CN112250636A - 5-氨基咪唑类化合物及其合成方法 - Google Patents
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/96—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一类5‑氨基咪唑类化合物及其合成方法。所述的5‑氨基咪唑类化合物具有如下式(I)所示结构,其合成方法为:取如下式(II)所示化合物、式(III)所示化合物、式(Ⅳ)所示化合物和钯催化剂置于有机溶剂中,于加热条件下反应,制得目标化合物粗品。本发明所述合成方法原料易得,操作简单易控,产率高。所述式(I)、式(II)、式(III)和式(Ⅳ)所示结构的化合物分别如下:
Description
技术领域
本发明涉及咪唑类化合物,具体涉及5-氨基咪唑类化合物及其合成方法。
背景技术
含氮杂环化合物的种类繁多,数量庞大,在自然界分布极为广泛,许多天然含氮杂环化合物在动植物体内起着重要的生理作用。其中,5-氨基咪唑是一类具有多种生物活性的杂环类化合物,广泛用于抗血小板、抗菌、抗炎、抗病毒等药物的研发中。如:Rehse报道了5-氨基咪唑类化合物在抗血小板方面表现出优异的作用(Arch.Pharm.2005,338,539-547.);Loza报道了5-氨基咪唑类化合物作为有效的腺苷A2A受体拮抗剂,显示出良好的选择性(Eur.J.Med.Chem.2012,54,303-310.);Dias报道了5-氨基咪唑类化合物在抑菌方面展现出良好的效率,尤其对克鲁斯酵母和新生隐球菌的生长有强烈的抑制作用(Bioorg.Med.Chem.Lett.2014,24,4699-4702);Liu报道了5-氨基咪唑类化合物作为一种腺苷酸活化蛋白激酶激活剂,能增加破骨细胞内腺苷酸活化蛋白激酶磷酸化水平,上调破骨细胞内的自噬水平,抑制破骨细胞分化和骨吸收蛋白活性,为骨质疏松症等骨骼相关疾病的防治或药物开发提供新的思路(畜牧兽医学报.2019,50,2339-2347.)。
5-氨基咪唑类化合物在医药领域具有重要的应用价值,但传统合成5-氨基咪唑类化合物的方法大都存在着原子经济性和步骤经济性差、产率低下、反应条件相对苛刻以及副产物较多、后处理难度大等不足,因此亟待需要发展新的绿色合成方法高效合成此类化合物。
发明内容
本发明要解决的技术问题是提供一类结构新颖的5-氨基咪唑类化合物及其合成方法。
本发明所述的5-氨基咪唑类化合物为具有下述式(I)所示化合物或其药学上可接受的盐:
其中:
R1表示苯基、卤原子取代的苯基、烷基取代的苯基、烷氧基取代的苯基或三氟甲基取代的苯基,或者是萘基或取代的萘基,或者是噻吩基或取代的噻吩基;
R2表示叔丁基、金刚烷基或1,1,3,3-四甲基丁烷基;
R3表示苯基、卤原子取代的苯基、烷基取代的苯基、烷氧基取代的苯基或三氟甲基取代的苯基。
上述化合物中,R1进一步优选为苯基、4-氯苯基、4-氟苯基、4-溴苯基、2-甲基苯基、4-甲基苯基、2,3-二甲基苯基、3,4-二甲基苯基、4-甲氧基苯基、4-三氟甲基苯基、萘基或噻吩基;R3进一步优选为苯基、4-氯苯基、4-氟苯基、4-溴苯基、4-甲基苯基、4-甲氧基苯基、4-三氟甲基苯基或萘基。
上述式(I)所示化合物的合成方法,主要包括以下步骤:取如下式(II)所示化合物、式(III)所示化合物、式(Ⅳ)所示化合物和钯催化剂置于有机溶剂中,于加热条件下反应,制得目标化合物粗品;
其中:
R1表示苯基、卤原子取代的苯基、烷基取代的苯基、烷氧基取代的苯基或三氟甲基取代的苯基,或者是萘基或取代的萘基,或者是噻吩基或取代的噻吩基;
R2表示叔丁基、金刚烷基或1,1,3,3-四甲基丁烷基;
