CN1431195A - 合成5-(3-〔外-双环〔2.2.1〕庚-2-基氧基〕-4-甲氧基苯基)-3,4,5,6-四氢嘧啶-2(1h)-酮的中间体及制备方法 - Google Patents
合成5-(3-〔外-双环〔2.2.1〕庚-2-基氧基〕-4-甲氧基苯基)-3,4,5,6-四氢嘧啶-2(1h)-酮的中间体及制备方法 Download PDFInfo
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- CN1431195A CN1431195A CN03104212A CN03104212A CN1431195A CN 1431195 A CN1431195 A CN 1431195A CN 03104212 A CN03104212 A CN 03104212A CN 03104212 A CN03104212 A CN 03104212A CN 1431195 A CN1431195 A CN 1431195A
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- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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Abstract
本发明涉及制备药物活性化合物5-(3-[(2S)-外-双环[2.2.1]庚-2-基氧基]-4-甲氧基苯基)-3,4,5,6-四氢嘧啶-2(1H)-酮和其对应的2R对映体的中间体和制备该中间体的新方法。
Description
本发明是1995年5月4日递交的发明名称为“合成5-(3-[外-双环[2.2.1]庚-2-基氧基]-4-甲氧基苯基)-3,4,5,6-四氢嘧啶-2(1H)-酮的方法和中间体”的专利申请95194538.6的分案申请。
技术领域
本发明涉及制备药物活性化合物5-(3-[(2S)-外-双环[2.2.1]庚-2-基氧基]-4-甲氧基苯基)-3,4,5,6-四氢嘧啶-2(1H)-酮和其对应的2R对映体的中间体和制备该中间体的新方法。
背景技术
国际专利申请WO87/06576(1987年11月5日公布)涉及5-(3-[(2-外-双环[2.2.1]庚-2-基氧基]-4-甲氧基苯基)-3,4,5,6-四氢嘧啶-2(1H)-酮,并声称它可用作抗抑郁剂。国际专利申请WO91/07178(1991年5月30日公布)涉及这一化合物在治疗气喘、炎性导气管疾病和皮肤疾病方面的用途。
US专利5,270,206(1993年12月14日公布)涉及制备(+)-(2R)-内-降冰片(也称作(2R)-内-双环[2.2.1]庚-2-醇或(1S,2R,4R)-双环[2.2.1]庚-2-醇)和(-)-(2S)-内-降冰片(也称作(2S)-内-双环[2.2.1]庚-2-醇或(1R,2S,4S)-双环[2.2.1]庚-2-醇)的方法,和涉及它们进一步转化成药物活性剂5-(3-[(2S)-外-双环[2.2.1]庚-2-基氧基]-4-甲氧基苯基)-3,4,5,6-四氢嘧啶-2(1H)-酮,如下所示,和5-(3-[(2R)-外-双环[2.2.1]庚-2-基氧基]-4-甲氧基苯基)-3,4,5,6-四氢嘧啶-2(1H)-酮,如下所示,
这里所引用的所有文件,包括前面的那些,它们的全部内容被引入本文供参考。
发明内容
本发明还涉及以下通式的化合物和其中每一R2独立地选自(C1-C6)烷基。
