTD4、LTE4)是重要的支气管收缩药和血管收缩药,并且还可以通过增加毛细管通透性引起血浆渗出。LTB4是有效的趋化剂,促进白细胞流入,并且引起其随后在炎性部位的脱粒。白三烯的病理生理学作用与多种人类疾病有关,这些疾病包括哮喘、类风湿性关节炎和痛风、牛皮癣、成人呼吸窘迫综合征(ARDS)、炎性肠疾病(例如节段性回肠炎)、内毒素休克和局部缺血引起的心肌炎。预期任何抑制脂氧合酶作用的试剂在治疗急性和慢性炎性疾病方面都具有很大的价值。
已经发表了几篇关于脂氧合酶抑制剂的回顾文章。参见J.A.Salmon and L.G.Garland:Progress in Drug Research,1991,37,pp9-90(Birkhauser Veriag),H.Masamune and L.S.Melvin,Sr.:Annual Reports in MedicinalChemistry,1989,24,pp71-80(Academic Press),and B.J.Fitzsimmons and J.Rokach:Leukotrenes and Lipoxygenases,1989,pp427-502(Elsevier)。
EP 0488602 A1、EP 0409413 A2和EP 0375404 A2公开了与本发明化合物结构类似的化合物。
本发明人旨在制备能够抑制脂氧合酶作用的化合物,并且经过深入研究后,成功地合成了如本文详细公开的一系列化合物。
发明的简要说明
本发明提供了化学式I的新的咪唑化合物及其可药用的盐:其中:
Y是氢、C1-C8烷基、卤代C1-C4烷基、苯基、取代苯基、C7-C14苯基烷基、C7-C14(取代苯基)烷基、吡啶基、取代吡啶基、C6-C13吡啶基烷基或C6-C13(取代吡啶基)烷基,其中每个取代基独立地为卤素、硝基、氰基、C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷基、卤代C1-C4烷氧基、NR4R5、CO2R4或CONR4R5,其中R4和R5各自独立地为氢或C1-C6烷基;
Ar1和Ar2各自独立地为亚苯基、一取代的亚苯基或二取代的亚苯基,其中取代基独立地为卤素、C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷基或卤代C1-C4烷氧基;
X和X1各自独立地为O、S、SO或SO2;
R1是氢或C1-C4烷基;和
R2和R3各自独立地为亚甲基、亚乙基或亚丙基。
优选的一组本发明化合物由下列式I化合物组成:其中Y在咪唑环的2-位;Ar1是1,4-亚苯基或一取代的1,4-亚苯基;Ar2是1,3-亚苯基或一取代的1,3-亚苯基;X是O或S;X1是O;且R2和R3各自为亚乙基。在此组优选的化合物中,特别优选的化合物是那些其中Y是2-烷基;Ar1是1,4-亚苯基或2-氟-1,4-亚苯基;Ar2是1,3-亚苯基、2-氟-1,3-亚苯基或5-氟-1,3-亚苯基;X是O;且R1是甲基的化合物。最优选的是Y是2-甲基。
第二组优选的本发明化合物由下列式I化合物组成:其中Y是2-烷基;Ar1是1,4-亚苯基或2-氟-1,4-亚苯基;Ar2是1,3-亚苯基、2-氟-1,3-亚苯基或5-氟-1,3-亚苯基;X是O;X1是S;R1是甲基;且R2和R3各自为亚乙基。在第二组优选的化合物中,特别优选的是其中Y是2-甲基的化合物。
第三组优选的本发明化合物由下列式I化合物组成:其中Y是2-烷基;Ar1是1,4-亚苯基或一取代的1,4-亚苯基;Ar2是2,5-二氟-1,3-亚苯基;X和X1各自为O;R1是甲基;且R2和R3各自为亚乙基。在第三组优选的化合物中,特别优选的是其中Y是2-甲基的化合物。
本发明的详细描述
在本申请中,使用下列术语。
所用术语“卤素”是指氟、氯、溴或碘。
所用术语“烷基”是指直链或支链烃链基团,它包括(但不限于):甲基、乙基、正丙基、异丙基和正丁基等。
本文所用术语“烷氧基”是指-OR5(R5是烷基),它包括(但不限于):甲氧基、乙氧基、正丙氧基、异丙氧基和正丁氧基等。
术语“卤代烷基”是指被一个或多个卤素取代的上述烷基,它包括(但不限于):氯甲基、溴乙基和三氟甲基等。优选的卤代烷基是三氟甲基。
所用术语“卤代烷氧基”是指被一个或多个卤素取代的上述烷氧基,它包括(但不限于):氯甲氧基、溴乙氧基、二氟甲氧基和三氟甲氧基等。优选的卤代烷氧基是三氟甲氧基。
本文所用术语“取代苯基”和“取代吡啶基”是指最多具有3个取代基的苯基和吡啶基,并且这些取代基可以相同或不同。但是,优选一取代的苯基和一取代的吡啶基。
在术语“C7-C14(取代苯基)烷基”中,C7-C14是指苯基和烷基中的碳原子数,不包括取代基中的任何碳原子。类似地,在C6-C13(取代吡啶基)烷基”中,C6-C13仅仅是指吡啶基和烷基中的碳原子数。
一般合成
式I化合物或其可药用盐可以按照本领域专业人员已知的、适用于结构相关化合物的任何合成方法进行制备。例如,按照反应方案1中概括的反应方法制备式I化合物。
反应方案1其中Z是OH或可置换基团,并且Y、Ar1、Ar2、X、X1、R1、R2和R3与上述定义的含义相同。
方法A
在一个具体实施方案中,通过脱水作用,将其中Z是羟基的式II化合物与其中X是O的式III化合物偶合。可以使用多种脱水剂,但是进行该转化的便利方法是使用在反应惰性溶剂中的偶氮二甲酸二乙酯和三苯膦。适合的溶剂是二氯甲烷、四氢呋喃和甲苯。反应温度优选为0℃至室温,但是如果需要,可以使用更低或更高的温度。反应时间一般为几分钟至几小时。
方法B
或者,将其中Z是可置换基团(离去基团)的式II化合物与式III化合物偶合,优选在合适的碱存在下进行。合适的可置换基团Z是卤素或磺酰氧基;例如,氯、溴、碘、三氟甲磺酰氧基、甲磺酰氧基或对甲苯磺酰氧基,这些基团均可以容易地通过常规方法由相应的醇得到。用于该偶合反应的优选的碱是:例如,碱金属或碱土金属氢氧化物、醇盐、碳酸盐或氢化物,例如氢氧化钠、氢氧化钾、甲醇钠、乙醇钠、叔丁醇钾、碳酸钠、碳酸钾、氢化钠或氢化钾,或者胺如三乙胺、二异丙基乙胺或二甲氨基吡啶。优选的反应惰性溶剂包括:例如,丙酮、乙腈、二氯甲烷、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、二甲亚砜或四氢呋喃。反应温度优选为室温至溶剂的回流温度,但是如果需要,可以使用更低或更高的温度。反应时间一般为几小时至几天。
为了制备其中X是亚磺酰基或磺酰基的式I化合物,可以通过常规方法将其中X是S的式I化合物氧化。适合的氧化剂是:例如,过氧化氢、过氧酸如间氯过苯甲酸或过乙酸、碱金属过硫酸盐如过一硫酸钾或类似的氧化剂。优选的反应惰性溶剂包括:例如,丙酮、二氯甲烷、氯仿、四氢呋喃或水。反应温度优选在0℃至室温之间,但是如果需要,可以使用更低或更高的温度。反应时间一般为几分钟至几小时。
式III的原料可以通过本领域专业人员已知的常规方法制备。例如,J.Med.Chem.,1992,35,2600-2609和EP0375404 A2中所述的方法。
式II的原料可以通过本领域专业人员已知的常规方法制备。例如,按照反应方案2概括的反应制备式II化合物。
在第一步中,优选在合适的碱存在下,将式IV化合物与式W-Arl-A化合物偶合,得到式V化合物。合适的可置换基团W是卤素或磺酰氧基,例如氟、氯、溴、碘或三氟甲磺酰氧基。合适的吸电子基团A是例如氰基、醛、羧酸或羧酸酯。用于该偶合反应的优选的碱是:例如,碱金属或碱土金属氢氧化物、醇盐、碳酸盐或氢化物,例如氢氧化钠、氢氧化钾、甲醇钠、乙醇钠、叔丁醇钾、碳酸钠、碳酸钾、氢化钠或氢化钾,或者烷基金属如正丁基锂、溴化乙基镁或类似的碱。优选的反应惰性溶剂包括:例如,甲醇、乙醇、吡啶、N,N-二甲基甲酰胺、二甲亚砜、N-甲基吡咯烷-2-酮、N,N-二甲基乙酰胺或四氢呋喃。反应温度优选在50℃至150℃之间,但是如果需要,可以使用更低或更高的温度。反应时间一般为几小时至几天。该反应可以方便地在合适的催化剂例如四二(三苯膦)-钯、氯化二(三苯膦)-钯(II)、氧化亚铜、碘化亚铜、氯化亚铜或溴化亚铜存在下进行。
按照本领域专业人员已知的标准方法,将式V化合物转化为其中Z是羟基的式II化合物。因此,在步骤2中,通过用常规的还原剂如硼氢化钠、氢化铝锂、氢化二异丁基铝、硼烷-四氢呋喃配合物、硼烷-二甲硫配合物等还原,可以容易地制备式II化合物。
在前面的一般合成中提及的以及在本文的试验实施例中说明的产物可以按照标准方法进行分离,并且可以通过本领域专业人员已知的常规方法进行纯化,这些方法是例如蒸馏、重结晶和色谱技术。
包括一个或多个不对称中心的本发明的化合物可以以各种立体异构体形式存在。所有各种异构体形式及其混合物均包括在本发明的范围内。各种异构体可以通过标准方法得到。例如通过标准拆分技术可以将外消旋混合物分离成单个的对映体。通过立体选择合成、或者通过采用分级结晶或色谱技术分离混合物,可以得到单个的非对映体。