R3表示苯基、卤原子取代的苯基、烷基取代的苯基、烷氧基取代的苯基或三氟甲基取代的苯基。
为了有效提高整个反应产率,优选是在反应之前加入还原剂,将钯催化剂中钯元素由+2价还原成0价以提高催化效果。所述的还原剂优选为选自三苯基膦、三环己基膦、三丁基膦、1,3-双(二苯基膦)丙烷和环己基二苯基膦中的一种或两种以上的组合。所述还原剂的加入量通常为式(II)所示化合物摩尔量的5%以上,优选为5~10%。
本发明所述合成方法中,R1和R2的优选选择如前所述;式(II)所示化合物、式(III)所示化合物和式(Ⅳ)所示化合物的摩尔比为化学计量比,在实际的操作中,式(II)所示化合物、式(III)所示化合物和式(Ⅳ)所示化合物的摩尔比通常为1:2~3:1~2。
本发明所述合成方法中,所述钯催化剂的选择与现技术相同,具体可以是选自四(三苯基膦)钯、氯化钯、醋酸钯、二(三苯基膦)氯化钯、二(氰基苯)二氯化钯和二溴化钯中的一种或两种以上的组合。所述钯催化剂的加入量通常为式(II)所示化合物摩尔量的3%以上,优选为3~5%。
本发明所述合成方法中,所述的有机溶剂具体可以是选自甲苯、二甲基亚砜、乙腈、N,N-二甲基甲酰胺、N-甲基吡咯烷酮、苯甲腈和1,4二氧六环中一种或两种以上的组合。所述有机溶剂的用量以能够溶解参加反应的原料为宜,通常情况下,以0.2mmol的式(II)所示化合物为基准,所有参加反应的原料通常用0.5~5mL的有机溶剂来溶解。
本发明所述合成方法中,反应优选是在50~120℃条件下进行。采用TLC跟踪监测反应是否完全。根据申请人的经验,当反应在50~120℃条件下进行时,反应时间控制在4~6h较为适宜。
由上述方法制得的是式(I)化合物的粗品,可采用现有常规的纯化方法对其进行纯化以提高式(I)化合物的纯度。通常采用硅胶柱层析的方式进行纯化,在层析时用的洗脱剂可以是由乙酸乙酯和石油醚按1:5~100的体积比组成的混合溶剂。所述的混合溶剂中,乙酸乙酯和石油醚的体积比优选为1:5~50,更优选为1:5~20。
与现有技术相比,本发明提供了一系列结构新颖的5-氨基咪唑类化合物,申请人以酰胺肟、异氰和胺类化合物为原料,在钯催化条件下三组份串联反应合成目标化合物,原料易得,操作简单易控,产率高。
具体实施方式
下面结合具体实施例对本发明作进一步的详述,以更好地理解本发明的内容,但本发明并不限于以下实施例。
实施例1
按下述合成路线合成本发明所述的5-氨基咪唑类化合物。
4aaa:R1=苯基,R2=叔丁基,R3=苯基;
4baa:R1=4-甲基苯基,R2=叔丁基,R3=苯基;
4caa:R1=4-甲氧基苯基,R2=叔丁基,R3=苯基;
4daa:R1=4-氯苯基,R2=叔丁基,R3=苯基;
4eaa:R1=4-三氟甲基苯基,R2=叔丁基,R3=苯基;
4fac:R1=2-甲基苯基,R2=叔丁基,R3=4-甲氧基苯基;
4gac:R1=3,4-二甲基苯基,R2=叔丁基,R3=4-甲氧基苯基;
4hac:R1=2,3-二甲基苯基,R2=叔丁基,R3=4-甲氧基苯基;
4iac:R1=萘-2-基,R2=叔丁基,R3=4-甲氧基苯基;
4iaa:R1=萘-2-基,R2=叔丁基,R3=苯基;
4jab:R1=噻吩-2-基,R2=叔丁基,R3=4-甲基苯基;
4jac:R1=噻吩-2-基,R2=叔丁基,R3=4-甲氧基苯基;
4aab:R1=苯基,R2=叔丁基,R3=4-甲基苯基;
4dab:R1=4-氯苯基,R2=叔丁基,R3=4-甲基苯基;
4eab:R1=4-三氟甲基苯基,R2=叔丁基,R3=4-甲基苯基;
4aac:R1=苯基,R2=叔丁基,R3=4-甲氧基苯基;
4dac:R1=4-氯苯基,R2=叔丁基,R3=4-甲氧基苯基;