本发明还涉及制备下式的化合物的方法其中X和Y是相同的并选自-CN,-CO2(C1-C6)烷基,-CONH2和-CONHOH,或X和Y连在一起形成下式的基团该方法包括:(1)让3-羟基-4-甲氧基苯甲醛与通式XCH2CO2H(其中X如上所定义)的化合物在碱(优选叔胺)存在下反应,得到其中X和Y同时是-CN,-CO2(C1-C6)烷基,-CONH2或-CONHOH的通式II的化合物;或者(2)(a)让其中X和Y同时是-CN的通式II化合物与过氧化氢(优选过氧化氢碱性水溶液)反应,形成其中两-CN基团都被-CONH2替代的相应的双酰胺;(b)用氧化剂(例如,双(乙酰氧基)碘代苯,双(三氟乙酰氧基)碘代苯,NaOCl,NaOBr或四乙酸铅)将步骤(a)中形成的双酰胺进行霍夫曼(Hoffman)重排以形成相应的双氨基甲酸酯;和(c)让步骤(b)中形成的双氨基甲酸酯与碱(例如,含有1-6个碳原子的碱金属醇盐或碱金属氢氧化物)反应,形成其中X和Y连在一起构成通式“a”的基团的环脲,正如以上所表述的。
本发明还涉及制备以下通式的化合物的方法,或其中X和Y与以上通式II中定义一样,该方法包括让以上所定义的通式II化合物分别与R-(+)-内-降冰片或S-(-)-内-降冰片,三芳基或三烷基膦和偶氮二羧酸酯反应。
本发明还涉及制备以下通式的化合物的方法,或其中X和Y是相同的并选自-CN,-CONH2,-CO2(C1-C6)烷基和-CONHOH,或X和Y连在一起形成下式的基团该方法包括:(1)让3-羟基-4-甲氧基苯甲醛与通式XCH2CO2H的化合物在碱(优选叔胺)存在下反应,其中X是-CN,-CO2(C1-C6)烷基,-CONH2或-CONHOH,形成以下通式II的化合物其中X和Y是相同的并选自-CN,-CONH2,-CO2(C1-C6)烷基和-CONHOH;或者(2)(a)让其中X和Y同时是-CN的通式II化合物与过氧化氢反应,形成其中两-CN基团都被-CONH2替代的相应的双酰胺:(b)用氧化剂(例如,双(乙酰氧基)碘代苯,双(三氟乙酰氧基)碘代苯,NaOCl,NaOBr或四乙酸铅)将步骤(a)中形成的双酰胺进行霍夫曼(Hoffman)重排以形成相应的双氨基甲酸酯;和(c)让步骤(b)中形成的双氨基甲酸酯与碱(例如,含有1-6个碳原子的碱金属醇盐)反应,形成其中X和Y连在一起构成以下通式的基团的环脲,和然后(3)让以上步骤1或2中形成的所述通式II化合物分别与R-(+)-内-降冰片或S-(-)-内-降冰片,三芳基或三烷基膦和偶氮二羧酸酯反应。
本发明还涉及制备以下通式的化合物的方法或其中R1和R2独立地选自氢和(C1-C6)烷基,该方法包括,让以下通式的化合物或分别与二乙酰氧基碘代苯,NaOZ和Z′OH反应,其中Z和Z′独立地选自氢和(C1-C6)烷基。
本发明还涉及制备以下通式的化合物的方法或包括让以下通式的化合物或其中R1和R2独立地选自氢和(C1-C6)烷基,分别与通式NaOZ和Z′OH的化合物反应,其中Z和Z′独立地选自氢和(C1-C6)烷基。
本发明还涉及制备以下通式的化合物的方法或包括:让以下通式的化合物或分别与二乙酰氧基碘代苯,NaOZ和Z′OH反应,其中Z和Z′独立地选自氢和(C1-C6)烷基,形成以下通式的中间体或其中R1和R2独立地选自氢和(C1-C6)烷基;和然后或者 (b1)分离出所述通式V或V′的中间体并让它与通式NaOZ和Z′OH的化合物反应,其中Z和Z′如上所定义;或者(b2)让所述通式V或V′的中间体就地与通式NaOZ和Z′OH的化合物反应,其中Z和Z′如上所定义。
这里所使用的短语“反应惰性溶剂”指不以一种不利地影响所需产物的产率的方式与起始原料、试剂、中间体或产物相互作用的溶剂。
所使用的术语“烷基”,包括具有直链、支链或环状部分或它们的组合的饱和单价烃基,除非另有说明。
