CN103588707B - 多氮化合物及其合成方法 - Google Patents

多氮化合物及其合成方法 Download PDF

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CN103588707B
CN103588707B CN201310229542.1A CN201310229542A CN103588707B CN 103588707 B CN103588707 B CN 103588707B CN 201310229542 A CN201310229542 A CN 201310229542A CN 103588707 B CN103588707 B CN 103588707B
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麻生明
陈波
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Shanghai Institute of Organic Chemistry of CAS
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
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Abstract

本发明涉及多氮化合物及其合成方法。是一种醋酸铜参与2,3-联烯酸酯、胺、腈多组分反应的多氮杂环化合物的合成方法，即是一种吡唑和1,2,4-***化合物的高效合成方法。使用此合成方法，从简单的胺出发可以通过调节是否加入2,3-联烯酸酯得到两种具有重要生理活性的多氮杂环化合物：吡唑或1,2,4-***。该化合物具有如下的结构式：？本发明利用醋酸铜作为氧化剂，腈作为溶剂以及反应物，从2,3-联烯酸酯以及胺得到两种具有生理活性多氮杂环化合物。通过该方法合成的1,2,4-***化合物4a可以按照已知步骤转化为具有抗疟原虫活性的***盐化合物。

Description

多氮化合物及其合成方法
技术领域
本发明涉及一种多氮化合物的合成，具体说指一种吡唑和1,2,4-***化合物的高效合成。使用此合成方法，从简单的胺出发可以通过调节是否加入2,3-联烯酸酯得到两种具有重要生理活性的杂环化合物：吡唑以及1,2,4-***。
背景技术
在各种具有生理活性的杂环中，吡唑杂环是最重要的骨架之一，主要由于其在制药工业以及农业化学方面的广泛应用前景(Fustero,S.;Sánchez-Roselló,M.;Barrio,P.;Simón-Fuentes,A.Chem.Rev.2011,111,6984-7034)。一些含有吡唑骨架化合物，比如利莫那班(Rimonabant),西乐宝(Celebrex),伟哥(Viagra),和氟虫腈(Fipronil)已经成为商品化的药物以及杀虫剂(结构式1)[(a)Terrett,N.K.;Bell,A.S.;Brown,D.;Ellis,P.Bioorg.Med.Chem.Lett.1996,6,1819–1824.(b)Christopoulou,F.D.;Kiortsis,D.N.J.Clin.Pharm.Ther.2011,36,10-18.(c)Gunasekara,A.S.;Truong,T.;Goh,K.S.;Spurlock,F.;Tjeerdema,R.S.J.Pestic.Sci.2007,32,189-199.]。此外，吡唑化合物也被应用到聚合物、超分子化学、化妆品以及作为紫外稳定剂使用。取代的吡唑化合物被当做配体使用到一些过渡金属催化的反应中。因此，发展高效、通用的合成吡唑骨架的方法吸引了化学家极大的兴趣。
结构式1
众所周知，1,2,4-***在药物化学中具有很广阔的应用(Moulin,A.;Bibian,M.;Blayo,A.-L.;ElHabnouni,S.;Martinez,J.;Fehrentz,J.-A.Chem.Rev.2010,110,1809-1827.)。很多含有1,2,4-***类化合物被上市为药物销售，比如瑞宁得(anastrozole),氟康唑(fluconazole),伏立康唑(voriconazole),利扎曲坦(maxalt),地拉罗司(deferasirox),氟硅唑(fluotrimazole),丙环唑(Propiconazole),戊唑醇（tebuconazole）等(结构式2),以下所有被列出来的化合物(除Deferasirox)均含有无取代的1,2,4-***母环。因此，发展高效、新颖的方法来引入不同取代基到1,2,4-***环，对于药物化合家具有重要意义。迄今为止，直接通过简单的胺以及腈来合成全取代的1,2,4-***还未见报道。
结构式2