4eac:R1=4-三氟甲基苯基,R2=叔丁基,R3=4-甲氧基苯基;
4aad:R1=苯基,R2=叔丁基,R3=4-氯苯基;
4cae:R1=4-甲氧基苯基,R2=叔丁基,R3=4-氟苯基;
4aaf:R1=苯基,R2=叔丁基,R3=4-三氟甲基苯基;
4bag:R1=4-甲基苯基,R2=叔丁基,R3=萘-1-基;
4bbb:R1=4-甲基苯基,R2=1,1,3,3-四甲基丁烷基,R3=4-甲基苯基;
4bcc:R1=4-甲基苯基,R2=金刚烷基,R3=4-甲氧基苯基。
通用合成方法:在15mL一端封闭的反应管中加入0.2mmol酰胺肟衍生物1(即式(II)所示化合物)、0.4mmol异腈衍生物2(即式(III)所示化合物)、0.3mmol胺类化合物3(即式(Ⅳ)所示化合物)、相当于酰胺肟衍生物1摩尔量5%的醋酸钯、相当于酰胺肟衍生物1摩尔量10%的三苯基膦,然后加入二甲亚砜0.5mL,熔封后置于100℃条件下反应至完全(TLC跟踪反应,4~6h)。待反应完全后,冷却到室温,过滤,减压除去溶剂,滤液减压除去溶剂,所得残留物经快速硅胶柱层析纯化(乙酸乙酯/石油醚=1:5~20,体积比),得到目标化合物4(即式(I)所示化合物)。不同的目标化合物及其表征如下:
4aaa:顺-N-(叔丁基)-2-苯基-4-(苯基亚胺基)-4氢-咪唑-5-胺
红色固体,产率:92%.1H NMR(400MHz,CDCl3,δppm)8.58-8.51(m,2H),7.91-7.86(m,2H),7.61(t,J=7.3Hz,1H),7.52(t,J=7.5Hz,2H),7.46(dd,J=10.6,5.0Hz,2H),7.31-7.26(m,1H),1.66(s,9H);13C NMR(101MHz,CDCl3,δppm)189.9,169.0,162.6,146.6,133.5,132.4,130.5,128.9,128.4,127.2,126.4,54.1,28.7.HRMS(ESI)m/z:calcd forC19H21N4[M+H]+305.1766;found 305.1761.
4baa:顺-N-(叔丁基)-4-(苯基亚氨基)-2-(对甲苯基)-4氢-咪唑-5-胺
红色固体,产率:89%.1H NMR(400MHz,CDCl3,δppm)8.41(d,J=8.1Hz,2H),7.88-7.81(m,2H),7.43(dd,J=10.7,5.0Hz,2H),7.30-7.22(m,3H),2.45(s,3H),1.62(s,9H);13CNMR(101MHz,CDCl3,δppm)189.8,169.0,162.7,146.7,144.5,130.7,129.7,129.2,128.8,127.0,126.4,54.0,28.7,22.0.HRMS(ESI)m/z:calcd for C20H23N4[M+H]+319.1923;found319.1920.
4caa:顺-N-(叔丁基)-2-(4-甲氧基苯基)-4-(苯基亚胺基)-4氢-咪唑-5-胺
红色固体,产率:91%.1H NMR(400MHz,CDCl3,δppm)8.52-8.46(m,2H),7.84(d,J=7.4Hz,2H),7.45-7.38(m,2H),7.26-7.17(m,1H),7.02-6.96(m,2H),3.90(s,3H),1.62(s,9H);13C NMR(101MHz,CDCl3,δppm)189.1,168.9,164.3,162.7,146.8,132.8,128.8,126.8,126.3,124.9,113.9,55.5,53.9,28.7.HRMS(ESI)m/z:calcd for C20H23N4O[M+H]+335.1872;found 335.1878.