由于本发明化合物是碱性化合物,因此它们均可以与各种无机酸和有机酸形成多种酸加成盐。通过将本发明的新化合物与所选择的无机或有机酸在含水溶剂介质中或在合适的有机溶剂如甲醇或乙醇中接触,可以容易地制备其酸加成盐。然后通过沉淀或小心地蒸发溶剂,可以得到所需的固体盐。
用于制备上述本发明化合物的可药用酸加成盐的酸是那些形成无毒酸加成盐的酸,所述酸加成盐是例如盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐、乙酸盐、富马酸盐、酒石酸盐、琥珀酸盐、马来酸盐、葡糖酸盐、糖二酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐(即1,1′-亚甲基-二(2-羟基-3-萘甲酸)盐)。
还具有酸性基团的本发明化合物可以与各种可药用阳离子形成碱盐。这些盐的实例包括碱金属或碱土金属盐,特别是钠盐和钾盐。这些盐均可通过常规技术制备。用作制备本发明可药用碱盐的试剂的化学碱包括那些形成无毒碱盐的碱。这些具体的无毒碱盐包括那些从可药用阳离子如钠、钾、钙和镁等衍生的盐。通过用含有所需可药用阳离子的水溶液处理上述化合物,然后蒸发所得溶液至干(优选在减压条件下),可以容易地制备这些盐。或者,通过将酸性化合物的低级链烷酸溶液与所需碱金属醇盐混合在一起,然后采用与前面同样的方法将所得溶液蒸发至干,也可以制备这些盐。在每种情况下,优选使用化学计量量的试剂,以确保反应完全和所需终产物的最大产率。
本发明化合物抑制5-脂氧合酶的活性。该抑制作用可以采用大鼠腹膜腔(RPC)居留细胞(Japnese Journal ofInflammation:1987,7,145-150)和肝素化的人全血(HWB)(Br.J.of Pharmacol.:1990,99,113-118)经体外测定证实,二者均测定了所述化合物对花生四烯酸代谢的影响。所有在上述测定中试验的下列实施例均显示出具有抑制脂氧合酶活性的效力。对于脂氧合酶活性而言,某些优选化合物的IC50值很低,为0.001-1μM。
本发明化合物抑制脂氧合酶的能力使其适用于控制由花生四烯酸产生的内源性代谢物引起的哺乳动物、特别是人的症状。因此这些化合物在预防和治疗这些以花生四烯酸代谢物聚积为成因的疾病中是有价值的;这些疾病是例如变应性支气管哮喘、皮肤病、类风湿性关节炎和骨关节炎。
特别是,本发明化合物及其可药用盐适用于治疗或减轻人的炎性疾病。
为了治疗上述各种疾病,可以将该化合物及其可药用盐给人单独施用,或者优选按照标准制药技术,将其与可药用载体或稀释剂结合、以药物组合物的形式施用。该化合物可以以常规方式经口或非肠道途径施用。
当该化合物给人施用,用于预防或治疗炎性疾病时,口服剂量范围是每天每公斤接受治疗患者的体重约0.1-10mg,优选每天约0.1-4mg/kg,以单次剂量或多次剂量施用。如果需要经非肠道途径施用,则有效剂量为每天每公斤接受治疗患者的体重约0.05-5mg。在某些情况下,可能需要使用超出这些界限的剂量,因为剂量必需根据每个患者的年龄、体重和应答情况以及患者症状的严重程度和所施用的具体化合物的效力而变化。
对于口服施用来说,本发明化合物及其可药用盐可以例如以片剂、粉末、锭剂、糖浆剂或胶囊剂的形式或者以水溶液或悬浮液的形式施用。对于口服使用的片剂来说,常用的载体包括乳糖和玉米淀粉。通常还加入润滑剂如硬脂酸镁。对于胶囊剂来说,适用的稀释剂是乳糖和干玉米淀粉。当需要口服使用水悬浮液时,将活性成分与乳化剂和悬浮剂结合。如果需要,可以加入某些甜味剂和/或调味剂。对于肌内、腹膜内、皮下和静脉内使用来说,通常制备活性成分的无菌溶液,并且应该适当地调节溶液的pH并进行缓冲。对于静脉使用来说,应该控制溶质的总浓度使制剂等渗。
此外,特别是对于治疗哮喘而言,本发明的式I化合物可以经吸入法给人施用。为此,可以采用标准方法以喷雾剂或雾剂的形式施用。
通过下列实施例说明本发明。但是应该理解,本发明并不限于这些实施例的具体详述。除非另外指明,在270MHz测定质子核磁共振图谱(NMR),峰位以自四甲基硅烷向低场方向的每百万分之份数(ppm)表示。峰形如下给出:s-单峰,d-双峰,t-三峰,q-四峰,quint-五峰,m-多峰,br-宽峰。
实施例14-[3-[4-(1-咪唑基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃
在氮气氛下,于20分钟内向冷却至0℃并搅拌着的4-(1-咪唑基)苄醇(Eur.J.Med.Chem.,1992,27,219)(0.87g,5.0mmol)、4-(3-羟基苯基)-4-甲氧基-3,4,5,6-四氢-2H-吡喃(J.Med.Chem.,1992,35,2600)(1.03g,4.9mmol)和三苯膦(1.55g,5.9mmol)在THF(30ml)中的溶液中滴加偶氮二甲酸二乙酯(DEAD)(1.03g,12.0mmol)在THF(10ml)中的溶液。滴加完毕后,在0℃搅拌该混合物30分钟,并使其温热至室温,然后减压除去挥发性物质。残余物进行色谱法纯化(SiO2,230g;梯度洗脱,在二氯甲烷中的15%-30%丙酮),得到0.27g胶状标题化合物,它在室温下放置时固化。合并混有三苯膦氧化物的级分,浓缩至于,通过用二异丙醚研制进行固化,并且从二异丙醚/乙酸乙酯中重结晶,得到0.16g标题化合物。通过在二异丙醚/乙酸乙酯中重结晶进一步纯化合并的固体,得到标题化合物,为细小的无色针状结晶(0.30g,17%)。m.p.:129-130.5℃IR(KBr)cm-1:2960,2875,1607,1579,1524,1480,1306,1281,1251,1073,1061,1026.1H NMR(CDCl3)δ:7.78(t,1H,J=1Hz),7.56(d,2H,J=8Hz),7.43(d,2H,J=8Hz),7.32(t,1H,J=8Hz),7.28(dd,1H,J=1,8Hz),7.22(t,1H,J=1Hz),7.08-6.98(m,2H),6.94-6.88(m,1H),5.12(s,2H).3.92-3.81(m,4H),2.98(s,3H),2.10-1.92(m,4H).C22H24N2O3的分析计算值:C,72.51;H,6.64;N,7.69.实测值:C,72.37;H,6.74;N,7.66.
实施例24-甲氧基-4-[3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-3,4,5,6-四氢-2H-吡喃a.4-(2-甲基咪唑-1-基)苄醇
在氮气氛下,向冷却至10℃的NaH(0.612g,15.3mmol:60%矿物油悬浮液)在无水DMF(10ml)中的悬浮液中加入2-甲基咪唑(1.23g,15mmol)的DMF(8ml)溶液,在室温搅拌该混合物30分钟。向反应混合物中加入4-氟苯甲醛(1.90g,15.3mmol),并将所得溶液搅拌14小时。将反应混合物倒入冰冷却的饱和氯化铵水溶液(100ml)中,用乙酸乙酯(100ml×2)萃取。有机层用水(100ml)和盐水(80ml)洗涤,用硫酸镁干燥,减压除去溶剂。所得残余物经柱色谱法纯化(SiO2;用己烷:乙酸乙酯=1∶1洗脱,然后用乙酸乙酯洗脱),得到粗品4-(2-甲基咪唑-1-基)苯甲醛(1.0g),不需进一步纯化即可使用。
在15分钟内,向冷却至0℃并搅拌着的粗品4-(2-甲基咪唑-1-基)苯甲醛(1.0g)在甲醇(15ml)中的溶液中分批加入NaBH4(0.2g,5.2mmol),并将其搅拌1小时。向反应混合物中加入饱和氯化铵水溶液(50ml),用乙酸乙酯(100ml×2)萃取。有机层用水(100ml)、盐水(50ml)洗涤,用硫酸镁干燥,减压除去溶剂。粗产物用Et2O/乙酸乙酯混合物(3∶1,15ml)洗涤,得到标题化合物(0.51g,50%),为白色粉末。1H NMR(CDCl3)δ:7.5(d,2H,J=8Hz),7.28(d,2H,J=8Hz),7.01(d,1H,J=1Hz),6.99(d,1H,J=1Hz),4.78(s,2H),2.35(s,3H).b.4-甲氧基-4-[3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-3,4,5,6-四氢-2H-吡喃
按照对4-[3-[4-(1-咪唑基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃(实施例1)所述的方法,由4-(2-甲基咪唑-1-基)苄醇和4-(3-羟基苯基)-4-甲氧基-3,4,5,6-四氢-2H-吡喃制备标题化合物。m.p.:135.5-137℃IR(KBr)cm-1:1520,1416,1248,1073.1H NMR(CDCl3)δ:7.57(d,2H,J=8Hz).7.30-7.36(m,3H),7.00-7.07(m,4H),6.93(ddd,1H,J=8,3,1Hz),5.14(s,2H),3.82-3.91(m,4H),2.98(s,3H),2.38(s,3H),1.92-2.09(m,4H).