以上通式II,和V和V′包括与所列举的那些化合物相同的化合物,但对于以下这些情况除外:一个或多个氢,碳,氮或氧原子被其放射性或稳定的同位素所替代。这些放射性标记的化合物可用作在代谢药物动力学研究中和在结合分析中的科研和诊断工具。
本发明的详细描述
在下面的反应历程和讨论中描述了本发明的方法和制备本发明新型化合物的方法。除非另有说明,在下面的反应历程和讨论中的取代基X,Y,R,R1,R2,R3和R4,基团“(a)”和通式II,III,III′,IV,IV′,V,V′,VI和VI′如上所定义。
反应历程1
反应历程2
反应历程3
反应历程1说明了通式II和III的化合物的制备方法。反应历程2说明了通式V的化合物的制备方法和从其中X和Y同时是-CN的通式III化合物制备5-(3-[(2S)-外-双环[2.2.1]庚-2-基氧基]-4-甲氧基苯基)-3,4,5,6-四氢嘧啶-2(1H)-酮(化合物VI)的方法。(其中X和Y同时是-CN的通式III的该化合物在反应历程2中和下文中称作通式IIIA的化合物)。反应历程3说明了从其中X和Y同时是-CO2(C1-C6)烷基或-CONHOH的通式III化合物制备通式VI化合物的方法。(其中X和Y同时是-CO2(C1-C6)烷基或-CONHOH的通式III化合物在反应历程3中和下文中分别称作通式IIIB或IIIC的化合物)。
参见反应历程1,在碱(优选叔胺)存在下在反应惰性溶剂中让异香草醛(化合物I)与两摩尔当量的通式XCH2CO2H的化合物进行缩合,其中X是-CN,-CO2(C1-C6)烷基,-CONH2和-CONHOH,按照顺序的诺文葛尔-米切尔反应(Knoevenagel-Michael)方式及伴随脱羧反应,得到通式II化合物,其中X和Y是相同的并选自X的以上定义中所给定的值。这一反应可在约10℃-约130℃之间的温度下进行。优选大约在回流温度下进行该反应。合适的溶剂包括,但不限于,N-甲基吗啉,三乙胺,吡啶,以及非碱性反应惰性溶剂如四氢呋喃(THF),二甲基甲酰胺(DMF),乙腈和甲苯。优选地,仲胺(例如哌啶或吡咯烷)也作为催化剂添加。在该反应的一个优选实施方案中,N-甲基吗啉被用作溶剂/碱和哌啶也被加入到反应混合物中。
其中X和Y连在一起形成基团“a”的通式II化合物(即环脲)可以通过让其中X和Y同时是-CN的通式II化合物进行一系列的在反应历程2中说明的和随后在本申请中将要描述的反应来制备。
在以上反应中形成的通式II化合物通过以下方法被转化成相应的通式III化合物:在Mitsunobu条件下,让通式II化合物与下面表示的R-(+)-内-降冰片或下面表示的S-内-降冰片进行偶合反应,分别得到相应的具有相反的立体化学(由该内-降冰片反应物决定)的通式III或III′化合物。因此,如果使用R-内-降冰片,产物将是具有“S”构型的通式III化合物,和如果使用S-内-降冰片,产物将是具有“R”构型的通式III′化合物。
这一反应通常是在三芳基或三烷基膦如三苯基膦或三丁基膦和偶氮二羧酸酯氧化剂存在下进行的。一般来说,它也可在约10℃-约150℃的温度下,优选大约在回流温度下,在非质子传递溶剂如四氢呋喃(THF),乙腈,二氯甲烷,DMF,甲苯和苯中,优选THF中进行。合适的偶氮化合物包括偶氮二羧酸二异丙基酯,偶氮二羰基二哌啶和偶氮二羧酸二乙基酯。偶氮二羧酸二异丙基酯和偶氮二羰基二哌啶是优选的。
在以上步骤中形成的通式III或III′化合物的立体化学在所有后面的步骤中被保留,如反应历程2和3中所示。
正如以上所指出的,反应历程2说明了通式IIIA的化合物转化成通式VI化合物的方法。参见反应历程2,通式IIIA化合物用过氧化氢(优选过氧化氢碱性水溶液)水解,形成通式IV的双酰胺。该反应通常在极性溶剂如丙酮、乙醇、异丙醇或丁酮中(其中丙酮是优选的),在约0℃-约100℃的温度下(其中大约室温是优选的)进行。碳酸钠或另一种具有类似碱性的无机盐可以加入到反应混合物中以促进反应。