4daa:顺-N-(叔丁基)-2-(4-氯苯基)-4-(苯基亚胺基)-4氢-咪唑-5-胺
红色固体,产率:87%.1H NMR(400MHz,CDCl3,δppm)8.42(d,J=8.5Hz,2H),7.82(d,J=7.8Hz,2H),7.42(dd,J=16.1,8.2Hz,4H),7.24(t,J=7.3Hz,1H),1.60(s,9H);13CNMR(101MHz,CDCl3,δppm)188.8,169.1,162.4,146.5,139.7,131.8,130.9,128.9,128.7,127.4,126.5,54.1,28.7.HRMS(ESI)m/z:calcd for C19H20N4Cl[M+H]+339.1376;found339.1375.
4eaa:顺-N-(叔丁基)-4-(苯基亚氨基)-2-(4-(三氟甲基)苯基)-4氢-咪唑-5-胺
红色固体,产率:84%.1H NMR(400MHz,CDCl3,δppm)8.59(d,J=8.1Hz,2H),7.88-7.82(m,2H),7.74(d,J=8.3Hz,2H),7.45(dd,J=10.8,4.9Hz,2H),7.30-7.26(m,1H),1.64(s,9H);13C NMR(101MHz,CDCl3,δppm)188.5,169.1,162.1,146.3,135.8,134.2(q,J=32Hz),130.6,128.9,127.7,126.6,125.2(q,J=3.9Hz),124.1(q,J=272Hz),54.3,28.7.HRMS(ESI)m/z:calcd for C20H20N4F3[M+H]+373.1640;found 373.1637.
4fac:顺-N-(叔丁基)-4-((4-甲氧基苯基)亚胺基)-2-(邻甲苯基)-4氢-咪唑-5-胺
红色液体,产率:78%.1H NMR(400MHz,CDCl3,δppm)8.52(d,J=7.6Hz,1H),8.07-8.02(m,2H),7.4-7.39(m,1H),7.32(t,J=7.4Hz,2H),6.98-6.87(m,2H),3.86(s,3H),2.88(s,3H),1.61(s,9H);13C NMR(101MHz,CDCl3,δppm)189.5,168.3,160.4,159.3,141.5,139.9,132.2,132.0,131.9,131.6,129.2,125.7,114.1,55.5,53.7,28.7,23.4.HRMS(ESI)m/z:calcd for C21H25N4O[M+H]+349.2028;found 349.2024.
4gac:顺-N-(叔丁基)-2-(3,4-二甲基苯基)-4-((4-甲氧基苯基)亚胺基)-4氢-咪唑-5-胺
红色固体,产率:85%.1H NMR(400MHz,CDCl3,δppm)8.28(d,J=8.5Hz,2H),8.06-8.00(m,2H),7.29-7.25(m,1H),7.00-6.95(m,2H),3.86(s,3H),2.38(s,3H),2.37(s,3H),1.63(s,9H);13C NMR(101MHz,CDCl3,δppm)188.6,169.1,160.7,159.1,142.9,140.1,136.7,131.2,130.2,129.8,129.0,128.2,114.2,55.5,53.7,28.7,20.3,19.8.HRMS(ESI)m/z:calcd for C22H27N4O[M+H]+363.2185;found 363.2187.
4hac:顺-N-(叔丁基)-2-(2,3-二甲基苯基)-4-((4-甲氧基苯基)亚胺基)-4氢-咪唑-5-胺
红色液体,产率:75%.1H NMR(400MHz,CDCl3,δppm)8.20(d,J=7.7Hz,1H),8.05-7.98(m,2H),7.31(d,J=7.3Hz,1H),7.20(t,J=7.6Hz,1H),6.97-6.92(m,2H),3.85(s,3H),2.75(s,3H),2.37(s,3H),1.60(s,9H);13C NMR(101MHz,CDCl3,δppm)190.7,168.3,160.3,159.3,139.9,139.3,138.0,133.5,132.5,129.7,129.1,125.1,114.1,55.5,53.7,28.7,20.8,17.8.HRMS(ESI)m/z:calcd for C22H27N4O[M+H]+363.2185;found 363.2184.