实施例34-甲氧基-4-[3-[4-(4-甲基咪唑-1-基)苄氧基]苯基]-3,4,5,6-四氢-2H-吡喃
按照对4-甲氧基-4-[3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-3,4,5,6-四氢-2H-吡喃(实施例2)所述的方法,用4-甲基咪唑和4-氟苯甲醛制备标题化合物。m.p.:120-121℃IR(KBr)cm-1:1525,1251,1076.1H NMR(CDCl3)δ:7.76(d,1H,J=1Hz),7.55(d,2H,J=9Hz),7.39(d,2H,J=-9Hz),7.32(t,1H,J=8Hz),7.00-7.26(m,3H),6.91(dd,1H,J=8,2Hz),5.11(s,2H),3.82-3.87(m,4H),2.98(s,3H),2.31(s,3H),1.92-2.04(m,4H).
实施例44-甲氧基-4-[3-[4-(2-苯基咪唑-1-基)苄氧基]苯基]-3,4,5,6-四氢-2H-吡喃a.4-(2-苯基咪唑-1-基)苄腈
在氮气氛下,将4-氟苄腈(3.63g,30mmol)、2-苯基咪唑(3.72g,30mmol)和无水K2CO3(4.15g,30mmol)在无水DMSO(30ml)中的混合物于100℃加热20小时。冷却至室温后,将反应混合物倾入冰冷却的饱和氯化铵水溶液(100ml)中,用Et2O(150ml×2)萃取。合并的萃取液用水(100ml)和盐水(80ml)洗涤,用硫酸镁干燥,减压除去溶剂。所得残余物经柱色谱法纯化(SiO2;用二氯甲烷∶乙酸乙酯∶乙醇=20∶1∶1洗脱),得到标题化合物(3.61g,49%)。IR(KBr)cm-1:2220.1H NMR(CDCl3)δ:7.74(d,2H,J=8Hz),7.27-7.38(m,8H),7.20(s,1H).b.4-(2-苯基咪唑-1-基)苄醇
在氮气氛下,向冷却至-78℃的4-(2-苯基咪唑-1-基)苄腈(3.2g,13mmol)在二氯甲烷(30ml)和甲苯(20ml)中的溶液中滴加氢化二异丁基铝(13ml,13mmol:在甲苯中的1.02M溶液),并将其搅拌1.5小时。然后向反应混合物中小心地加入饱和氯化铵水溶液(20ml),使其温热至室温。所得胶凝状混合物经硅藻土垫过滤,用乙酸乙酯(200ml)洗涤。滤液用0.3NHCl溶液(100ml)、水(200ml)和盐水(100ml)洗涤,用硫酸镁干燥有机层。减压除去溶剂,得到粗产物(2.5g),将粗产物溶于甲醇(30ml)中,并冷却至0℃。分批加入NaBH4(0.3g,8mmol),并将反应混合物搅拌30分钟。向反应混合物中加入饱和氯化铵水溶液(30ml),用乙酸乙酯(20ml×3)萃取。有机层用水(10ml)、盐水(10ml)洗涤,用硫酸镁干燥,减压除去溶剂。所得粗产物用乙酸乙酯(35ml)洗涤,得到标题化合物(0.81g,25%),为白色粉末。1H NMR(CDCl3)δ:7.37-7.41(m,4H),7.18-7.29(m,6H),7.15(t,1H,J=1Hz),4.75(s,2H),2.6(br,1H).c.4-甲氧基-4-[3-[4-(2-苯基咪唑-1-基)苄氧基]苯基]-3,4,5,6-四氢-2H-吡喃
按照对4-甲氧基-4-[3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-3,4,5,6-四氢-2H-吡喃(实施例2)所述类似的方法,制备标题化合物。m.p.:117-117.5℃IR(KBr)cm-1:1519,1468,1418,1310,1249,1070,706.1H NMR(CDCl3)δ:7.49(d,2H,J=9Hz),7.38-7.42(m,2H),7.32(t,1H,J=8Hz),7.23-7.30(m,6H),7.16(d,1H,J=1Hz),7.00-7.05(m,2H),6.91(dd,1H,J=9,2Hz),5.12(s,2H),3.82-3.91(m,4H),2.98(s,3H),1.92-2.09(m,4H).
实施例54-甲氧基-4-[3-[4-(4-苯基咪唑-1-基)苄氧基]苯基]-3,4,5,6-四氢-2H-吡喃
按照对4-甲氧基-4-[3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-3,4,5,6-四氢-2H-吡喃(实施例2)所述的方法,用4-苯基咪唑和4-氟苯甲醛制备标题化合物。m.p.:98-100.5℃IR(KBr)cm-1:1526,1487,1256,1072.1H NMR(CDCl3)δ:7.91(d,1H,J=1Hz),7.85(dd,2H,J=7,1Hz),7.60(d,2H,J=8Hz),7.58(s,1H),7.28-7.50(m,6H),7.06(d,1H,J=2Hz),7.02(d,1H,J=8Hz),6.92(dd,1H,J=8,2Hz),5.14(s,2H),3.83-3.87(m,4H).2.99(s,3H),1.92-2.09(m,4H).
实施例64-[5-氟-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃
按照与实施例2 b部分类似的方法制备标题化合物,不同的是使用4-(5-氟-3-羟基苯基)-4-甲氧基-3,4,5,6-四氢-2H-吡喃作为原料。m.p.:168-168.5℃IR(KBr)cm-1:1590,1520,1416,1138,1072.1H NMR(CDCl3)δ:7.56(d,2H,J=8Hz),7.34(d,2H,J=8Hz),7.04(d,1H,J=1Hz),7.01(d,1H,J=1Hz),6.83(br s,1H),6.75(ddd,1H,J=10,2,2Hz),6.64(ddd,1H,J=10,2,2Hz),5.11(s,2H),3.81-3.86(m,4H),2.99(s,3H),2.38(s,3H),1.88-1.99(m,4H).
实施例74-[3-[2-氟-4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃
按照与实施例2类似的方法,使用2,4-二氟苯甲酸乙酯和2-甲基咪唑作为原料,制备标题化合物。m.p.:121-122℃IR(KBr)cm-1:1585,1515,1299,1249,1073,900.1H NMR(CDCl3)δ:7.67(dd,1H,J=8,8Hz),7.34(dd,1H,J=8,8Hz),7.15(dd,1H,J=8,2Hz),7.01-7.11(m,5H),6.94(dd,1H,J=8,3Hz),5.19(s,2H),3.83-3.91(m,4H),2.99(s,3H),2.40(s,3H),1.92-2.10(m,4H).
使用适当的原料,按照与实施例1-7类似的方法制备实施例8-24的化合物。在某些情况下,于分离后将产物转化为盐酸盐。
实施例84-甲氧基-4-[3-[4-(2-苄基咪唑-1-基)苄氧基]苯基]-3,4,5,6-四氢-2H-吡喃m.p.:油状IR(KBr)cm-1:2955,1606,1586,1519,1485,1437,1306,1260,1079.1H NMR(CDCl3)δ:7.74-6.85(m,15H),5.12(s,2H),4.03(s,2H),3.94-3.76(m,4H),2.98(s,3H),2.10-1.89(m,4H).
实施例94-[3-[4-(2-乙基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃m.p.:油状IR(纯样)cm-1:1519,1429,1306,1255,1073.1H NMR(CDCl3)δ:7.57(d,2H,J=8Hz),7.33(dd,1H,J=8,8Hz),7.32(d,2H,J=8Hz),7.07(d,1H,J=1Hz),7.06(d,1H,J=3Hz),7.02(d,1H,J=8Hz),6.98(d,1H,J=1Hz),6.93(ddd,1H,J=8,3,1Hz),5.14(s,2H),3.82-3.88(m,4H),2.98(s,3H),2.67(q,2H,J=8Hz),1.92-2.09(m,4H),1.26(t,3H,J=8Hz).
实施例104-甲氧基-4-[3-[3-甲基-4-(2-甲基咪唑-1-基)苄氧基]苯基]-3,4,5,6-四氢-2H-吡喃m.p.:121.5-122℃IR(纯样)cm-1:1584,1305,1251,1072.1H NMR(CDCl3)δ:7.44(s,1H),7.38(d,1H,J=8Hz),7.33(dd,1H,J=8,8Hz),7.21(d,1H,J=8Hz),7.06-7.07(m,2H),7.02(d,1H,J=8Hz),6.93(dd,1H,J=8,2Hz),6.86(d,1H,J=1Hz),5.10(s,2H),3.82-3.88(m,4H),2.99(s,3H),2.19(s,3H),2.08(s,3H),1.97-2.04(m,4H).
实施例114-甲氧基-4-[3-[4-(2-吡啶-2-基)咪唑-1-基)苄氧基]苯基]-3,4,5,6-四氢-2H-吡喃m.p.:103-105℃IR(纯样)cm-1:3360,1598,1515,1455,1267.1H NMR(CDCl3)δ:8.32(d,1H,J=4Hz),7.92(d,1H,J=8Hz),7.70(dd,1H,J=1.8,8Hz),7.47(d,2H,J=8.4Hz),7.39-7.24(m,4H),7.21-7.11(m,2H),7.08-6.98(m,2H),6.96-6.87(m,1H),5.12(s,2H),3.94-3.77(m,4H),2.98(s,3H),2.10-1.90(m,4H).