如此形成的通式IV化合物然后进行霍夫曼重排反应,其中两羧酰胺基团被转变成通式V的氨基甲酸酯基团(氮发生迁移)。可以使用合适的氧化剂,包括双(乙酰氧基)碘代苯,双(三氟乙酰氧基)碘代苯,NaOCl,NaOBr或四乙酸铅。双(乙酰氧基)碘代苯是优选的。这一反应通常在碱存在下进行。当使用双(乙酰氧基)碘代苯时,可接受的碱包括碱金属的氢氧化物和(C1-C6)醇盐。反应温度可以是大约-20℃至大约100℃,大约0℃至大约25℃的温度是优选的。合适的反应惰性溶剂的实例是(C1-C6)链烷醇,THF,DMF和乙腈。
在该序列中的最后步骤是通式V的双氨基甲酸酯的碱催化闭环,形成通式VI的对称性嘧啶-2-酮。这一反应可以在约0℃至约100℃之间的温度下进行,和优选在回流温度下进行。合适的溶剂包括,但不限于,低级醇类,甲醇是优选的。合适的碱类包括含有1-6个碳原子的碱金属醇盐。优选的碱是甲醇钠。
此外,该序列的最后两步骤可以在没有分离出双氨基甲酸酯V的情况下按照合并的方式来完成。这一改进基本上等同于前面有关霍夫曼重排的叙述。优选的是该反应在溶剂回流温度下进行。也优选的是将附加的碱加入到反应混合物中。可接受的氧化剂、碱和溶剂的选择范围与前面所述的相同。优选的反应使用了双(乙酰氧基)碘代苯,甲醇钠和甲醇。
通式V的化合物形成通式VI的化合物的反应,如以上所述,可以通过如反应历程2A中所示的通式VII和VIII的中间体中的一种或两种来进行。
其中X和Y同时是-CONH2的通式III化合物与通式IV化合物相同,因而能够通过使用反应历程2中所说明的方法将前者转化成化合物(VI)。
通过使用反应历程3中所说明的方法,其中X和Y同时是-CONHOH或-CO2(C1-C6)烷基的通式III化合物可以转化成通式VI的化合物。
参见反应历程3,通式IIIB的二酯与羟胺盐酸盐在碱(例如叔胺碱)存在下进行反应,形成通式IIIC的异羟肟酸。该反应能够在不具有强烈的亲核特性的各种反应惰性溶剂中在约0℃-约100℃的温度下,优选在约20℃下进行,这些溶剂包括,但不限于,低级醇类,环状和无环醚类(例如乙醚或THF),中性芳族化合物如苯和甲苯,DMF,二甲基乙酰胺,乙酸乙酯,乙腈和水。
然后在约0℃-约100℃的温度下,优选在约20℃下,通过使用能够将醇脱水的条件或试剂,经Loessen重排将通式IIIC的异羟肟酸转化成化合物VI。优选的试剂是对甲苯磺酰氯。此外,还能够形成异羟肟酸的不同酯,任意性地就地完成,和然后通过使用本技术领域中众所周知的方法,经热和/或酸处理将该酯转化成通式VI的化合物。
没有特意在前面的实验部分中描述的本发明的其它化合物的制备能够通过使用本技术领域中的熟练人员十分清楚的上述反应的结合来完成。
在以上反应历程中所讨论的或说明的每一个反应中,压力不是严格的,除非另有说明。约0.5大气压-约3大气压的压力一般是可接受的,和环境压力,即约1大气压,在方便的意义上说是优选的。
本发明的方法和产物可用于药物活性化合物VI和VI′的合成。化合物VI和VI′以及这些化合物的外消旋混合物(下面总称为“活性化合物”)可用于治疗抑郁症,气喘、炎性导气管疾病和皮肤疾病(例如牛皮癣和特应性皮炎)。
活性化合物是不依赖于钙的c-AMP磷酸二酯酶抑制剂。这些化合物抑制c-AMP磷酸二酯酶的能力可以由Davis,生物化学及生物物理杂志(
Biochimica et Biophysica.Acta.),
797,354-362(1984)的方法来测定。
活性化合物的抗抑郁活性可以由Porsult等人,国际药效学杂志(
