CN1234398A - 制备α-肾上腺素能受体拮抗剂的方法 - Google Patents
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
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Abstract
本方法对于制备式Ⅰ化合物是十分有用的:其中R为氢,甲基或氟。本方法中有价值的中间体包括式Ⅳ和式Ⅴ化合物,其中R为氢,甲基或氟,且L为离去基团。
Description
c)在断裂剂的存在下,从式Ⅴ化合物上将对甲苯磺酰基团断开;其中R为氢,甲基或氟,且L为离去基团。
具有下列通式Ⅰ的α1L-肾上腺素能受体拮抗剂:其中R为氢,甲基或氟,在治疗变性***增生方面很有用。已知α1L-肾上腺素能受体拮抗剂可以选择性地降低***和/或下尿道平滑肌中α1L-肾上腺素能受体的机能亢进,而不明显地影响血压或引起***性低血压。
公开于1996年12月18目的EP-A-0 748 800中描述了包括式Ⅰ化合物的化合物以及它们的制备方法。本发明提供了一种经济的制备此α1L-肾上腺素能受体拮抗剂的方法。
本发明还提供了制备式Ⅳ化合物的方法:其中R为氢,甲基或氟,其包含使与
在碱性条件进行反应,其中R为氢,甲基或氟,得到式Ⅳ化合物本发明进一步提供了制备式Ⅴ化合物的方法:其中R为氢,甲基或氟,其包含使与
在碱性条件进行反应,其中R为氢,甲基或氟,且L为离去基团,得到式Ⅴ化合物。
更进一步地,本发明提供了制备式Ⅵ化合物的方法:其中R为氢,甲基或氟,且L为离去基团,其包含在断裂剂的存在下,从具下式的化合物上将对甲苯磺酰基团断开;其中R为氢,甲基或氟,且L为离去基团,得到式Ⅵ化合物。
本发明中优选的实施例是制备式Ⅳ化合物的方法:其包含使式Ⅱ化合物:
与式Ⅲ化合物:
在碱性条件下进行反应,其中R为氢,甲基或氟。特别优选的是上述方法,其中反应在选自下列碱的条件下进行:Et3N,K2CO3,NaOH,KOH以及LiOH,优选NaOH。也优选上述方法,其中反应是在一或多种溶剂的存在下进行的,这些溶剂选自CH3CN/H2O,H2O,丙酮/H2O,以及CH3CN/N,N-二甲基甲酰胺。本方法另一个优选的方面是,反应在约-10℃-80℃之间进行,优选约15℃-25℃。
本发明另一个优选的方面是制备式Ⅴ化合物或其盐的方法:其包含使式Ⅳ化合物:与具下式的化合物:
在碱性条件下进行反应,其中R为氢,甲基或氟,且L为离去基团。术语盐代表碱金属盐。另外优选的也是本方法,其中反应是在下列碱的存在下进行:三乙胺,三甲胺以及Hunig’s碱。术语Hunig碱代表二异丙基乙基胺。特别优选的也是本方法,其中的碱是K2CO3。本发明另一个优选的方面是此方法,其中反应是在一或多种溶剂中进行的,这些溶剂选自N-甲基吡咯烷酮,丙酮,N,N-二甲基甲酰胺,四氢呋喃,环砜烷以及1,3-二甲基-2-咪唑烷酮,它们可以单独使用也可以和水一起使用。本方法另一个优选的方面是,反应在约-40℃-70℃之间进行,优选的是约-10℃-10℃,更优选的是约0℃-5℃。
本方法另一个优选的方面涉及式Ⅵ化合物的制备:其中包含在断裂剂的存在下,从具式Ⅴ的化合物上将对甲苯磺酰基团断开:其中其中R为氢,甲基或氟,且L为离去基团。优选的断裂剂为酸碱剂或亲核剂,断裂剂尤其选自甲醇钠,乙醇钠,HCL,HF以及H2SO4,优选的是浓H2SO4。本方法另一个优选的方面是,反应在约-20℃-130℃之间进行,优选的是约-5℃-80℃。本方法特别优选的是反应在约5±5℃下进行。本方法另外优选的是反应在约45±5℃下进行。
b)任意地制备相应的盐;其中R为氢,甲基或氟,且L为离去基团。
本方法进一步优选的方面涉及式Ⅴ化合物或其盐:其中R为氢,甲基或氟,且L为选自下列卤素的离去基团,例如溴或氯,特别是氯,烷磺酰氧基,例如,甲磺酰氧基和乙磺酰氧基,芳烃磺酰氧基,例如苄磺酰氧基或甲苯磺酰氧基,噻吩氧基,二卤代膦酰氧基以及四卤代磷杂氧(tetrahalophosphaoxy)。特别优选的是(3-3-氯代丙基)-1-甲苯磺酰胸腺嘧啶。