实施例124-[3-[3-氟-4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃MW 396.46mp:101.5-102℃IR(KBr):1584,1524,1434,1304,1351,1073cm-1 1H NMR(CDCl3)δ:7.41-7.29(m,4H),7.07(d,J=1Hz,1H),7.05-7.02(m,2H),6.96(br,1H),6.91(dd,J=7,3Hz,1H),5.13(s,2H),3.91-3.82(m,4H),2.99(s,3H),2.31(s,3H),2.1-1.9(m,4H).
实施例134-[5-氟-3-[2-氟-4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃MW:414.46mp:133.5-134℃IR(KBr):1622,1593,1515,1139,1072,1039cm-1 1H NMR(CDCl3)δ:7.64(dd,J=8,8Hz,1H),7.15(dd,J=8,2Hz,1H),7.10(dd,J=10,2Hz,1H),7.05(d,J=2Hz,1H)7.01(d,J=2Hz,1H),6.85(br,1H),6.76(d,J=10Hz,1H,),6.65(ddd,J=10,2,2Hz,1H),5.16(s,2H),3.9-3.8(m,4H),3.00(s,3H),2.40(s,3H),2.1-1.8(m,4H).
实施例144-[3-[4-氟-2-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃MW:396.46mp:油状IR(纯样):1612,1603,1508,1253,1217,1073cm-1 1H NMR(CDCl3)δ:7.69(dd,J=9,4Hz,1H),7.3-7.2(m,2H),7.1-6.9(m,4H),6.88(t,J=2Hz,1H),6.73(dd,J=8,2Hz,1H),4.70(s,2H),3.9-3.8(m,4H),2.95(s,3H),2.25(s,3H),2.1-1.8(m,4H).
实施例154-[3-[2-氯-4-(2-甲基咪唑-1-基)苄氧基]-5-氟苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃盐酸盐MW:467.37mp:204-205℃IR(KBr):1613,1602,1441,1303,1146,1039cm-1 1H NMR(CDCl3)δ:7.89(d,J=8Hz,1H),7.51(br,1H),7.45(d,J=1Hz,1H),7.40(d,J=8Hz,1H),7.20(d,J=1Hz,1H),6.87(br,1H),6.79(ddd,J=10,2,2Hz,1H),6.65(ddd,J=10,2,2Hz,1H),5.22(s,2H),3.9-3.8(m,4H),3.02(s,3H),2.80(s,3H),2.0-1.8(m,4H).
实施例164-[3-[2-氯-4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃盐酸盐MW:449.38mp:224-225℃IR(KBr):1606,1305,1243,1066,1046,1038,755cm-1 1H NMR(CDCl3)δ:7.93(d,J=8Hz,1H),7.48(d,J=2Hz,1H),7.45(d,J=2Hz,1H),7.4-7.3(m,2H),7.19(d,J=2Hz,1H),7.1-7.0(m,2H),6.94(dd,J=8,2Hz,1H),5.25(s,2H),3.9-3.8(m,4H),3.01(s,3H),2.79(s,3H),2.1-1.9(m,4H).
实施例174-[5-氟-3-[2-甲基-4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃盐酸盐MW:446.95mp:207-208℃IR(KBr):1624,1591,1528,1439,1151,1073cm-1 1H NMR(CDCl3)δ:7.70(d,J=9Hz,1H),7.42(d,J=2Hz,1H),7.3-7.2(m,2H),7.17(d,J=2Hz,1H),6.85(br,1H),6.87(ddd,J=9,2,2Hz,1H),6.65(ddd,J=10,2,2Hz,1H),5.10(s,2H),3.9-3.8(m,4H),3.02(s,3H),2.76(s,3H),2.49(s,3H),2.0-1.8(m,4H).
实施例184-[5-氟-3-[4-(2-甲基咪唑-1-基)-2-三氟甲基苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃盐酸盐MW:500.92mp:198.5-199.5℃IR (KBr):1595,1314,1176,1141,1125,1062cm-1 1H NMR(CDCl3)δ:8.11(d,J=9Hz,1H),7.78(br,2H),7.48(d,J=2Hz,1H),7.24(d,J=2Hz,1H),6.85(br,1H),6.80(d,J=10Hz,1H),6.61(ddd,J=10,2,2Hz,1H),5.34(s,2H),3.9-3.8(m,4H),3.01(s,3H),2.81(s,3H),2.0-1.8(m,4H).
实施例194-甲氧基-4-[3-[4-(2-甲基咪唑-1-基)-2-三氟甲基苄氧基]苯基]-3,4,5,6-四氢-2H-吡喃盐酸盐MW:482.93mp:213-215℃IR(KBr):1442,1315,1172,1123,1065,1054cm-1 1H NMR(CDCl3)δ:8.15(d,J=8Hz,1H),7.8-7.6(m,2H),7.48(d,J=2Hz,1H),7.35(dd,J=8,8Hz,1H),7.23(d,J=2Hz,1H),7.1-7.0(m,2H),6.90(dd,J=7,3Hz,1H),5.37(s,2H),3.9-3.8(m,4H),3.00(s,3H),2.80(s,3H),2.1-1.9(m,4H).
实施例204-[2,4-二氟-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃盐酸盐MW:450.92mp:174.5-175.5℃IR(KBr):1606,1498,1455,1444,1281,1094,1023,818cm-1 1H NMR(CDCl3)δ:7.75(d,J=8Hz,2H),7.5-7.4(m,3H),7.20(d,J=2Hz,1H),7.09-6.91(m,2H),5.25(s,2H),3.9-3.8(m,4H),3.05(s,3H),2.76(s,3H),2.2-2.1(m,4H).
实施例214-[5-氟-3-[2-甲氧基-4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃盐酸盐MW:462.95mp:197.5-198.5℃IR(KBr):1612,1590,1440,1329,1242,1150,1042cm-1 1H NMR(CDCl3)δ:7.70(d,J=7Hz,1H),7.42(br,1H),7.21(d,J=2Hz,1H),7.1-6.9(m,2H),6.86(br,1H),6.75(d,J=9Hz,1H),6.64(d,J=10Hz,1H),5.14(s,2H),3.97(s,3H),3.9-3.8(m,4H),3.01(s,3H),2.79(s,3H),1.9-2.0(m,4H).
实施例224-[3-[4-(2-乙基咪唑-1-基)苄氧基]-5-氟苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃盐酸盐MW:446.95mp:210-211℃IR(KBr):1624,1596,1523,1148,1073,1038cm-1 1H NMR(CDCl3)δ:7.71(d,J=8Hz,2H),7.47(d,J=2Hz,1H),7.42(d,J=8Hz,2H),7.15(d,J=2Hz,1H),6.85(br,1H),6.77(ddd,J=10,2,2Hz,1H),6.63(ddd,J=10,2,2Hz,1H),5.17(s,2H),3.9-3.8(m,4H),3.06(q,J=8Hz,2H),3.01(s,3H),2.0-1.9(m,4H),1.41(t,J=8Hz,3H).
实施例234-[2,5-二氟-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃盐酸盐MW:450.92mp:228-231℃(分解)IR(KBr):1527,1484,1335,1103,853,771cm-1 1H NMR(CDCl3)δ:7.73(d,J=8Hz,2H),7.43(d,J=8Hz,2H),7.43(d,J=2Hz,1H),7.19(d,J=2Hz,1H),6.8-6.7(m,2H),5.20(s,2H),3.9-3.8(m,4H),3.12(s,3H),2.77(s,3H),2.3-2.0(m,4H).
实施例244-[6-氟-2-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃MW:396.46mp:149-150.5℃IR(KBr):1606,1518,1454,1418,1304,1282,1071cm-1 1H NMR(CDCl3)δ:7.62(d,J=9Hz,2H),7.33(d,J=8Hz,2H),7.23(ddd,J=88,6Hz,1H),7.04(d,J=2Hz,1H),7.02(d,J=2Hz,1H),6.79(d,J=8Hz,1H),6.73(ddd,J=13,8Hz,1H),5.17(s,2H),4.0-3.9(m,2H),3.8-3.7(m,2H),3.12(s,3H),2.5-2.4(m,2H),2.39(s,3H),2.4-2.3(m,2H).