4iac:顺-N-(叔丁基)-4-((4-甲氧基苯基)亚胺基)-2-(萘-2-基)-4氢-咪唑-5-胺
红色固体,产率:86%.1H NMR(400MHz,CDCl3,δppm)9.12(s,1H),8.56(dd,J=8.6,1.4Hz,1H),8.13-8.00(m,3H),7.92(dd,J=15.0,8.2Hz,2H),7.66-7.50(m,2H),7.07-6.94(m,2H),3.87(s,3H),1.67(s,9H);13C NMR(101MHz,CDCl3,δppm)188.3,169.1,160.5,159.3,140.1,136.0,133.0,131.8,130.1,129.7,129.2,128.1,128.0,127.9,126.4,126.2,114.3,55.5,53.8,28.8.HRMS(ESI)m/z:calcd for C24H25N4O[M+H]+385.2028;found385.2025.
4iaa:顺-N-(叔丁基)-2-(萘-2-基)-4-(苯基亚胺基)-4氢-咪唑-5-胺
红色固体,产率:90%.1H NMR(400MHz,CDCl3,δppm)9.09(s,1H),8.51(dd,J=8.6,1.2Hz,1H),8.02(d,J=7.9Hz,1H),7.89(dd,J=13.7,5.9Hz,4H),7.59-7.51(m,2H),7.45(t,J=7.8Hz,2H),7.25(dd,J=13.0,5.6Hz,1H),1.65(s,9H);13C NMR(101MHz,CDCl3,δppm)189.8,169.0,162.6,146.7,136.2,132.9,132.3,129.9,129.8,128.9,128.3,128.0,127.9,127.3,126.5,126.4,126.2,54.1,28.8.HRMS(ESI)m/z:calcd for C23H23N4[M+H]+355.1923;found 355.1924.
4jab:顺-N-(叔丁基)-2-(噻吩-2-基)-4-(对甲苯基氨基)-4氢-咪唑-5-胺
红色液体,产率:70%.1H NMR(400MHz,CDCl3,δppm)8.21(d,J=3.5Hz,1H),7.78(d,J=8.2Hz,2H),7.70(d,J=4.8Hz,1H),7.24-7.18(m,3H),2.38(s,3H),1.60(s,9H);13CNMR(101MHz,CDCl3,δppm)183.4,168.9,161.4,144.1,137.5,137.4,134.2,133.9,129.6,128.6,126.7,53.9,28.7,21.4.HRMS(ESI)m/z:calcd for C18H21N4S[M+H]+325.1487;found325.1487.
4jac:顺-N-(叔丁基)-4-((4-甲氧基苯基)亚胺基)-2-(噻吩-2-基)-4氢-咪唑-5-胺
红色液体,产率:72%.1H NMR(400MHz,CDCl3,δppm)8.20(dd,J=3.7,1.1Hz,1H),8.00-7.94(m,2H),7.70-7.67(m,1H),7.25-7.20(m,1H),6.98-6.92(m,2H),3.85(s,3H),1.59(s,9H);13C NMR(101MHz,CDCl3,δppm)182.7,169.0,160.1,159.1,140.0,137.6,133.9,133.7,129.0,128.6,114.2,55.5,53.8,28.7.HRMS(ESI)m/z:calcd for C18H21N4OS[M+H]+341.1436;found 341.1435.
4aab:顺-N-(叔丁基)-2-苯基-4-(对甲苯基氨基)-4氢-咪唑-5-胺
红色固体,产率:87%.1H NMR(400MHz,CDCl3,δppm)8.54-8.48(m,2H),7.82(d,J=8.3Hz,2H),7.58(t,J=7.3Hz,1H),7.49(t,J=7.5Hz,2H),7.24(d,J=8.2Hz,2H),2.39(s,3H),1.63(s,9H);13C NMR(101MHz,CDCl3,δppm)189.2,169.1,161.9,144.1,137.6,133.3,132.5,130.4,129.6,128.4,126.8,53.9,28.7,21.4.HRMS(ESI)m/z:calcd for C20H23N4[M+H]+319.1923;found 319.1917.