多组分反应(MCR)是通过简单原料制备复杂化合物的有效方法之一，其可以一锅实现多个化学键的高效构建，而不需要分离或者纯化反应的中间体。这类反应具有操作简单，步骤少,污染小等优点，多组分反应已经成为有机化学家研究的热点。随着联烯化学的逐渐发展，联烯参与的多组分反应也成为构建各种杂环骨架的有效手段之一。本发明利用简单胺，2,3-联烯酸酯、腈的多组分反应，提供一类高效合成多取代吡唑类化合物的途径。有趣的是，在无2,3-联烯酸酯的条件下，又合成了1,2,4-***类化合物。
本发明利用醋酸铜作为氧化剂，腈作为溶剂以及反应物，从2,3-联烯酸酯以及胺得到两种具有生理活性的杂环化合物，对于吡唑以及***类的药物衍生物的合成具有很大的意义。
发明内容
本发明的目的是提供一种多氮杂环化合物及其合成方法。
进一步说，本发明的目的之一是提供多取代吡唑类化合物。
本发明的目的之二是提供一种高效制备多取代吡唑类化合物的方法。
本发明的目的之三是提供一种1,2,4-***类化合物。
本发明的目的之四是提供一种高效制备1,2,4-***类化合物的方法。
本发明提供的一种多氮杂环化合物：多取代吡唑（Pyrzole）以及1,2,4-***类化合物（1,2,3-trazole）具有如下的结构式：
其中，R1=H或C1～C10的烷基，优先选择C1～C4的烷基，R2=苄基，R3=苯基或C1～C10的烷基，R4=C1～C12的烷基、苄基、卤代苄基、C1～C4的烷基苄基或C1～C4烷氧基苄基，R5=苯基、含有C1～C4的烷基苯基。
本发明提供的一种多氮杂环化合物的合成方法，反应式如下：
其中，R1、R2、R3、R4、R5如前所述。
在100-150℃温度下和有机腈类溶剂中，以醋酸铜为氧化剂，以胺和2,3-联烯酸酯为底物，加入或不加入分子筛除水剂，反应时间为6-48小时，，发生反应生成吡唑类化合物；其中，所述醋酸铜：胺：2,3-联烯酸酯和分子筛的摩尔比为1-3：1-2：0-1：0-5；所述的铜盐优选为醋酸铜。有趣的是，当所述醋酸铜：胺：2,3-联烯酸酯和分子筛的摩尔比为1-3：1-2：0.5-1：0-5时，获得吡唑类化合物；所述醋酸铜：胺：2,3-联烯酸酯和分子筛的摩尔比为1-3：1-2：1：0：0-5时，获得1,2,4-***类化合物。所述的有机腈类溶剂可以是C1～C10的烷基、苯基或含有C1～C4的烷基苯基，优先选择苯甲腈。反应温度优选120℃。
进一步的描述方法可以是：
吡唑类化合物合成
氩气氛围下，于干燥的反应管中依次加入2,3-联烯酸苄酯,胺和腈，室温剧烈搅拌0.5h后，加入Cu(OAc)2,加热至120℃,TLC监控反应，约6-48小时后原料完全转化，回至室温，加入50mL***稀释，滤短柱，滤液浓缩，硅胶柱层析得到吡唑类化合物。
1,2,4-***的合成
于一干燥反应管中依次加入Cu(OAc)2、胺、腈,120度反应20-48h，冷却至室温，加入50mL***稀释，滤短柱，滤液浓缩，硅胶柱层析得到1,2,4-***类化合物。
本发明方法具有以下优点：1）反应中原料易于制备，2,3-联烯酸酯可以大量制备（Lang,R.W.;Hansen,H.-J.Org.Synth.1984,62,202.Rout,L.;Harned,A.M.Chem.Eur.J.2009,15,12926.），胺以及腈均为市售产品，醋酸铜价格廉价；2）高效地将多步反应一锅法实现；3）填补此类骨架化合物合成方法的空白。
具体实施方式
以下实施例有助于理解本发明，但不限于本发明的内容。
实施例1
其中，equiv表示当量，h表示小时。
氩气氛围下，于干燥的Schlenk管中依次加入2,3-联烯酸苄酯1a(35.1mg,0.2mmol),2a(33.2mg,0.3mmol)和苯甲腈(1+1mL)，室温剧烈搅拌0.5h后，加入Cu(OAc)2(72.9mg,0.4mmol),体系放入油浴中，油浴加热至120℃,TLC监控反应，约6小时后原料完全转化，回至室温，加入50mL***稀释，滤短柱，滤液浓缩，硅胶柱层析(石油醚petroleumether/乙酸乙酯ethylacetate=20/1)得到3a(57.9mg,75%):油;1HNMR(300MHz,CDCl3)δ7.63-7.52(m,2H,ArH),7.38-7.22(m,9H,ArH),7.19-7.10(m,4H,ArH),5.33(s,2H,OCH2),5.18(s,2H,NCH2),2.47(s,3H,CH3);13CNMR(75MHz,CDCl3)δ163.8,152.9,144.6,135.81,135.77,133.3,129.4,128.8,128.3,128.1,128.0,127.8,127.7,126.8,109.6,65.6,53.3,11.5;IR(纯样neat)1702,1539,1454,1293,1209,1158,1130,1066,cm-1;MS(EI)(m/z)383((M+1)+,14.27),382(M+,51.56),91(100);HRMS计算值C25H22N2O2[M+]:382.1681;实测值（Found）:382.1679.