本发明进一步涉及式Ⅳ化合物和式Ⅴ化合物在制备式Ⅰ化合物方面的用途:其中R为氢,甲基或氟。
本发明的另一个优选的方面是利用本发明的制备方法获得的化合物。
本发明将通过其优选的实施例来描述本发明。提出这些实施例是为了帮助理解本发明,而不是限制本发明。
下列路线将说明式Ⅰ化合物制备方法的优选实施例。步骤1-3代表本发明的新的方面。步骤4-5在先前的欧洲专利申请0 748 800中已做过描述。
用本领域内已知的方法,可以很容易地制备式Ⅱ,Ⅲ,和Ⅶ化合物。步骤一
本发明方法的第一步包含使式Ⅱ化合物(尿嘧啶,当R为氢时;胸腺嘧啶,当R为甲基时;或5-氟尿嘧啶,当R为氟时)与对甲基苯磺酰氯(式Ⅲ)如下进行反应形成式Ⅲ化合物:
在第一步中优选的碱是NaOH。然而,也可以用其他碱,例如K2CO3或Et3N。反应典型的是在包括CH3CN/H2O的溶剂中进行。然而也可以使用其它溶剂,如N-甲基吡咯烷酮(“NMP”),丙酮,N,N-二甲基甲酰胺(“DMF”),四氢呋喃(“THF”),环砜烷以及1,3-二甲基-2-咪唑烷酮(“DMI”),它们可以单独使用也可以和水一起使用。在使用氢氧化钠的乙腈溶液/水的情况下,尽管可以采用更大的温度范围,但较为优选的是约15℃-25℃。例如从约-10℃-80℃是可以操作的。为了获得合适的回收率,在进行了上述的处理后,应将反应混合物的pH调节至小于8.0。步骤二
第二步涉及式Ⅳ化合物与1-L-3-溴丙烷(L为离去基团)在碱性条件下如下进行反应,生成式Ⅴ化合物:L为离去基团,并具有合成有机化学中常用术语“离去基团”相关的含义,其为在烷基化的条件下可取代的原子或基团。术语“离去基团”包括卤素,例如氯和溴;烷磺酰氧基,例如,甲磺酰氧基和乙磺酰氧基;芳烃磺酰氧基,例如苄磺酰氧基或甲苯磺酰氧基;噻吩氧基;二卤代膦酰氧基;四卤代磷杂氧(tetrahalophosphaoxy)等等。选用的离去基团应比反应基团溴具较少活性(当然除了当离去基团为溴时活性相当),以保证合适的反应。
第二步骤中所用的碱为K2CO3,当然也可以使用其它碱。对于那些看过本发明专利说明书的本领域内专家来说,合适的碱的选择在其知识范围内。为指导起见,应选择亲核性较差的化合物,例如三乙胺,三甲胺,Hunig’s碱或其它叔胺。
反应典型地是在包含DMF的溶剂中进行。优选的反应条件包括,将含有式Ⅳ化合物(R为甲基(1-对甲苯磺酰基胸腺嘧啶)),无水碳酸钾,和DMF的混合物冷却到-40-70℃,优选-10-10℃,最优选的是0-5℃,然后迅速地加入1-溴-3-氯丙烷。反应混合物在-40-70℃,优选-5-15℃,最优选的是5±5℃下搅拌2-20小时,优选的是3-7小时,最好是5小时。然后使之在6小时内逐渐升温至5-25℃,较好的是15±5℃。接着将反应混合物的温度升至50±5℃,用去离子水稀释以沉淀产品。也可以单独或与水合用其他溶剂,例如NMP,丙酮,DMF,THF,环砜烷以及DMI。步骤三第三步包括在断裂剂的存在下将甲苯磺酰基断裂掉:
第三步中的断裂剂可以是酸,碱或亲核剂,包括甲醇钠,乙醇钠,浓HCL,无水HF,或最优选的是浓硫酸。在两个化合物混合的过程中,反应温度应在-20-130℃,优选的是-5-80℃,最优选的是0±5℃。在反应的平衡阶段,反应温度应保持在45±5℃。
下列实施例是实际操作的。
实施例
实施例1
在氮气下,对存在于1.33L水以及65g氢氧化钠(1.6mol)混合物中的200.0g胸腺嘧啶(1.586mol)溶液进行机械搅拌,同时于60分钟内向其中加入378.1g(1.98mol)对甲苯磺酰氯的1.0L乙腈溶液并于65分钟内加入95.16g NaOH(2.38mol)的0.330L水溶液。此过程中将反应用水浴由最初的40℃冷却至35℃。加入完毕后再继续搅拌50分钟,冷却至0-5℃。在10分钟内加入242g浓HCL(2.45mol)进行酸化。再于0-5℃下搅拌20分钟,随后真空过滤固体于55℃下真空干燥过夜。得到433.1g1-对甲苯磺酰胸腺嘧啶(产率97%,白色结晶)。