实施例254-[5-氟-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃
按照EP 0385662 A2所述方法得到4-(5-氟-3-羟基苯基)-4-甲氧基-3,4,5,6-四氢-2H-吡喃,为白色固体。mp:130-132℃1H NMR(CDCl3)δ:6.70-6.61(m,2H),6.50(dt,J=10and2Hz,1H),6.30(s,1H),3.88-3.84(m,4H),3.02(s,3H),2.05-1.90(m,4H).IR(KBr):3250,1620,1610,1440,1320,1130cm-1元素分析: C12H15FO3计算值 C63.70;H6.70%实测值 C63.72;H6.83%a.4-(2-甲基咪唑-1-基)苯甲酸乙酯
在氮气氛下,将2-甲基咪唑(50g,0.6mol)、4-氟苯甲酸乙酯(100g,0.6mol)和碳酸钾(415g,3mol)在无水DMSO(1.51)中的混合物在120℃加热66小时。冷却至室温后,将反应混合物倒入冰冷却的水(11)中,用乙醚(750ml×2)萃取。有机相用水(500ml)和盐水(500ml)洗涤,用硫酸镁干燥并蒸发。残余固体用从乙酸乙酯-己烷重结晶,得到4-(2-甲基咪唑-1-基)苯甲酸乙酯(47g,33%),为黄色针状晶体。mp:72-73℃1H NMR(CDCl3)δ:8.22-8.12(m,2H),7.43-7.33(m,2H),7.10-6.99(m,2H),4.42(q,J=7Hz,2H),2.42(s,3H),1.43(t,J=7Hz,3H).IR(KBr):1720,1610,1520,1420,1280cm-1元素分析: C13H14N2O2计算值 C67.80;H6.10;N12.20%实测值 C67.97;H6.17;N12.20%b.4-(2-甲基咪唑-1-基)苄醇
在氮气氛下,在30分钟内向冷却至-75℃的4-(2-甲基咪唑-1-基)苯甲酸乙酯(46g,0.2mol)的无水二氯甲烷(11)溶液中小心地加入氢化二异丁基铝(540ml,0.93M的己烷溶液),然后将混合物慢慢地温热至室温。搅拌5小时后,在冰浴中冷却反应混合物,并小心地加入甲醇(30ml)。然后加入罗谢尔盐的30%水溶液(500ml),在室温搅拌该混合物16小时。滤出不溶性物质(主要是产物),分离有机相,并用水(500ml)洗涤,用硫酸镁干燥并蒸发。合并所得固体,将其从乙醇(约300ml)中重结晶,得到4-(2-甲基咪唑-1-基)苄醇(35.6g,95%),为白色针状晶体。mp:167-168℃1H NMR(DMSO-d6)δ:7.50-7.33(m,4H),7.25(d,J=1.5Hz,1H),6.90(d,J=1.1Hz,1H),5.33(t,J=6Hz,1H),4.56(d,J=6Hz,2H),2.27(s,3H).IR(KBr):3200,1520,1420,1520,1310,1060cm-1元素分析: C11H12N2O计算值 C70.20;H6.40;N14.90%实测值 C70.12;H6.41;N14.81%c.4-(2-甲基咪唑-1-基)苄基氯盐酸盐
在室温下将4-(2-甲基咪唑-1-基)苄醇(1.28g,6.8mmol)在SOCl2(5ml)中搅拌30分钟,然后减压除去挥发性物质。所得粗产物用最少量的无水乙醚洗涤,并真空干燥,得到4-(2-甲基咪唑-1-基)苄基氯盐酸盐(1.65g,定量),为白色固体。对于游离碱:1H NMR(CDCl3)δ:7.56-7.47(m,2H),7.34-7.25(m,2H),7.03(s,1H),7.00(s,1H),4.65(s,2H),2.37(s,3H).d.4-[5-氟-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃
将4-(5-氟-3-羟基苯基)-4-甲氧基-3,4,5,6-四氢-2H-吡喃(1.4g,6.8mmol)、4-(2-甲基咪唑-1-基)苄基氯盐酸盐(1.65g,6.8mmol)和碳酸钾(7.2g,68mmol)在无水DMF(10ml)中的混合物在120℃搅拌2小时。将混合物倒入水(100ml)中,用乙酸乙酯-苯(300ml,2∶1v/v)萃取。有机相用水(100ml)和盐水(100ml)洗涤,用硫酸镁干燥并蒸发。残余的黄色固体在硅胶(100g)上进行柱色谱法纯化,用二氯甲烷/甲醇=10∶1洗脱,从乙酸乙酯-己烷中重结晶,得到4-[5-氟-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃(1.0g,39%),为米色固体。mp:168-168.5℃1H NMR(CDCl3)δ:7.56(d,J=8Hz,2H),7.34(d,J=8Hz,2H),7.04(d,J=1Hz,1H),7.01(d,J=1Hz,1H),6.83(br,s,1H),6.75(ddd,J=10,2and2Hz,1H),6.64(ddd,J=10.2and2Hz,1H),5.11(s,2H),3.86-3.81(m,4H),2.99(s,3H),2.38(s,3H),1.99-1.88(m,4H).IR(KBr):1590,1520,1416,1138,1072cm-1元素分析: C23H25FN2O3计算值 C69.68;H6.36;N7.07;F4.79%实测值 C69.62;H6.39;N7.02;F4.62%
按照实施例25d部分的一般方法,由适当的咪唑基苄基氯和酚制备实施例26-40的化合物。在某些情况下,将产物进一步转化为其盐酸盐。
实施例264-[5-氟-3-[4-(2-异丙基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃盐酸盐MW:460.97mp:140-143℃IR(KBr):1620,1590,1520,1300,1l50cm-1 1H NMR(DMSO-d6)δ:7.86(d,J=2.2Hz,1H),7.83(d,J=2.2Hz,1H),7.74(d,J=8.4Hz,2H),7.68(d,J=8.4Hz,2H),6.95-6.77(m,3H),5.28(s,2H),3.78-3.59(m,4H),3.15-3.00(m,1H),2.89(s,3H),2.00-1.80(m,4H),1.31(d,J=7.0Hz,6H).
实施例274-[5-氟-3-[4-(2-丙基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃盐酸盐MW:460.97mp:142-146℃IR(KBr):1620,1590,1530,1440,1290,1140cm-1 1H NMR(DMSO-d6)δ:7.89(d,J=1.8Hz,1H),7.82(d,J=2.2Hz,1H),7.88-7.63(m,4H),6.95-6.77(m,3H),5.27(s,2H),3.77-3.59(m,4H),2.89(s,3H),2.86(t,J=7.7Hz,2H),2.00-1.80(m,4H),1.70-1.52(m,2H),0.79(t,J=7.3,3H).
实施例284-[2,3-二氟-5-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃盐酸盐MW:450.92mp:>200℃IR(KBr):1600,1520,1480,1220,880cm-1 1H NMR(DMSO-d6)δ:7.90(d,J=1.8Hz,1H),7.79(d,J=1.8Hz,1H),7.77-7.62(m,4H),7.26-7.15(m,1H),6.84-6.75(m,1H),5.24(s,2H),3.79-3.60(m,4H),2.98(s,3H),2.54(s,3H),2.10-1.90(m,4H).
实施例294-[2-氟-5-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃盐酸盐MW:432.93mp:>200℃IR(KBr):1600,1580,1520,1480,1060,1050,870cm-1 1H NMR(DMSO-d6)δ:7.89(d,J=2.2Hz,1H),7.79(d,J=2.2Hz,1H),7.76-7.62(m,4H),7.14(dd,J=8.8,11.7Hz,1H),7.07-6.91(m,2H),5.22(s,2H),3.78-3.60(m,4H),2.95(s,3H),2.55(s,3H),2.10-1.90(m,4H).
实施例304-[2,6-二氟-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃MW:414.45mp:油状IR(膜):2950,1580,1480,1420,1300,1250cm-1 1H NMR(CDCl3)δ:7.57(d,J=8.4Hz,m,2H),7.33(d,J=8.4Hz,2H),7.04(d,J=1.5Hz,1H),7.01(d,J=1.5Hz,1H),6.97(ddd,4.8,8.8,8.8Hz,1H),6.88-6.75(m,1H),5.13(s,2H),4.00-3.70(m,4H),3.13(s,3H),2.37(s,3H),2.40-2.20(m,4H).
实施例314-[2-氟-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃MW:396.46mp:油状IR(膜):1520,1460,1420,1270,1070cm-1 1H NMR(CDCl3)δ:7.62-7.54(m,2H),7.38-7.29(m,2H),7.12-6.92(m,5H),5.18(s,2H),3.98-3.78(m,4H),3.09(s,3H),2.38(s,3H),2.29-2.05(m,4H).
按照与实施例43类似的方法,将该产物转化为其对甲苯磺酸盐。MW:568.67mp:170-171℃IR(KBr):1620,1530,1480,1280,1240,1160cm-1 1H NMR(DMSO-d6)δ:7.91(d,J=2.2Hz,1H),7.81-7.62(m,5H),7.52-7.43(m,2H),7.32-7.06(m,4H),7.01-6.91(m,1H),5.28(s,2H),3.80-3.61(m,4H),2.95(s,3H),2.53(s,3H),2.28(s,3H),2.13-1.90(m,4H).
实施例324-甲氧基-4-[4-[3-(2-甲基咪唑-1-基)苄氧基]苯基]-3,4,5,6-四氢-2H-吡喃MW:378.47mp:123-126℃IR(KBr):1610,1507,1230,1183,1072,1008cm-1 1H NMR(CDCl3)δ:7.56-7.21(m,6H),7.06-6.93(m,4H),5.14(s,2H),3.94-3.75(m,4H),2.95(s,3H),2.34(s,3H),2.10-1.90(m,4H).
实施例334-甲氧基-4-[4-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-3,4,5,6-四氢-2H-吡喃MW:378.47mp:150-151℃IR(KBr):1610,1520,1510,1420,1305,1245,1210,1075,1000cm-1 1H NMR(CDCl3)δ:7.57(d,J=8.4Hz,2H),7.39-7.28(m,4H),7.06-6.95(m,4H),5.13(s,2H),3.95-3.75(m,4H),2.96(s,3H),2.38(s,3H),2.10-1.90(m,4H).
实施例344-[5-氟-3-[3-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃MW:396.46mp:油状IR(膜):2960,1595,1500,1445,1305cm-1 1H NMR(CDCl3)δ:7.58-7.44(m,2H),7.39(br s,1H),7.33-7.21(m,1H),7.08-6.98(m,2H),6.86-6.56(m,3H),5.12(s,2H),3.93-3.73(m,4H),2.98(s,3H),2.36(s,3H),2.12-1.85(m,4H).
实施例354-[5-氟-3-[4-(2-三氟甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃MW:450.44mp:96-98℃IR(KBr):1695,1440,1190,1130cm-1 1H NMR(CDCl3)δ:7.57(d,J=8.8Hz,2H),7.41(d,J=8.4Hz,2H),7.24(d,J=1.5Hz,1H),7.16(d,J=1.1,1H),6.85-6.60(m,3H),5.14(s,2H),3.90-3.80(m,4H),2.98(s,3H),2.05-1.85(m,4H).