Arch. Int.Pharmacodyn.),227,327-336(1977)描述的行为绝望范例(behavioral despair paradigm)和由Roe等人,药理试验治疗学杂志(
J. Pharmacol.Exp.Therap.),
226,686-700(1983)描述的用来测定试验药物在老鼠体内对抗利血平降温的能力的方法来测定。
当用于治疗抑郁症时,活性化合物本身可以使用或以包含活性化合物和药理上可接受的载体或稀释剂的药物组合物形式使用。对于口服,一种施用活性化合物的优选途径,合适的药物载体包括惰性稀释剂或填料,从而形成剂量形式如片剂、粉剂、胶囊剂和类似药剂。如果需要,这些药物组合物含有附加的成分,如调味剂、粘结剂、赋形剂和类似物。例如,含有各种赋形剂如柠檬酸钠的片剂与各种崩解剂如淀粉、藻酸和某些配合硅酸盐以及粘结剂如聚乙烯基吡咯烷酮、蔗糖、明胶和阿拉伯胶一起使用。另外,润滑剂如硬脂酸镁,十二烷基硫酸钠和滑石常常用于制造片剂。类似类型的固体组合物也在软和硬填充的明胶胶囊中用作填料。其优选的材料是乳糖或奶糖和高分子量聚乙二醇。
对于口服,活性剂的每日剂量是约0.1mg-约10mg,和对于肠胃外施用,优选i.v.或i.m.,约0.01mg-约5mg。药剂师当然会尽可能地确定对于所给定的人的合适剂量,该剂量取决于病人的症状的严重性和病人对具体药物的反应等因素。
有关活性化合物在气喘和皮肤病治疗中的用途的体内和体外试验已经在国际专利申请WO91/07178中在说明书的第4和5页和在实施例1-3中讨论,与以上有关并全部被引入本文供参考。
在用一种活性化合物的气喘或炎性皮肤病的系统治疗中,剂量一般是约0.01-2毫克/公斤/天(0.5-100毫克/天,体重50公斤的普通人),一次或分次给药,与施用途径无关。当然,取决于具体的化合物和各疾病的具体性质,在此范围以外的剂量将在护理医师的判断下加以规定。在气喘的治疗中,鼻内施用(滴剂或喷雾剂),气雾剂通过口的吸入和普通口服一般是优选的。然而,如果病人无法吞咽,或口吸收受到影响,优选的系统性施药途径是肠胃外途径(i.m.,i.v.)。在炎性皮肤病的治疗中,优选的施用途径是口服或局部施用。在炎性导气管疾病的治疗中,优选的施用途径是鼻内或口服。
该活性化合物一般以含有该化合物中的一种与药理上可接受的载体或稀释剂的药物组合物形式施用。该组合物一般按照已知方式,通过使用与所需施用方式相适应的固体或液体载体或稀释剂来配制:对于口服,以片剂,硬或软明胶胶囊,悬浮液,粒剂,粉剂等形式;对于肠胃外施用,以可注射的溶液或悬浮液等形式;对于局部施用,以溶液剂、洗剂、膏剂、软膏等形式,一般含有约0.1-1%(w/v)的活性化合物;和对于鼻内或吸入器施用,一般以0.1-1%(w/v)溶液形式。
本发明由下面的实施例加以说明。然而,应该理解,本发明并不限于这些实施例的特定细节。
实施例1
3-(3-羟基-4-甲氧基苯基)-戊烷-1,5-二腈
向含有异香草醛(30.4g,200mmol)和氰基乙酸(68.0g,800mmol)的500ml烧瓶中装入一种由3.0ml(30mmol)哌啶和151mlN-甲基吗啉组成的溶液。将最初形成的黄色淤浆加热使之温和回流21小时和然后冷却至室温并在旋转蒸发器上浓缩。将所得到的棕色油溶于430ml乙酸乙酯(EtOAc)中,顺序用水(H2O)洗涤,5当量浓度盐酸(5N HCl)和H2O洗涤,洗出的水相经合并后再用二氯乙烷反萃取。将有机层合并和然后除去溶剂得到粘稠的橙色油,它再从乙酸乙酯/二氯甲烷(EtOAc/CH2Cl2)中结晶,在过滤和干燥之后得到38.3g橙色固体物。从EtOAc/二异丙基醚重结晶得到35.3g(82%)浅黄色固体,m.p.90-92℃。
实施例2