4dab:顺-N-(叔丁基)-2-(4-氯苯基)-4-(对甲苯基氨基)-4氢-咪唑-5-胺
红色液体,产率:84%.1H NMR(400MHz,CDCl3,δppm)8.40(d,J=8.1Hz,2H),7.83(d,J=8.7Hz,2H),7.38(d,J=8.7Hz,2H),7.30(d,J=8.0Hz,2H),2.45(s,3H),1.62(s,9H);13C NMR(101MHz,CDCl3,δppm)190.1,169.1,163.0,145.2,144.7,132.5,130.7,129.5,129.3,128.9,128.0,54.0,28.7,22.1.HRMS(ESI)m/z:calcd for C20H22N4Cl[M+H]+353.1533;found 353.1535.
4eab:顺-N-(叔丁基)-4-(对甲苯基氨基)-2-(4-(三氟甲基)苯基)-4氢-咪唑-5-胺
红色固体,产率:83%.1H NMR(400MHz,CDCl3,δppm)8.59(d,J=8.1Hz,2H),7.82(d,J=8.3Hz,2H),7.73(d,J=8.3Hz,2H),7.26-7.23(m,2H),2.40(s,3H),1.63(s,9H);13CNMR(101MHz,CDCl3,δppm)187.8,169.1,161.4,143.9,138.2,135.9,134.3(q,J=32Hz),130.4,129.7,126.9,125.2(q,J=3.8Hz),124.0(q,J=271Hz),54.1,28.7,21.4.HRMS(ESI)m/z:calcd for C21H22N4F3[M+H]+387.1797;found 387.1792.
4aac:顺-N-(叔丁基)-4-((4-甲氧基苯基)亚胺基)-2-苯基-4氢-咪唑-5-胺
红色液体,产率:88%.1H NMR(400MHz,CDCl3,δppm)8.53(dd,J=4.6,3.2Hz,2H),8.07-7.99(m,2H),7.61-7.48(m,3H),7.03-6.91(m,2H),3.86(s,3H),1.62(s,9H);13C NMR(101MHz,CDCl3,δppm)188.4,169.2,160.5,159.3,140.0,133.1,132.6,130.3,129.2,128.4,114.2,55.5,53.8,28.7.HRMS(ESI)m/z:calcd for C20H23N4O[M+H]+335.1872;found335.1878.
4dac:顺-N-(叔丁基)-2-(4-氯苯基)-4-((4-甲氧基苯基)亚胺基)-4氢-咪唑-5-胺
红色固体,产率:81%.1H NMR(400MHz,CDCl3,δppm)8.44(d,J=8.5Hz,2H),8.01(d,J=8.9Hz,2H),7.46(d,J=8.5Hz,2H),6.96(d,J=9.0Hz,2H),3.86(s,3H),1.61(s,9H);13C NMR(101MHz,CDCl3,δppm)187.2,169.2,160.2,159.4,139.9,139.2,131.5,131.2,129.2,128.7,114.2,55.5,53.9,28.7.HRMS(ESI)m/z:calcd for C20H22N4 OCl[M+H]+369.1482;found 369.1481.
4eab:顺-N-(叔丁基)-4-((4-甲氧基苯基)亚胺基)-2-(4-(三氟甲基)苯基)-4氢-咪唑-5-胺
红色固体,产率:80%.1H NMR(400MHz,CDCl3,δppm)8.59(d,J=8.1Hz,2H),8.06-8.00(m,2H),7.73(d,J=8.2Hz,2H),7.00-6.94(m,2H),3.86(s,3H),1.61(s,9H);13C NMR(101MHz,CDCl3,δppm)186.9,169.2,159.9,159.7,139.8,136.0,133.9(q,J=32Hz),130.3,129.4,125.2(q,J=3.8Hz),124.0(q,J=271Hz),114.3,55.5,54.0,28.9.HRMS(ESI)m/z:calcd for C21H22N4OF3[M+H]+403.1746;found 403.1749.