实施例364-乙氧基-4-[5-氟-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-3,4,5,6-四氢-2H-吡喃盐酸盐MW:446.95mp:195-197℃IR(KBr):3235,2905,2870,1621,1593,1516,1417,1382,1335,1299,1145cm-1 1H NMR(DMSO-d6)δ:7.87(d,J=1.8Hz,1H),7.77(d,J=21.8Hz,1H),7.71(d,J=8.4Hz,2H),7.68(d,J=8.4Hz,2H),6.92-6.77(m,3H),5.26(s,2H),3.70-3.65(m,4H),3.02(q,J=7.0Hz,2H),2.56(s,3H),1.97-1.81(m,4H),1.05(t,J=7.0Hz,3H).
实施例374-[5-氟-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-羟基-3,4,5,6-四氢-2H-吡喃MW:382.44mp:190-191℃IR(KBr):3235,2905,2870,1621,1593,1516,1417,1382,1335,1299,1145cm-1.1H NMR(CDCl3)δ:7.57-7.53(m,2H),7.35-7.31(m,2H),7.02(d,J=1.5Hz,1H),7.01(d,J=1.5Hz,1H),6.96(m,1H),6.85(ddd,J=1.5,2.2,9.5Hz,1H),6.63(ddd,J=2.2,2.6,9.9Hz,1H),5.11(s,2H),3.99-3.83(m,4H),2.37(s,3H),2.21-2.08(m,2H),1.97(br s,1H),1.70-1.61(m,2H).
实施例384-[5-氟-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲硫基-3,4,5,6-四氢-2H-吡喃盐酸盐MW:448.99mp:216.0-217.0℃IR(KBr):2600,1620,1590,1530,1430,1140cm-1 1H NMR(DMSO-d6)δ:7.89(d,J=2.2Hz,1H),7.78(d,J=2.2Hz,1H),7.74(d,J=8.4Hz,2H),7.66(d,J=8.4Hz,2H),6.89(s,2H),6.85(d,J=1.8Hz,1H),5.26(s,2H),3.85-3.75(m,2H),3.62-3.53(m,2H),2.54(s,3H),2.14-2.05(m,4H),1.63(s,3H).
实施例394-[5-氟-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲亚磺酰基-3,4,5,6-四氢-2H-吡喃盐酸盐MW:464.99mp:175.1-175.9℃IR(KBr):2600,1620,1600,1590,1530,1150,1055,1030,990cm-1 1H NMR(DMSO-d6)δ:7.89(d,J=1.8Hz,1H),7.78(s,1H),7.74(d,J=8.2Hz,2H),7.67(d,J=8.2Hz,2H),7.02(d,J=11.0Hz,1H),6.95-6.87(m,2H),5.29(s,2H),3.92(d,J=11.6Hz,1H),3.80(d,J=11.6Hz,1H),3.40-3.18(m,2H),2.55(s,3H),2.38-2.20(m,2H),2.19-1.96(m,2H),1.91(s,3H).
实施例404-[5-氟-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲磺酰基-3,4,5,6-四氢-2H-吡喃盐酸盐MW:480.99mp:230.1-230.9℃IR(KBr):2850,1625,1590,1530,1330,1300,1290,1270,1140,1130,1100cm-1 1H NMR(DMSO-d6)δ:7.87(d,J=2.2Hz,1H),7.78(d,J=2.2Hz,1H),7.75(d,J=8.4Hz,2H),7.65(d,J=8.4Hz,2H),7.11(s,1H),7.07(s,2H),5.29(s,2H),3.89-3.82(m,2H),3.18-3.02(m,2H),2.67(s,3H),2.62-2.48(m,2H),2.54(s,3H),2.29-2.14(m,2H).
实施例414-[5-氟-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃盐酸盐
在室温下,向4-[5-氟-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃(0.5g,1.3mmol)的无水二氯甲烷(5ml)溶液中加入“氯化氢;甲醇试剂10”(4ml,Tokyo Chemical Industries)。搅拌10分钟后,减压除去溶剂。粗产物从异丙醇(4ml)-乙醇(3ml)中重结晶,得到4-[5-氟-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃盐酸盐(0.3g,55%),为白色固体。mp:233-234℃(分解)1H NMR(CDCl3)δ:7.71(d,J=8Hz,2H),7.43(d,J=2Hz,1H),7.42(d,J=8Hz,2H),7.19(d,J=2Hz,1H),6.84(br,s,1H),6.77(ddd,J=10,2and2Hz,1H),6.62(ddd,J=10,2and2Hz,1H),5.16(s,2H),3.9-3.8(m,4H),3.00(s,3H),2.77(s,3H),2.0-1.8(m,4H).IR(KBr):1625,1590,1528,1327,1147cm-1元素分析: C23H25FN2O3HCl计算值 C63.81;H6.05;N6.47;Cl8.19;F4.39%实测值 C63.63;H6.17;N6.42;Cl8.18;F4.32%
实施例424-[5-氟-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃富马酸盐
向4-[5-氟-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃(150mg,0.38mmol)的甲醇(3ml)溶液中加入富马酸(44mg,0.38mmol)。将所得溶液真空浓缩。残余的固体从乙醇中重结晶,得到152mg(77%)4-[5-氟-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃富马酸盐,为白色粉末。mp:154-155℃IR(KBr):1626,1595,1529,1392,1290,1144,1075cm-1 1H NMR(DMSO-d6)δ:7.62(br d,J=8.4Hz,2H),7.49(br d,J=8.4Hz,2H),7.31(d,J=1.1Hz,1H),7.00-6.74(m,4H),6.62(s,2H),5.21(s,2H),3.80-3.58(m,4H),2.89(s,3H),2.30(s,3H),2.00-1.80(m,4H).
实施例434-[5-氟-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃对甲苯磺酸盐
按照与实施例42类似的方法,用对甲苯磺酸代替富马酸制备4-[5-氟-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃对甲苯磺酸盐。mp:168-171℃IR(KBr):1625,1595,1530,1220,1190cm-1 1H NMR(DMSO-d6)δ:7.90(d,J=2.2Hz,1H),7.78(d,J=2.2Hz,1H),7.74(br d,J=8.4Hz,2H),7.66(br d,J=8.4Hz,2H),7.47(br d,J=8.2Hz,2H),7.11(br d,J=7.7Hz,2H),6.95-6.75(m,3H),5.26(s,2H),3.80-3.60(m,4H),2.89(s,3H),2.52(s,3H),2.28(s,3H),2.00-1.80(m,4H).
实施例444-[5-氟-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃L-酒石酸盐
按照与实施例42类似的方法,用L-酒石酸代替富马酸制备4-[5-氟-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃L-酒石酸盐。mp:167-171℃IR(KBr):1614,1528,1439,1300,1075cm-1 1H NMR(DMSO-d6)δ:7.62(br d,J=8.4Hz,2H),7.49(br d,J=8.4Hz,2H),7.32(br s,1H),7.08-6.73(m,4H),5.21(s,2H),4.28(s,2H),3.78-3.55(m,4H),3.40(br,2H),2.89(s,3H),2.29(s,3H),2.00-1.78(m,4H).
实施例454-甲氧基-4-[3-[4-(2-甲基咪唑-1-基)苄硫基]苯基]-3,4,5,6-四氢-2H-吡喃mp:95.5-96℃IR(KBr):1518,1421,1303,1070,762cm-1 1H NMR(CDCl3)δ:7.38(d,J=8Hz,2H),7.33-7.23(m,4H),7.20(d,J=8Hz,2H),7.02(d,J=1Hz,1H),6.97(d,J=1Hz,1H),4.16(s,2H),3.85-3.79(m,4H),2.93(s,3H),2.34(s,3H),1.95-1.90(m,4H).
实施例46
采用标准方法,按照下列反应程序,由合适的酚制备下列4-甲氧基-4-(羟基苯基)-3,4,5,6-四氢-2H-吡喃化合物:
(i)以其叔丁基二甲基甲硅烷基醚的形式保护酚羟基;
(ii)在-78℃,用仲丁基锂或正丁基锂锂化(lithiation);
(iii)与四氢-4H-吡喃-4-酮缩合;
(iv)用氢化钠或正丁基锂/碘甲烷将如此形成的叔羟基甲基化;和
(v)用氟化四丁铵除去甲硅烷基保护基。1. 4-(2,4-二氟-3-羟基苯基)-4-甲氧基-3,4,5,6-四氢-2H-吡喃
由2,6-二氟苯酚制备。MW:244.261H NMR(CDCl3)δ:6.7-6.9(m,2H),3.8-4.0(m,4H),3.06(s,3H),2.0-2.2(m,4H).2. 4-(2-氟-3-羟基苯基)-4-甲氧基-3,4,5,6-四氢-2H-吡喃
由2-氟苯酚制备。MW:226.271H NMR(CDCl3)δ:7.07-6.92(m,2H),6.88-6.79(m,1H),5.71(d,J=5.5Hz,1H),4.00-3.78(m,4H),3.08(s,3H),2.27-2.02(m,4H).3. 4-(2-氟-5-羟基苯基)-4-甲氧基-3,4,5,6-四氢-2H-吡喃
由4-氟苯酚制备。MW:226.271H NMR(CDCl3)δ:6.92(dd,J=8.4,11.7Hz,1H),6.81(dd,J=2.9,6.2Hz,1H),6.72(ddd,J=3.3,3.3,8.4Hz,1H),5.58(br s,1H),3.99-3.78(m,4H),3.10(s,3H),2.26-2.03(m,4H).4. 4-(2,3-二氟-5-羟基苯基)-4-甲氧基-3,4,5,6-四氢-2H-吡喃
由3,4-二氟苯酚制备。MW:244.261H NMR(CDCl3)δ:6.70-6.50(m,2H),3.98-3.76(m,4H),3.11(s,3H),2.25-2.00(m,4H).5. 4-(2,6-二氟-3-羟基苯基)-4-甲氧基-3,4,5,6-四氢-2H-吡喃
由2,4-二氟苯酚制备。MW:244.261H NMR(CDCl3)δ:6.94(ddd,J=4.8,9.2,9.2Hz,1H),6.78(ddd,J=2.2,9.2,11.3Hz,1H),5.24(d,J=6.23Hz,1H),4.00-3.70(m,4H),3.13(s,3H),2.39-2.17(m,4H).6. 4-(4-羟基苯基)-4-甲氧基-3,4,5,6-四氢-2H-吡喃
由4-溴苯酚制备。MW:208.281H NMR(CDCl3)δ:7.30-7.21(m,2H),6.87-6.78(m,2H),5.45(s,1H),3.95-3.76(m,4H),2.95(s,3H),2.11-1.90(m,4H).