3-(3-[(2S)-外-双环[2.2.1]庚-2-基氧基]-4-甲氧基苯基)-1,5-戊烷二腈
在室温下向含有R-(+)-内-降冰片(1.12g,10.0mmol),3-(3-羟基-4-甲氧基苯基)-戊烷-1,5-二腈(4.33g,20mmol)和三苯基膦(TPP)(3.93g,15mmol)的四氢呋喃(THF)溶液(20ml)中加入1,1′-(偶氮二羰基)-二哌啶(ADDP)(3.78g,15mmol)。所得到的棕色淤浆加热回流12小时,然后用10mlTHF和30ml甲苯稀释,冷却至室温和粒化30分钟。在过滤除去还原的ADDP之后,滤液两次用20ml 1N氢氧化钠(NaOH)洗涤和剩余的有机相与0.2g活性炭和20g硫酸钠(Na2SO4)一起搅拌,过滤和浓缩成粘稠的深棕色油。从异丙醇/己烷中重结晶得到2.34g(75%)的灰白色固体,m.p.126-127℃。
实施例3
3-(3-[(2S)-外-双环[2.2.1]庚-2-基氧基]-4-甲氧基苯基)-戊烷-1,5-二腈
向含有降冰片(2.243g,20.0mmol)和三苯基膦(5.272g,20.10mmol)的THF(30ml)回流溶液中加入第二种含有3-(3-羟基-4-甲氧基苯基)-戊烷-1,5-二腈(4.350g,20.10mmol)和偶氮二羧酸二异丙基酯(DIAD)(4.044g,21.00mmol)的THF溶液。混合物加热回流18小时,冷却和在旋转蒸发器上浓缩,和然后溶于60ml甲苯中。所得到的棕色甲苯溶液两次用1N NaOH洗涤,经硫酸钠干燥,然后过滤和浓缩得到18g米色固体。从1/1异丙醇/己烷重结晶得到4.26g(69%)白色固体,m.p.127-128℃。
实施例4
3-(3-[(2S)-外-双环[2.2.1]庚-2-基氧基]-4-甲氧基苯基)戊二酰胺
向3-(3-[(2S)-外-双环[2.2.1]庚-2-基氧基]-4-甲氧基苯基)-戊烷-1,5-二腈(2.29g,7.38mmol)的冷却的(6℃)丙酮溶液(46ml)中加入24ml的10%碳酸钠水溶液(Na2CO3)(23mmol),然后加入5.2ml 30%过氧化氢(H2O2)。所得到的淤浆在室温下搅拌4天,用附加的1.7ml 30%H2O2处理和然后再搅拌2天。通过添加4当量的亚硫酸氢钠(NaHSO3)使多余的过氧化物分解和在旋转蒸发器上干燥将其体积减少至约80ml。粘稠的淤浆然后用6.5ml的浓HCl酸化,用浓氢氧化铵(NH4OH)中和并冷凝至约50ml的体积。过滤和真空干燥得到2.20g(86%)白色固体,m.p.161-163℃。
实施例5
5-(3-[(2S)-外-双环[2.2.1]庚-2-基氧基]-4-甲氧基苯基)-3,4,5,6-四氢嘧啶
-2(1H)-酮
向二乙酰氧基碘代苯(43.60g,133mmol)的冷却(2℃)甲醇(MeOH)悬浮液(40ml)中经10分钟加入152ml 25%甲醇钠(NaOMe)在甲醇中的溶液。在3℃下搅拌20分钟之后,将3-(3-[(2S)-外-双环[2.2.1]庚-2-基氧基]-4-甲氧基苯基)戊二酰胺(22.98g,66.5mmol)作为在45ml甲醇中的预冷淤浆添加,和然后经3小时升温至室温进行反应,随后加热回流45分钟。淤浆被冷却至室温,用152ml 25%NaOMe在MeOH中的溶液处理并加热回流16小时。冷凝器然后更换成蒸馏头并除去350ml MeOH。所得到的淤浆冷却至12℃,用200ml CH2Cl2和100ml H2O2稀释和然后用浓HCl中和。将各层相互分离并用CH2Cl2两次萃取水层,得到3个有机层,将它们合并,经硫酸钠(Na2SO4)干燥,过滤和然后浓缩得到39g浅橙色固体。在回流EtOAc中再制成淤浆,最终得到15.48g白色固体(77%),m.p.199-200℃。