实施例2
操作参考实施例1。1a(35.1mg,0.2mmol),2b(37.5mg,0.3mmol)Cu(OAc)2(73.1mg,0.4mmol)在苯甲腈(1+1mL)中反应得到3b(64.8mg,80%)(petroleumether/ethylacetate=10/1)，油（oil）;1HNMR(400MHz,CDCl3)δ7.63-7.54(m,2H,ArH),7.40-7.24(m,6H,ArH),7.20-7.11(m,4H,ArH),7.04-6.93(m,2H,ArH),5.29(s,2H,OCH2),5.18(s,2H,NCH2),2.47(s,3H,CH3);13CNMR(75MHz,CDCl3)δ163.7,162.3(d,J=245.0Hz),152.9,144.4,135.7,133.2,131.5(d,J=3.4Hz),129.3,128.6(d,J=8.1Hz),128.3,128.1,128.0,127.9,127.7,115.7(d,J=21.8Hz),109.7,65.6,52.5,11.4;19FNMR(CDCl3,376MHz)-114.0;IR(neat)2925,2853,1705,1606,1538,1510,1481,1450,1427,1375,1356,1318,1298,1215,1143,1111,1076cm-1;MS(EI)(m/z)401((M+1)+,11.06),400(M+,39.29),109(100);HRMS计算值C25H21N2O2F[M+]:400.1587;实测值:400.1589.
实施例3
操作参考实施例1。1a(34.4mg,0.2mmol),2(42.7mg,0.3mmol),Cu(OAc)2(72.7mg,0.4mmol)在苯甲腈(1+1mL)中反应得到3c(53.9mg,65%)(petroleumether/ethylacetate=20/1to10/1):油;1HNMR(300MHz,CDCl3)δ7.65-7.53(m,2H,ArH),7.41-7.22(m,8H,ArH),7.20-7.05(m,4H,ArH),5.28(s,2H,OCH2),5.18(s,2H,NCH2),2.46(s,3H,CH3);13CNMR(75MHz,CDCl3)δ163.7,153.0,144.5,135.7,134.2,133.7,133.1,129.3,128.9,128.3,128.2,128.1,127.9,127.7,109.7,65.7,52.5,11.4;IR(neat)2923,2851,1693,1489,1453,1291,1215,1162,1092,1065,1013cm-1;MS(EI)(m/z)419((M(37Cl)+1)+,3.18),418(M(37Cl)+,11.66),417((M(35Cl)+1)+,9.49),416(M(35Cl)+,32.75),91(100);HRMS计算值C25H21N2O2 35Cl[M+]:416.1292;实测值:416.1289.
实施例4
操作参考实施例1。1a(33.8mg,0.2mmol),2d(41.5mg,0.3mmol)Cu(OAc)2(72.8mg,0.4mmol)在苯甲腈(1+1mL)中反应得到3d(48.7mg,61%)(petroleumether/ethylacetate=10/1):油;1HNMR(300MHz,CDCl3)δ7.65-7.53(m,2H,ArH),7.37-7.29(m,3H,ArH),7.29-7.20(m,3H,ArH),7.20-7.08(m,4H,ArH),6.89-6.78(m,2H,ArH),5.26(s,2H,OCH2),5.17(s,2H,NCH2),3.75(s,3H,OMe),2.47(s,3H,CH3);13CNMR(75MHz,CDCl3)δ163.8,159.2,152.7,144.3,135.8,133.4,129.4,128.28,128.26,128.0,127.9,127.8,127.6,114.1,109.6,65.6,55.2,52.8,11.4;IR(neat)1701,1612,1586,1539,1513,1484,1453,1295,1248,1210,1129,1067,1030cm-1;MS(EI)(m/z)413((M+1)+,3.77),412(M+,13.05),121(100);HRMS计算值C26H24N2O3[M+]:412.1787;实测值:412.1789.
实施例5
操作参考实施例1。1a(35.1mg,0.2mmol),2e(37.0mg,0.3mmol)Cu(OAc)2(72.5mg,0.4mmol)在苯甲腈(1+1mL)中反应得到3e(56.9mg,71%)(petroleumether/ethylacetate=20/1):固体;m.p.86-87℃(hexane/Et2O);1HNMR(300MHz,CDCl3)δ7.65-7.53(m,2H,ArH),7.39-7.26(m,6H,ArH),7.20-7.03(m,6H,ArH),5.29(s,2H,OCH2),5.17(s,2H,NCH2),2.47(s,3H,CH3),2.30(s,3H,CH3);13CNMR(75MHz,CDCl3)δ163.8,152.8,144.4,137.6,135.8,133.3,132.7,129.40,129.35,128.3,128.0,127.9,127.8,127.7,126.8,109.5,65.6,53.1,21.0,11.5;IR(neat)1695,1541,1515,1486,1451,1432,1291,1214,1158,1064cm-1;MS(EI)(m/z)397((M+1)+,12.20),396(M+,41.13),105(100);元素分析（elementalanalysis）计算值C26H24N2O2:C78.76,H6.10,N7.07;实测值:C78.44,H6.16,N6.97.