实施例474-(3-羟基-5-氟苯基)-4-甲亚磺酰基-3,4,5,6-四氢-2H-吡喃
向冷却至0℃并搅拌着的4-(3-羟基-5-氟苯基)-4-甲硫基-3,4,5,6-四氢-2H-吡喃(749mg,3.1mmol)(EP 462830 A2(1991))在甲醇-水(1∶1v/v;20ml)中的溶液中加入NaIO4(710mg,3.3mmol),移走冰浴,在室温搅拌该混合物2小时。将反应混合物倒入水(50ml)中,用乙酸乙酯(50ml)萃取。有机萃取物用水(50ml)、盐水(50ml)洗涤,用硫酸镁干燥并真空浓缩。残余的固体在硅胶上经柱色谱法纯化(SiO2,150g;乙酸乙酯),得到752mg(94%)标题化合物,为白色固体。1H-NMR(CDCl3)δ:8.93(s,1H),6.77(s,1H),6.60(d,J=9.9Hz,1H),6.53(d,J=10.3Hz,1H),4.09-3.88(m,2H),3.66-3.48(m,2H),2.50-2.29(m,2H),2.20-2.00(m,2H),2.06(s,3H).
实施例484-(5-氟-3-羟基苯基)-4-甲磺酰基-3,4,5,6-四氢-2H-吡喃
向搅拌着的4-(5-氟-3-羟基苯基)-4-甲硫基-3,4,5,6-四氢-2H-吡喃(660mg,2.7mmol)的氯仿(20ml)溶液中加入mCPBA(1.48g,6.0mmol),并将该混合物在室温搅拌过夜。向反应混合物中加入氢氧化钙(3mmol),并且剧烈搅拌反应混合物。过滤除去不溶性物质并浓缩滤液。残余的固体在硅胶上经柱色谱法纯化(SiO2,150g;己烷/乙酸乙酯(1∶2)),得到545mg(81%)标题化合物,为白色固体。1H-NMR(CDCl3)δ:6.86(dd,J=2.2,2.2Hz,1H),6.82(ddd,J=10.2,2.2,2.2Hz,1H),6.64(ddd,J=9.5,2.2,2.2Hz,1H),5.55(s,1H),4.08-3.97(m,2H),3.49-3.36(m,2H),2.66-2.50(m,2H),2.53(s,3H),2.41-2.30(m,2H).
实施例49
按照与实施例2(对醛)、实施例4(对腈)或实施例25(对酯)所述的类似方法,由合适的原料合成下列(1-咪唑基)苄醇化合物。1. 2-氯-4-(2-甲基咪唑-1-基)苄醇
由2-甲基咪唑和2-氯-4-氟苯甲酸乙酯制备。MW:222.671H NMR(CDCl3)δ:7.69(d,J=8Hz,1H),7.32(d,J=2Hz,1H),7.24(dd,J=8,2Hz,1H),7.01(d,J=1Hz,1H),6.99(d,J=1Hz,1H),4.86(s,2H),3.1(br,1H),2.36(s,3H).2. 3-甲基-4-(2-甲基咪唑-1-基)苄醇
由2-甲基咪唑和4-氟-3-甲基苯甲酸乙酯制备。MW:202.261H NMR(CDCl3)δ:7.37(br,1H),7.31(d,J=8Hz,1H),7.17(d,J=8Hz,1H),7.04(d,J=1Hz,1H),6.86(d,J=1Hz,1H),4.76(s,2H),2.17(s,3H),2.05(s,3H).3. 3-氟-4-(2-甲基咪唑-1-基)苄醇
由2-甲基咪唑和3,4-二氟苯甲酸乙酯制备。MW:206.221H NMR(CDCl3)δ:7.2-7.4(m,3H),7.03(d,J=1Hz,1H),6.95(br,1H),4.80(s,2H),3.3(br,1H),2.28(s,3H).4. 2-甲基-4-(2-甲基咪唑-1-基)苄醇
由2-甲基咪唑和4-氟-2-甲基苯甲酸乙酯制备。MW:202.261H NMR(CDCl3)δ:7.51(d,J=8Hz,1H),7.1-7.2(m,2H),7.00(d,J=1Hz,1H),6.97(d,J=1Hz,1H),4.77(s,2H),2.40(s,3H),2.35(s,3H).5. 4-(2-甲基咪唑-1-基)-2-三氟甲基苄醇
由2-甲基咪唑和4-氟-2-三氟甲基苯甲酸乙酯制备。MW:256.231H NMR(CDCl3)δ:7.93(d,J=8Hz,1H),7.6(br,1H),7.53(d,J=8Hz,1H),7.05(d,J=1Hz,1H),7.02(d,J=1Hz,1H),4.98(s,2H),2.37(s,3H).6. 2-氟-4-(2-甲基咪唑-1-基)苄醇
由2-甲基咪唑和2,4-二氟苯甲酸乙酯制备。MW:206.221H NMR(CDCl3)δ:7.60(dd,J=8,8Hz,1H),7.14(dd,J=8,2Hz,1H),7.03(dd,J=10,2Hz,1H),7.05(d,J=1Hz,1H),6.99(d,J=1Hz,1H),4.85(s,2H),2.6(br,1H),2.38(s,3H).7. 2-甲氧基-4-(2-甲基咪唑-1-基)苄醇
由2-甲基咪唑和2-甲氧基-4-氟苯甲酸乙酯制备。MW:218.251H NMR(CDCl3)δ:7.43(d,J=8Hz,1H),7.02(d,J=1Hz,1H),7.00(d,J=1Hz,1H),6.88(dd,J=8,2Hz,1H),6.78(d,J=2Hz,1H),4.74(s,2H),3.89(s,3H),2.7(br,1H),2.36(s,3H).8. 4-(4-甲基咪唑-1-基)苄醇
由4-甲基咪唑和4-氟苯甲酸乙酯制备。MW:250.301H NMR(CDCl3)δ:7.65(br,1H),7.4-7.5(m,2H),7.3-7.4(m,2H),7.0(br,1H),4.8(s,2H),2.3(s,3H).9. 4-(4-苯基咪唑-1-基)苄醇
由4-苯基咪唑和4-氟苯甲醛制备。1H NMR(CDCl3)δ:7.8-7.9(m,3H),7.4-7.6(m,7H),7.25-7.3(m,1H),4.8(br,2H).10. 4-(2-乙基咪唑-1-基)苄醇
由2-乙基咪唑和4-氟苯甲酸乙酯制备。MW:202.261H NMR(CDCl3)δ:7.50(d,J=8Hz,2H),7.28(d,J=8Hz,2H),7.02(d,J=1Hz,1H),6.97(d,J=1Hz,1H),4.80(s,2H),2.63(dq,J=1,8Hz,2H),1.23(dt,J=3,8Hz,3H).11. 4-(2-丙基咪唑-1-基)苄醇
由2-丙基咪唑和4-氟苯甲酸乙酯制备。MW:216.291H NMR(CDCl3)δ:7.60-7.80(m,6H),4.80(s,2H),2.70-2.45(m,2H),2.00-1.50(m,3H),1.00-0.70(m,3H).12. 4-(2-异丙基咪唑-1-基)苄醇
由2-异丙基咪唑和4-氟苯甲酸乙酯制备。MW:216.291H NMR(CDCl3)δ:7.55-6.80(m,6H),4.79(s,2H),3.07-2.85(m,1H),2.37(br s,1H),1.24(d,J=6.9Hz,6H).13. 4-(2-苄基咪唑-1-基)苄醇
由2-苄基咪唑和4-氟苯甲酸乙酯制备。MW:264.331H NMR(CDCl3)δ:7.45-7.37(m,2H),7.28-7.10(m,8H),7.00(d,J=1.5Hz,1H),4.77(d,J=4.0Hz,2H),4.02(s,2H),2.20-2.07(br,1H).14. 4-[2-(吡啶-2-基)咪唑-1-基]苄醇
由2-(吡啶-2-基)咪唑和4-氟苄腈制备。MW:251.281H NMR(CDCl3)δ:8.36-8.27(m,1H),7.89(d,J=8.1Hz,1H),7.70(dd,J=1.8,8.1Hz,1H),7.39(d,J=8.8Hz,2H),7.30-7.07(m,5H),4.76(d,J=4.8Hz,2H),2.07(br,1H).15. 4-(2-三氟甲基咪唑-1-基)苄醇
由2-三氟甲基咪唑和4-氟苄腈制备。MW:242.21H NMR(CDCl3)δ:7.55-7.05(m,6H),4.80(br d,2H),1.95(br t,1H).