实施例6
N,N′-二甲氧基羰基-2-(3-[(2S)-外-双环[2.2.1]庚-2-基氧基]-4-甲氧基苯
基)-1,3-丙二胺
向3-(3-[(2S)-外-双环[2.2.1]庚-2-基氧基]-4-甲氧基苯基)戊二酰胺(0.346g,1.00mmol)在1.75ml MeOH中的冷却(0℃)悬浮液中加入0.140g氢氧化钾(KOH)(2.50mmol),随后加入0.657g(3.0mmol)二乙酰氧基碘苯。让所得到的略带黄色的溶液升温至室温,搅拌80分钟和然后在旋转蒸发器上浓缩成糊状物。用水将该物质转移到分液漏斗中并用CH2Cl2萃取两次。合并的有机层经硫酸钠干燥,过滤和浓缩,得到0.506g(125%)不纯的黄色泡沫状所需双氨基甲酸酯。薄层色谱分析(TLC):Rf=0.74,在9∶1CH2Cl2/MeOH中。气相色谱-质谱分析法显示出分子离子为406的主峰,它是标题化合物的分子量。
实施例7
5-(3-[(2R)-外-双环[2.2.1]庚-2-基氧基]-4-甲氧基苯基)-3,4,5,6-四氢嘧啶
-2(1H)-酮
来自实施例6的粗双氨基甲酸酯泡沫(98mg,0.2mmol)被溶于MeOH(0.5ml)中,用0.5ml 25%NaOMe(在MeOH中)处理,和回流18小时。在除去溶剂之后,所得到的固体溶于水中,用CH2Cl2萃取两次,合并的有机层经硫酸镁(MgSO4)干燥。滤液的过滤和浓缩得到48mg(75%)的黄色固体形式的所需要的脲。薄层色谱分析(TLC):Rf=0.57,在9∶1CH2Cl2/MeOH中。
Claims (12)
2.根据权利要求1的化合物,其中X和Y同时是-CONH2。
3.根据权利要求1的化合物,其中X和Y连在一起形成以下通式的基团
4.根据权利要求1的化合物,其中X和Y同时是-CO2(C1-C6)烷基。
5.根据权利要求1的化合物,其中X和Y同时是-CONHOH。
6.一种制备以下通式的化合物的方法其中X和Y是相同的并选自-CO2(C1-C6)烷基,-CONH2和-CONHOH,或X和Y连在一起形成下式的基团该方法包括:(1)让3-羟基-4-甲氧基苯甲醛与通式XCH2CO2H的化合物在碱存在下反应,其中X选自-CO2(C1-C6)烷基,-CONH2和-CONHOH,得到其中X和Y同时是-CO2(C1-C6)烷基,-CONH2和-CONHOH的通式II的化合物;或者(2)(a)让其中X和Y同时是-CN的通式II化合物与过氧化氢反应,形成其中两-CN基团都被-CONH2替代的相应的双酰胺;(b)用氧化剂将步骤(a)中形成的双酰胺进行霍夫曼重排以形成相应的双氨基甲酸酯;和(c)让步骤(b)中形成的双氨基甲酸酯与碱反应,形成其中X和Y连在一起构成以下通式的基团的环脲。
7.根据权利要求6的方法,其中3-羟基-4-甲氧基苯甲醛与HOOCCH2CONHOH反应。
8.根据权利要求6的方法,其中3-羟基-4-甲氧基苯甲醛与HOOCCH2CONH2反应。
9.根据权利要求6的方法,其中3-羟基-4-甲氧基苯甲醛与HOOCCH2CO2(C1-C6)烷基反应。
10.根据权利要求6的方法,其中所述碱是叔胺。
11.根据权利要求6的方法,其中同时将叔胺和仲胺加入到反应混合物中。
12.根据权利要求11的方法,其中所述仲胺是哌啶或吡咯烷。
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CN03104211A Pending CN1431194A (zh) | 1994-08-05 | 2003-01-30 | 合成5-(3-〔外-双环〔2.2.1〕庚-2-基氧基〕-4-甲氧基苯基)-3,4,5,6-四氢嘧啶-2(1h)酮的中间体及其制备方法 |