实施例6
操作参考实施例1。1a(35.8mg,0.2mmol),2f(22.5mg,0.3mmol)Cu(OAc)2(72.7mg,0.4mmol)在苯甲腈(1+1mL)中反应得到3f(47.9mg,67%)(petroleumether/ethylacetate=15/1to10/1):油;1HNMR(400MHz,CDCl3)δ7.58-7.51(m,2H,ArH),7.35-7.23(m,6H,ArH),7.20-7.11(m,2H,ArH),5.18(s,2H,OCH2),4.08(t,J=7.4Hz,2H,NCH2),2.55(s,3H,Me),1.87-1.75(m,2H,CH2),1.41-1.30(m,2H,CH2),0.94(t,J=7.4Hz,3H,CH3);13CNMR(100MHz,CDCl3)δ163.9,152.6,143.8,135.9,133.5,129.3,128.2,128.0,127.84,127.78,127.6,108.8,65.5,49.0,31.9,19.8,13.6,11.3;IR(neat)1951,1879,1807,1701,1538,1454,1296,1208,1161,1128,1068cm-1;MS(EI)(m/z)349((M+1)+,13.05),348(M+,53.02),305(100);HRMS计算值C22H24N2O2[M+]:348.1838;实测值:348.1840.
实施例7
操作参考实施例1。1a(36.6mg,0.2mmol),2g(31.7mg,0.3mmol)Cu(OAc)2(72.4mg,0.4mmol)在苯甲腈(1+1mL)中反应得到3g(44.4mg,56%)(treatwith20mgNaBH4,thenpetroleumether/ethylacetate=20/1):液体;1HNMR(300MHz,CDCl3)δ7.61-7.48(m,2H,ArH),7.35-7.23(m,6H,ArH),7.20-7.11(m,2H,ArH),5.18(s,2H,OCH2),4.07(t,J=7.4Hz,2H,NCH2),2.55(s,3H,Me),1.87-1.75(m,2H,CH2),1.40-1.23(m,6H,(CH2)3),0.88(t,J=6.9Hz,3H,CH3);13CNMR(75MHz,CDCl3)δ163.9,152.6,143.8,135.9,133.6,129.3,128.3,128.0,127.84,127.78,127.6,108.8,65.5,49.3,31.3,29.9,26.2,22.4,13.9,11.3;IR(neat)1950,1879,1806,1701,1537,1514,1485,1453,1297,1249,1159,1128,1067cm-1;MS(EI)(m/z)377((M+1)+,8.67),376(M+,32.26),91(100);HRMS计算值C24H28N2O2[M+]:376.2151;实测值:376.2150.
实施例8
操作参考实施例1。1a(35.4mg,0.2mmol),2h(39.0mg,0.3mmol)Cu(OAc)2(72.7mg,0.4mmol)在苯甲腈(1+1mL)中反应得到3h(49.3mg,60%)(petroleumether/ethylacetate=20/1fortwice):液体（liquid）;1HNMR(300MHz,CDCl3)δ7.59-7.48(m,2H,ArH),7.37-7.23(m,6H,ArH),7.20-7.09(m,2H,ArH),5.18(s,2H,OCH2),4.08(t,J=7.2Hz,2H,NCH2),2.56(s,3H,Me),1.92-1.75(m,2H,CH2),1.40-1.23(m,10H,(CH2)5),0.87(t,J=6.8Hz,3H,CH3);13CNMR(75MHz,CDCl3)δ163.9,152.7,143.8,135.9,133.5,129.3,128.3,128.0,127.9,127.8,127.7,108.8,65.5,49.3,31.7,30.0,29.09,29.07,26.6,22.6,14.0,11.3;IR(neat)1702,1537,1454,1297,1159,1128,1068cm-1;MS(EI)(m/z)405((M+1)+,7.52),404(M+,24.60),91(100);HRMS计算值C26H32N2O2[M+]:404.2464;实测值:404.2463.
实施例9
操作参考实施例1。1a(33.8mg,0.2mmol),2i(30.0mg,0.3mmol)Cu(OAc)2(72.9mg,0.4mmol)在苯甲腈(1+1mL)中反应得到3i(37.6mg,52%)(petroleumether/ethylacetate=20/1两次):油;1HNMR(300MHz,CDCl3)δ7.58-7.48(m,2H,ArH),7.36-7.22(m,6H,ArH),7.16-7.09(m,2H,ArH),5.17(s,2H,OCH2),4.05(tt,J=11.6,3.8Hz,1H,NCH),2.57(s,3H,Me),2.11-1.83(m,6H,(CH2)3),1.75-1.64(m,1H,一个质子（oneprotonin），CH2),1.50-1.20(m,3H,三个质子（threeprotonin），(CH2)2);13CNMR(75MHz,CDCl3)δ164.2,152.3,143.0,136.0,133.9,129.4,128.3,128.0,127.8,127.6,108.6,65.5,57.7,32.3,25.5,25.0,11.0;IR(neat)2932,2856,1700,1537,1498,1451,1426,1299,1259,1221,1160,1151,1128,1091,1029cm-1;MS(EI)(m/z)375((M+1)+,8.73),374(M+,32.55),185(100);HRMS计算值C24H26N2O2[M+]:374.1994;实测值:374.1993.