实施例503-(2-甲基咪唑-1-基)苄醇a.3-(2-甲基咪唑-1-基)苄腈
在氮气氛下,向搅拌着的2-甲基咪唑(25g,0.3mol)和3-溴苄腈(55g,0.3mol)的吡啶(60ml)溶液中加入K2CO3(42g)、CuO(1.5g)、铜粉(1.5g)和CuBr(1.5g)。将所得混合物在回流温度下加热64小时。反应混合物经硅藻土垫过滤,并真空浓缩滤液。残余物在硅胶上、用二氯甲烷-甲醇(10∶1)洗脱,进行柱色谱法纯化,得到12.9g(23%)3-(2-甲基咪唑-1-基)苄腈,为白色固体。1H-NMR(CDCl3)δ:7.80-7.63(m,4H),7.07(d,J=1.5Hz,1H),7.02(d,J=1.5Hz,1H),2.39(s,3H).b.3-(2-甲基咪唑-1-基)苄醇
按照实施例4b部分的方法,用氢化二异丁基铝将3-(2-甲基咪唑-1-基)苄腈还原成3-(2-甲基咪唑-1-基)苄醇。MW:188.231H NMR(CDCl3)δ:7.51-7.15(m,4H),7.00(s,2H),4.79(s,2H),2.34(s,3H).
实施例51
基本上按照前述方法制备下列本发明的化合物。1. 4-甲氧基-4-[3-[4-(2-甲基咪唑-1-基)苄硫基]苯基]-3,4,5,6-四氢-2H-吡喃
MW:394.54
mp:95.5-96℃
IR:(KBr)n 1518,1421,1303,1070,762cm-1.
1H NMR:(DMSO-d6)δ7.38(d,J=8Hz,2H),7.33-7.23(m,4H),7.20(d,J=8Hz,2H),7.02(d,J=1Hz,1H),6.97(d,J=1Hz,1H),4.16(s,2H),3.85-3.79(m,4H),2.93(s,3H),2.34(s,3H),1.95-1.90(m,4H).2. 4-甲氧基-4-[3-[4-(2-甲基咪唑-1-基)苄氧基]-5-三氟甲基苯基]-3,4,5,6-四氢-2H-吡喃MW:446.47mp:148-150℃(分解)IR:(KBr)n 1605,1520,1350,1300,1135cm-1
1H NMR:(DMSO-d6)δ7.64(d,J=8.4Hz,2H),7.49(d,J=8.4Hz,2H),7.36-7.22(m,4H),6.92(d,J=1.5Hz,1H),5.30(s,2H),3.80(m,4H),2.89(s,3H),2.29(s,3H),2.05-1.85(m,4H).3. 4-[2-氟-5-甲氧基-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃盐酸盐
MW:462.95
mp:211.3-212.2℃
IR:(KBr)n 3070,2980,2960,2880,2590,1600,1525,1490,1445,1430,1210,1170,1100,1160cm-1,
1H NMR:(DMSO-d6)δ7.90(d,J=1.8Hz,1H),7.78(d,J=1.8Hz,1H),7.74(d,J=8.4Hz,2H),7.68(d,J=8.4Hz,2H),6.85(dd,J=6.6,2.9Hz,1H),6.44(dd,J=5.1,2.9Hz,1H),5.29(s,2H),3.76(s,3H),3.75-3.61(m,4H),2.98(s,3H),2.56(s,3H),2.12-1.92(m,4H).4. 4-[5-氯-2-氟-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃盐酸盐
MW:467.37
mp:>200℃
IR:(KBr)n 1525,1475,1430,1210cm-1
1H NMR:(DMSO-d6)δ7.90(d,J=2.2Hz,1H),7.80-7.62(m,5H),7.42(dd,J=2.6,7.0Hz,1H),6.97(dd,J=2.2,5.9Hz,1H),5.32(s,2H),3.77-3.59(m,4H),2.98(s,3H),2.55(s,3H),2.10-1.90(m,4H).5. 4-[2-氟-5-甲基-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃盐酸盐
MW:446.95
mp:>200℃
IR:(KBr)n 1600,1525,1325,1105cm-1.
1H NMR:(DMSO-d6)δ7.89(d,J=2.2Hz,1H),7.81-7.62(m,5H),7.15-7.05(m,1H),6.80-7.72(m,1H),5.25(s,2H),3.80-3.60(m,4H),2.95(s,3H),2.55(s,3H),2.30(s,3H),2.11-1.89(m,4H).6. 4-[2-氟-3-[4-(2-甲基咪唑-1-基)苄氧基]-5-三氟甲基苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃盐酸盐
MW:500.29
mp:239-240℃(分解)
IR:(KBr)n 1525,1442,1368,1308,1215,1118cm-1.
1H NMR:(DMSO-d6)δ 7.85(d,J=2Hz,1H),7.75(d,J=8Hz,2H),7.6-7.7(m,4H),7.2-7.3(m,1H),5.39(s,2H),3.7(br,4H),2.99(s,3H),2.1(br,4H).
Claims (13)
Y是氢、C1-C8烷基、卤代C1-C4烷基、苯基、取代苯基、C7-C14苯基烷基、C7-C14(取代苯基)烷基、吡啶基、取代吡啶基、C6-C13吡啶基烷基或C6-C13(取代吡啶基)烷基,其中每个取代基独立地为卤素、硝基、氰基、C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷基、卤代C1-C4烷氧基、NR4R5、CO2R4或CONR4R5,其中R4和R5各自独立地为氢或C1-C6烷基;
Ar1和Ar2各自独立地为亚苯基、一取代的亚苯基或二取代的亚苯基,其中取代基独立地为卤素、C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷基或卤代C1-C4烷氧基;
X和X1各自独立地为O、S、SO或SO2;
R1是氢或C1-C4烷基;和
R2和R3各自独立地为亚乙基、
2.按照权利要求1的化合物,其中Ar1和Ar2各自为亚苯基或一取代的亚苯基;X1是O。
3.按照权利要求2的化合物,其中Ar1是1,4-亚苯基或一取代的1,4-亚苯基,Ar2是1,3-亚苯基或一取代的1,3-亚苯基。
4.按照权利要求3的化合物,其中X是O或S;R2和R3各自为亚乙基;Y在咪唑环的2-位。
5.按照权利要求4的化合物,其中Ar1是1,4-亚苯基或2-氟-1,4-亚苯基;Ar2是1,3-亚苯基、2-氟-1,3-亚苯基或5-氟-1,3-亚苯基;X是O;R1是甲基;Y是C1-C8烷基。
6.按照权利要求5的化合物,其中Y是甲基。
7.按照权利要求1的化合物,其中Ar1是1,4-亚苯基或一取代的1,4-亚苯基,Ar2是2,5-二氟-1,3-亚苯基。
8.按照权利要求7的化合物,其中Y是咪唑环2-位上的烷基;X和X1各自为O;R1是甲基;且R2和R3各自为亚乙基。
9.按照权利要求8的化合物,其中Y是甲基。
10.按照权利要求1的化合物,选自下列一组化合物:4-甲氧基-4-[3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-3,4,5,6-四氢-2H-吡喃;4-[5-氟-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃;4-[3-[2-氟-4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃;4-[5-氟-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲硫基-3,4,5,6-四氢-2H-吡喃;和4-[2,5-二氟-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃。
11.按照权利要求1的化合物,该化合物是4-[5-氟-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃。
12.按照权利要求1的化合物,该化合物是4-[5-氟-3-[4-(2-甲基咪唑-1-基)苄氧基]苯基]-4-甲氧基-3,4,5,6-四氢-2H-吡喃盐酸盐。
13.治疗哺乳动物变应性或炎性疾病的药物组合物,该组合物含有治疗有效量的权利要求1的化合物和可药用载体。
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- 1994-05-25 EP EP94916398A patent/EP0703913B1/en not_active Expired - Lifetime
- 1994-05-25 WO PCT/JP1994/000836 patent/WO1994029299A1/en active IP Right Grant
- 1994-05-25 CA CA002163667A patent/CA2163667C/en not_active Expired - Fee Related
- 1994-05-25 BR BR9406822A patent/BR9406822A/pt not_active Application Discontinuation
- 1994-05-25 PL PL94312006A patent/PL175987B1/pl unknown
- 1994-05-25 ES ES94916398T patent/ES2103130T3/es not_active Expired - Lifetime
- 1994-05-30 TW TW083104929A patent/TW374088B/zh active
- 1994-06-06 IL IL10990394A patent/IL109903A/en not_active IP Right Cessation
- 1994-06-13 ZA ZA944140A patent/ZA944140B/xx unknown
- 1994-06-13 HU HU9401762A patent/HUT70767A/hu unknown
- 1994-06-13 FI FI942792A patent/FI942792A/fi unknown
-
1995
- 1995-12-13 NO NO955046A patent/NO955046L/no unknown
-
1997
- 1997-08-28 GR GR970402207T patent/GR3024568T3/el unknown
-
1999
- 1999-06-10 CN CN99108414A patent/CN1247191A/zh active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0106440A1 (en) * | 1982-08-12 | 1984-04-25 | Smith and Nephew Associated Companies p.l.c. | Wound dressing and its manufacture |
JPS60142966A (ja) * | 1983-09-05 | 1985-07-29 | Yoshitomi Pharmaceut Ind Ltd | イミダゾ−ル誘導体 |
EP0375404A2 (en) * | 1988-12-23 | 1990-06-27 | Imperial Chemical Industries Plc | Heterocyclic derivatives |
EP0488602A1 (en) * | 1990-11-28 | 1992-06-03 | Zeneca Limited | Aryl derivatives |
EP0496237A2 (en) * | 1991-01-22 | 1992-07-29 | PHARMACIA S.p.A. | N-imidazolyl derivatives of substituted tetrahydrocarbazole and cyclohept[b]indole |
EP0510398A2 (en) * | 1991-04-24 | 1992-10-28 | PHARMACIA S.p.A. | N-Imidazolyl derivatives of substituted indole |
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