实施例2
在氮气常压并室温下,向1.0L二甲基甲酰胺中的0.34kg1-甲苯磺酰基胸腺嘧啶(2.70mol)(按实施例1方法制备)机械搅拌溶液中加入0.240kg(28.8mol)1-溴-3-氯丙烷,然后再加0.235kg碳酸钾粉末(29.9mmol)(-325目)以及0.38L二甲基甲酰胺。由于放热此反应升温至31℃,随后加热至50℃。生成的悬浮液在50℃下搅拌2.5小时。反应混合物在搅拌下慢慢加入4.5L冷水,用1.7L的冷水将原反应容器中混合物淋洗至第二个反应容器中。将混合物冷却至0-5℃,并在此温度下搅拌析出产品。真空过滤后,滤液依次用1.0L冷水以及1.0L庚烷洗涤。产品于50℃下真空干燥过夜。得到0.414kg 3-(-3-氯丙基)-1-甲苯磺酰胸腺嘧啶(产率97%,细白色结晶)。
实施例3
在氮气下向1L带套的树脂烧瓶(“反应器1”)中加入0.395kg3-(3-氯丙基)-1-甲苯磺酰胸腺嘧啶(1.11mol)(按实施例2方法制备),然后再于室温下加入0.492L浓硫酸。观察到有放热升温(至45℃)现象。将此烧瓶于45℃下保持1小时,此期间向第二个容器(“反应器”)中加入3.0L水,用-5℃的套将其冷却至0-5℃。在35分钟内,将反应器1中的反应混合物慢慢计量性的转入反应器2中,后者在-5℃下进行振荡。将反应器的温度升至25℃。用1.0L的水将反应器1中的残余物淋洗至反应器2中。将反应器2冷却至3℃,进行真空过滤。固体用3×4L的冷水洗涤,于50℃下真空干燥过夜。得到0.204kg 3-(-3-氯丙基)-1-甲苯磺酰胸腺嘧啶(1.01mol,产率90.9%),其为白色结晶性固体。
本发明已通过其优选的实施例进行了说明。在阅读专利说明书时,其它变化的实施例对于本领域内的专家来说是显而易见的。这些变化也应包括在本发明的范围和实质内,这两者均仅仅应该由随后的权利要求及其它们的等价条款来限定。
Claims (25)
3、权利要求2中所述的方法,其中所述的方法是在有下列碱的存在下进行的,这些碱选自Et3N,K2CO3,NaOH,KOH以及LiOH。
4、权利要求2或3中所述的方法,其中所述的方法是在有下列溶剂的存在下进行的,这些溶剂选自CH3CN/H2O,H2O,丙酮/H2O,以及CH3CN/N,N-二甲基甲酰胺。
5、权利要求2至4中所述的方法,其中所述的反应在约15℃-25℃之间进行。
7、权利要求6中所述的方法,其中所述的方法是在有下列碱的存在下进行的,这些碱选自三甲胺,三乙胺和Hunig’s碱。
8、权利要求7中所述的方法,其中的碱为K2CO3。
9、权利要求6或8中所述的方法,其中所述的反应是在一或多种溶剂的存在下进行的,这些溶剂选自N-甲基吡咯烷酮,丙酮,N,N-二甲基甲酰胺,四氢呋喃,环砜烷以及1,3-二甲基-2-咪唑烷酮,它们可以单独使用也可以和水一起使用。
10、权利要求6至9任意一个中所述的方法,其中的反应是在约-10-10℃的条件下进行的。
12、权利要求11中所述的方法,其中的断裂剂选自甲醇钠,乙醇钠,HCL,HF,和H2SO4。
13、权利要求11或12中所述的方法,其中的反应在约-5-80℃之间进行。
14、权利要求11-13中任意一个所述的方法,其中的反应在约5±5℃之间进行。
15、权利要求11-14中任意一个所述的方法,其中的反应在约45±5℃之间进行。
21、式Ⅴ化合物或其盐:其中R为氢,甲基或氟,且L为离去基团,所述离去基团选自卤素,烷磺酰氧基,芳烃磺酰氧基,噻吩氧基,二卤代膦酰氧基以及四卤代磷杂氧(tetrahalophosphaoxy)。
22、权利要求20和21中所述的化合物,其选自1-甲苯磺酰胸腺嘧啶和3-(-3-氯丙基)-1-甲苯磺酰胸腺嘧啶。
23、使用权利要求20至22中所述的化合物制备具式Ⅰ的α1L-肾上腺素能受体拮抗剂:其中R为氢,甲基或氟。
24、按照权利要求1-19任意一个中所述的方法得到的化合物。
25、前述的本发明。
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