实施例10
其中，equiv表示当量，h表示小时，MS表示分子筛。
操作参考实施例1。1a(34.9mg,0.2mmol),2a(32.3mg,0.3mmol),MS(50.0mg),Cu(OAc)2(72.9mg,0.4mmol)在nBuCN(1+1mL)反应得到3j(35.4mg,49%)(petroleumether/ethylacetate=10/1):油;1HNMR(300MHz,CDCl3)δ7.50-7.22(m,8H,ArH),7.15-7.04(m,2H,ArH),5.27(s,2H,OCH2),5.25(s,2H,NCH2),2.90-2.78(m,2H,CH2),2.42(s,3H,Me),1.68-1.52(m,2H,CH2),1.40-1.22(m,2H,CH2),0.87(t,J=7.2Hz,3H,CH3);13CNMR(75MHz,CDCl3)δ164.2,154.9,144.4,136.2,136.1,128.7,128.5,128.3,128.1,127.7,126.6,109.1,65.6,52.9,31.7,28.2,22.7,13.9,11.4;IR(neat)2956,2930,1702,1546,1496,1455,1305,1235,1211,1189,1113,1086,1029cm-1;MS(EI)(m/z)362(M+,2.90),91(100);HRMS计算值C23H26N2O2[M+]:362.1994;实测值:362.1996.
实施例11
其中，equiv表示当量，h表示小时，sealed表示封管
操作参考实施例1。1a(34.7mg,0.2mmol),2a(32.4mg,0.3mmol)Cu(OAc)2(72.8mg,0.4mmol)在MeCN(1+1mL)中反应得到3k(38.3mg,60%)(petroleumether/ethylacetate=10/1to5/1):油;1HNMR(400MHz,CDCl3)δ7.45-7.24(m,8H,ArH),7.13-7.04(m,2H,ArH),5.28(s,2H,OCH2),5.24(s,2H,NCH2),2.45(s,3H,CH3),2.43(s,3H,CH3);13CNMR(100MHz,CDCl3)δ164.2,150.7,144.4,136.3,136.0,128.8,128.5,128.03,127.98,127.8,126.6,109.7,65.5,52.8,14.5,11.4;IR(neat)1685,1549,1495,1452,1430,1372,1295,1271,1205,1194,1115cm-1;MS(EI)(m/z)320(M+,15.65),91(100);HRMS计算值C20H20N2O2[M+]:320.1525;实测值:320.1526.
实施例12
其中，equiv表示当量，h表示小时，oilbath表示油浴加热。
于一干燥Schlenk反应管中依次加入Cu(OAc)2(367.9mg,2mmol),正丁胺BnNH2(108.6mg,1mmol),PhCN(2mL),加入完毕后将体系放入预先加热好的120℃油浴中，反应20h，冷却至室温，加入50mL***稀释，滤短柱，滤液浓缩，硅胶柱层析(eluent:petroleumether/ethylacetate=40/1to10/1)toafford4a(139.7mg,44%):固体;1HNMR(300MHz,CDCl3)δ8.25-8.14(m,2H,ArH),7.66-7.57(m,2H,ArH),7.52-7.27(m,9H,ArH),7.25-7.16(m,2H,ArH),5.46(s,2H,CH2).
克级合成4a:
于一干燥100mL三口瓶中依次加入Cu(OAc)2(3.6321g,20mmol),BnNH2(1.0704g,10mmol),PhCN(20mL).加入完毕后将体系放入预先加热好的120℃油浴中，反应48h，冷却至室温，加入50mL***稀释，滤短柱，滤液浓缩，硅胶柱层析(eluent:petroleumether/ethylacetate=30/1to10/1)得到4a(1.3062g,42%):固体;1HNMR(300MHz,CDCl3)δ8.27-8.14(m,2H,ArH),7.64-7.52(m,2H,ArH),7.48-7.13(m,11H,ArH),5.40(s,2H,CH2).
其中，equiv表示当量，mins表示分钟，MW表示微波加热。
于一干燥微波反应管中依次加入Cu(OAc)2(363.9mg,2mmol),BnNH2(106.8mg,1mmol),PhCN(5mL),拧紧旋塞，放入微波反应器MILESTONES.r.l微波加热(120℃,30minutes,maximumpower800W),然后待体系冷却至室温，加入50mL***稀释，滤短柱，滤液在油泵减压下旋去大部分溶剂，硅胶柱层析(eluent:petroleumether/ethylacetate=10/1)得到4a(127.0mg,41%):固体（solid）;m.p.99-100℃(己烷hexane/***Et2O)(lit.m.p.98.5-99.5℃);1HNMR(300MHz,CDCl3)δ8.21(d,J=7.2Hz,2H,ArH),7.62-7.51(m,2H,ArH),7.48-7.13(m,11H,ArH),5.39(s,2H,CH2);13CNMR(CDCl3,75MHz)δ161.4,156.0,135.9,130.9,130.0,129.0,128.70,128.67,128.6,128.4,127.9,127.8,126.6,126.3,52.6.IR(neat)3067,3035,2926,2854,1519,1497,1476,1463,1443,1406,1353,1266,1237,1131,1072,1016cm-1;MS(EI)(m/z)312((M+1)+,5.71),311(M+,27.09),91(100).