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1995
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1997
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1999
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2001
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2003
- 2003-01-30 CN CN03104212A patent/CN1431195A/zh active Pending
- 2003-01-30 CN CN03104211A patent/CN1431194A/zh active Pending
Also Published As
Publication number | Publication date |
---|---|
US6274733B1 (en) | 2001-08-14 |
JPH09508643A (ja) | 1997-09-02 |
US6022968A (en) | 2000-02-08 |
FI970470A (fi) | 1997-02-04 |
AU704116B2 (en) | 1999-04-15 |
FI970470A0 (fi) | 1997-02-04 |
MX9700960A (es) | 1997-05-31 |
IL114757A0 (en) | 1995-11-27 |
US6399776B2 (en) | 2002-06-04 |
AU2265595A (en) | 1996-03-04 |
NO310067B1 (no) | 2001-05-14 |
CN1431194A (zh) | 2003-07-23 |
US20010041798A1 (en) | 2001-11-15 |
CA2196309C (en) | 2001-10-16 |
JP2960965B2 (ja) | 1999-10-12 |
NO309471B1 (no) | 2001-02-05 |
NO970497D0 (no) | 1997-02-04 |
ZA956539B (en) | 1997-02-04 |
NO970497L (no) | 1997-04-02 |
MY114675A (en) | 2002-12-31 |
CA2196309A1 (en) | 1996-02-15 |
NO311429B1 (no) | 2001-11-26 |
NO20003899L (no) | 1997-04-02 |
KR100234602B1 (ko) | 1999-12-15 |
KR970704700A (ko) | 1997-09-06 |
NO20003899D0 (no) | 2000-07-31 |
WO1996004253A1 (en) | 1996-02-15 |
EP0775119A1 (en) | 1997-05-28 |
NO20000404D0 (no) | 2000-01-26 |
NO20000404L (no) | 1997-04-02 |
NZ284144A (en) | 1999-02-25 |
TW427981B (en) | 2001-04-01 |
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