该化合物为已知化合物，可以通过已知步骤一步(Vlahakis,J.Z.;Lazar,C.;Crandall,I.E.;Szarek,W.A.Biorg.Med.Chem.2010,18,6184)转化为具有抗疟原虫活性的***盐化合物IC50(7.8±0.2μM)P.falciparum。
实施例13
操作参考实施例13。Cu(OAc)2(362.4mg,2mmol),4-氟苯甲胺4-fluorobenzylamine(129.7mg,97%purity,1mmol),在PhCN(5mL)中反应得到4b(150.3mg,45%)(eluent:petroleumether/ethylacetate=10/1):油;1HNMR(300MHz,CDCl3)δ8.24-8.16(m,2H,ArH),7.64-7.52(m,2H,ArH),7.50-7.33(m,6H,ArH),7.20-7.10(m,2H,ArH),7.05-6.92(m,2H,ArH),5.37(s,2H,NCH2);13CNMR(CDCl3,75MHz)δ162.2(d,J=245.9Hz),161.5,155.9,131.6(d,J=3.5Hz),130.8,130.2,129.2,128.8,128.63,128.61(d,J=8.1Hz),128.45,127.8,126.3,115.7(d,J=20.9Hz),51.9;19FNMR(CDCl3,282MHz)-113.9;IR(neat)1605,1509,1478,1458,1446,1405,1353,1222,1156,1141,1016cm-1;MS(EI)(m/z)330((M+1)+,11.24),329(M+,49.41),109(100);HRMS计算值C21H16N3F(M+):329.1328,实测值:329.1329.
实施例14
操作参考实施例13。Cu(OAc)2(363.9mg,2mmol),正丁基胺n-BuNH2(73.1mg,1mmol),在PhCN(5mL)中反应得到4c(147.8mg,53%)(淋洗液eluent:petroleumether/ethylacetate=10/1):油;1HNMR(300MHz,CDCl3)δ8.19(d,J=7.2Hz,2H,ArH),7.66-7.61(m,2H,ArH),7.60-7.24(m,6H,ArH),4.18(t,J=7.2Hz,2H,NCH2),2.00-1.83(m,2H,CH2),1.40-1.21(m,2H,CH2),0.86(t,J=7.2Hz,3H,CH3);13CNMR(CDCl3,75MHz)δ161.0,155.3,131.1,129.8,128.8,128.6,128.3,126.2,48.8,31.9,19.5,13.3;IR(neat)3068,2959,2933,2873,1957,1893,1815,1767,1519,1476,1463,1442,1410,1354,1132,1019cm-1;MS(EI)(m/z)278((M+1)+,11.49),277(M+,55.63),234(100);HRMS计算值C18H19N3(M+):277.1579,实测值:277.1578.
Cu(OAc)2(363.2mg,2mmol),n-BuNH2(74.0mg,1mmol),在PhCN(2mL)反应得到4c(125.3mg,45%)(eluent:petroleumether/ethylacetate=10/1):油;1HNMR(300MHz,CDCl3)δ8.18(d,J=7.5Hz,2H,ArH),7.66-7.60(m,2H,ArH),7.59-7.30(m,6H,ArH),4.20(t,J=7.2Hz,2H,NCH2),2.00-1.80(m,2H,CH2),1.40-1.21(m,2H,CH2),0.87(t,J=7.2Hz,3H,CH3).
实施例15
操作参考实施例13。Cu(OAc)2(362.5mg,2mmol),异丁基胺isobutylNH2(74.1mg,1mmol),在PhCN(5mL)中反应得到4d(132.4mg,47%)(eluent:petroleumether/ethylacetate=10/1):油;1HNMR(300MHz,CDCl3)δ8.19(d,J=7.2Hz,2H,ArH),7.68-7.57(m,2H,ArH),7.55-7.30(m,6H,ArH),4.02(d,J=7.2Hz,2H,NCH2),2.45-2.25(m,1H,CH),0.86(d,J=6.6Hz,6H,(CH3)2);13CNMR(CDCl3,75MHz)δ161.0,156.0,131.1,129.8,128.9,128.7,128.5,128.4,126.3,56.2,29.2,19.7;IR(neat)3069,2940,2872,1958,1894,1815,1730,1519,1476,1463,1442,1409,1391,1354,1285,1193,1174,1132,1071,1018cm-1;MS(EI)(m/z)278((M+1)+,14.65),277(M+,67.21),104(100);HRMS计算值C18H19N3(M+):277.1579,实测值:277.1577.
实施例16
操作参考实施例13。Cu(OAc)2(363.3mg,2mmol),正戊基胺n-C5H11NH2(88.1mg,1mmol),在PhCN(5mL)中反应得到4e(135.1mg,46%)(eluent:petroleumether/ethylacetate=15/1):油;1HNMR(300MHz,CDCl3)δ8.18(d,J=7.5Hz,2H,ArH),7.72-7.60(m,2H,ArH),7.55-7.30(m,6H,ArH),4.19(t,J=7.4Hz,2H,NCH2),2.00-1.82(m,2H,CH2),1.38-1.20(m,4H,-(CH2)2-),0.85(t,J=5.9Hz,3H,CH3);13CNMR(CDCl3,75MHz)δ161.1,155.4,131.1,129.9,128.9,128.7,128.4,126.3,49.2,29.7,28.5,22.0,13.8;IR(neat)2958,2926,2856,1476,1463,1441,1408,1355cm-1;MS(EI)(m/z)292((M+1)+,12.96),291(M+,59.60),234(100);HRMS计算值C19H21N3(M+):291.1735,实测值:291.1734.
实施例17
操作参考实施例13。Cu(OAc)2(363.1mg,2mmol),环己基胺CyNH2(99.4mg,1mmol),在PhCN(5mL)中反应得到19f(137.7mg,45%)(eluent:petroleumether/ethylacetate=10/1):固体,107-108℃(petroleumether/Et2O)(lit.2m.p.106-107℃);1HNMR(300MHz,CDCl3)δ8.18(d,J=7.8Hz,2H,ArH),7.68-7.57(m,2H,ArH),7.56-7.47(m,3H,ArH),7.46-7.30(m,3H,ArH),4.22(tt,J=11.4,4.1Hz,1H,NCH2),2.23-2.02(m,2H,CH2),2.02-1.80(m,4H,-(CH2)2-),1.78-1.61(m,1H,oneprotoninCH2),1.40-1.20(m,3H,threeprotonin(CH2)2);13CNMR(CDCl3,75MHz)δ160.9,154.6,131.4,129.8,128.9,128.8,128.7,128.4,126.3,58.0,33.1,25.4,24.9;IR(neat)3060,3032,2928,2853,1476,1439,1402,1380,1350,1326,1300,1263,1174,1026cm-1;MS(EI)(m/z)304((M+1)+,8.77),303(M+,36.94),221(100).
实施例18
操作参考实施例13。Cu(OAc)2(363.5mg,2mmol),正己基胺n-hexylNH2(102.0mg,1mmol),在PhCN(5mL)中反应得到4g(146.1mg,48%)(eluent:petroleumether/ethylacetate=10/1):油;1HNMR(400MHz,CDCl3)δ8.17(d,J=7.2Hz,2H,ArH),7.70-7.63(m,2H,ArH),7.59-7.50(m,3H,ArH),7.49-7.35(m,3H,ArH),4.21(t,J=7.4Hz,2H,NCH2),2.00-1.87(m,2H,CH2),1.36-1.20(m,6H,-(CH2)3-),0.85(t,J=6.8Hz,3H,CH3);13CNMR(CDCl3,75MHz)δ161.1,155.4,131.2,129.9,128.9,128.8,128.4,126.3,49.2,31.1,30.0,26.1,22.4,13.9;IR(neat)3069,2954,2929,2857,1956,1893,1814,1764,1519,1476,1442,1410,1353,1132,1071,1018cm-1;MS(EI)(m/z)306((M+1)+,11.44),305(M+,50.21),234(100);HRMS计算值C20H23N3(M+):305.1892,实测值:305.1893.
实施例19
操作参考实施例13。Cu(OAc)2(363.8mg,2mmol),正辛基胺n-C8H17NH2(128.5mg,1mmol),在PhCN(5mL)中反应得到4h(166.9mg,50%)(eluent:petroleumether/ethylacetate=15/1):油;1HNMR(300MHz,CDCl3)δ8.18(d,J=7.8Hz,2H,ArH),7.67-7.60(m,2H,ArH),7.53-7.30(m,6H,ArH),4.19(t,J=7.4Hz,2H,NCH2),2.00-1.83(m,2H,CH2),1.38-1.07(m,10H,-(CH2)5-),0.85(t,J=6.5Hz,3H,CH3);13CNMR(CDCl3,75MHz)δ161.0,155.4,131.1,129.8,128.9,128.7,128.4,126.2,49.1,31.6,30.0,28.9,28.8,26.3,22.5,13.9;IR(neat)2926,2855,1955,1893,1813,1727,1519,1476,1442,1354,1133,1071cm-1;MS(EI)(m/z)334((M+1)+,3.84),333(M+,17.96),221(100).
操作参考实施例13。Cu(OAc)2(363.4mg,2mmol),n-C8H17NH2(128.9mg,1mmol),在PhCN(2mL)中油浴反应得到4h(143.6mg,43%)(eluent:petroleumether/ethylacetate=10/1):油;1HNMR(300MHz,CDCl3)δ8.22(m,2H,ArH),7.69-7.60(m,2H,ArH),7.55-7.30(m,6H,ArH),4.20(t,J=7.4Hz,2H,NCH2),2.00-1.84(m,2H,CH2),1.38-1.10(m,10H,-(CH2)5-),0.86(t,J=6.8Hz,3H,CH3).
实施例20
操作参考实施例13。Cu(OAc)2(363.4mg,2mmol),正十二烷基胺n-C12H25NH2(185.7mg,1mmol),在PhCN(5mL)中反应得到4i(214.7mg,55%)(eluent:petroleumether/ethylacetate=10/1):油;1HNMR(300MHz,CDCl3)δ8.17(d,J=7.5Hz,2H,ArH),7.72-7.60(m,2H,ArH),7.58-7.30(m,6H,ArH),4.20(t,J=7.2Hz,2H,NCH2),2.00-1.82(m,2H,CH2),1.38-1.12(m,18H,-(CH2)9-),0.88(t,J=6.0Hz,3H,CH3);13CNMR(CDCl3,75MHz)δ161.1,155.5,131.2,129.9,128.9,128.81,128.79,128.4,126.3,49.2,31.8,30.1,29.5,29.4,29.34,29.27,28.9,26.4,22.6,14.1;IR(neat)2924,2853,1953,1891,1812,1763,1464,1442,1354,1018cm-1;MS(EI)(m/z)390((M+1)+,5.76),389(M+,19.41),221(100);HRMS计算值C26H35N3(M+):389.2831,实测值:389.2832.
实施例21
操作参考实施例13。Cu(OAc)2(363.4mg,2mmol),苄胺BnNH2(107.1mg,1mmol),在PhCN(2mL)中反应得到4j(163.8mg,48%)(eluent:petroleumether/ethylacetate=15/1):油;1HNMR(300MHz,CDCl3)δ8.10-7.95(m,2H,ArH),7.46(s,1H,ArH),7.39-7.15(m,10H,ArH),5.40(s,2H,NCH2),2.38(s,3H,Me),2.33(s,3H,Me);13CNMR(CDCl3,75MHz)δ161.4,156.0,138.5,138.0,136.0,130.7,130.0,129.8,129.4,128.6,128.5,128.3,127.71,127.67,126.8,126.6,125.4,123.4,52.5,21.19,21.14;IR(neat)1611,1592,1512,1496,1452,1433,1358,1339,1301,1262,1143cm-1;MS(EI)(m/z)340((M+1)+,23.42),339(M+,94.69),91(100);HRMS计算值C23H21N3(M+):339.1735,实测值:339.1736.

Claims (5)

1.一种多氮化合物，其具有如下的结构式的多取代吡唑：
其中，R1＝H或C1～C10的烷基，R2＝苄基，R3＝苯基或C1～C10的烷基，R4＝苄基、卤代苄基、C1～C4的烷基取代苄基或C1～C4烷氧基取代苄基。
2.一种多氮化合物的合成方法，其特征是所述的多氮化合物为1,2,4-***类化合物，通过下述步骤获得：
在100-150℃温度下和有机腈类溶剂中，以醋酸铜为氧化剂，胺为底物，反应6-48小时，生成1,2,4-***类化合物；其中，所述醋酸铜：胺的摩尔比为1-3：1-2；所述的R4＝C1～C12的烷基、苄基、卤代苄基、C1～C4的烷基取代苄基或C1～C4烷氧基取代苄基，R5＝苯基、含有C1～C4的烷基取代苯基。
3.一种多氮化合物的合成方法，其特征是所述的多氮化合物为多取代吡唑，通过下述步骤获得：
在100-150℃温度下和有机腈类溶剂中，以醋酸铜为氧化剂，胺和2,3-联烯酸酯为底物，加入或不加入分子筛除水剂，反应时间为6-48小时，生成吡唑类化合物，所述醋酸铜：胺：2,3-联烯酸酯和分子筛的摩尔比为1-3：1-2：0.5-1：0-5；所述的R1＝H或C1～C10的烷基，R2＝苄基，R3＝苯基或C1～C10的烷基，R4＝C1～C12的烷基、苄基、卤代苄基、C1～C4的烷基取代苄基或C1～C4烷氧基取代苄基。
4.如权利要求2所述的多氮化合物的合成方法，其特征是，所述的1,2,4-***类化合物中R5＝苯基，含有C1～C4的烷基取代苯基，R4＝卤代苄基、C1～C4的烷基取代苄基或C1～C4烷氧基取代苄基。
5.如权利要求2所述的多氮化合物的合成方法，其特征是：所述的产物经过***稀释，短柱分离，滤液浓缩，硅胶柱层析纯化。
CN201310229542.1A 2013-06-09 2013-06-09 多氮化合物及其合成方法 Active CN103588707B (zh)

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