4aad:顺-N-(叔丁基)-4-((4-氯苯基)亚胺基)-2-苯基-4氢-咪唑-5-胺
红色固体,产率:86%.1H NMR(400MHz,CDCl3,δppm)8.51(d,J=7.3Hz,2H),7.84(t,J=5.8Hz,2H),7.60(t,J=7.4Hz,1H),7.50(t,J=7.6Hz,2H),7.38(t,J=5.8Hz,2H),1.63(s,9H);13C NMR(101MHz,CDCl3,δppm)190.2,169.1,162.9,145.1,133.7,132.8,132.2,130.6,129.0,128.4,128.0,54.1,28.7.HRMS(ESI)m/z:calcd for C19H20N4Cl[M+H]+339.1376;found 339.1375.
4cae:顺-N-(叔丁基)-4-((4-氟苯基)亚胺基)-2-(4-甲氧基苯基)-4氢-咪唑-5-胺
红色固体,产率:84%.1H NMR(400MHz,CDCl3,δppm)8.49(d,J=8.9Hz,2H),7.96-7.90(m,2H),7.10(t,J=8.7Hz,2H),7.00(d,J=8.9Hz,2H),3.90(s,3H),1.61(s,9H);13CNMR(101MHz,CDCl3,δppm)189.1,169.0,164.3,162.3,161.5(d,J=246.3Hz),143.0(d,J=3.1Hz),132.8,128.5(d,J=8.3Hz),124.8,115.5(d,J=22.2Hz),113.9,55.5,53.9,28.7.HRMS(ESI)m/z:calcd for C20H22N4OF[M+H]+353.1778;found 353.1772.
4aaf:顺-N-(叔丁基)-2-苯基-4-((4-(三氟甲基)苯基)亚胺基)-4氢-咪唑-5-胺
红色固体,产率:77%.1H NMR(400MHz,CDCl3,δppm)8.53-8.48(m,2H),7.83(d,J=8.3Hz,2H),7.67(d,J=8.5Hz,2H),7.61(t,J=7.4Hz,1H),7.50(t,J=7.6Hz,2H),1.64(s,9H);13C NMR(101MHz,CDCl3,δppm)191.3,169.0,164.3,150.0,134.0,132.0,131.4(q,J=32Hz),130.8,128.7,128.3(q,J=3.7Hz),126.0,125.8(q,J=272Hz),54.4,28.6.HRMS(ESI)m/z:calcd for C20H20N4F3[M+H]+373.1640;found 373.1639.
4bag:顺-N-(叔丁基)-4-(萘-1-亚氨基)-2-(对甲苯基)-4氢-咪唑-5-胺
红色固体,产率:85%.1H NMR(400MHz,CDCl3,δppm)8.47(d,J=8.1Hz,2H),8.29(d,J=0.9Hz,1H),8.18(dd,J=8.7,1.8Hz,1H),7.93-7.83(m,3H),7.48(dt,J=10.7,3.5Hz,2H),7.33(d,J=8.2Hz,2H),2.47(s,3H),1.66(s,9H);13C NMR(101MHz,CDCl3,δppm)189.8,169.1,162.9,144.5,144.4,133.9,132.5,130.7,129.7,129.3,128.7,128.5,127.7,126.2,126.1,125.4,125.2,54.0,28.7,22.1.HRMS(ESI)m/z:calcd for C24H25N4[M+H]+369.2079;found 369.2074.
4bbb:顺-2-(对甲苯基)-4-(对甲苯基氨基)-N-(2,4,4-三甲基戊烷-2-基)-4氢-咪唑-5-胺
红色固体,产率:76%.1H NMR(400MHz,CDCl3,δppm)8.40(d,J=8.1Hz,2H),7.81(d,J=8.2Hz,2H),7.30(d,J=8.0Hz,2H),7.22(d,J=8.2Hz,2H),5.30(s,1H),2.45(s,3H),2.38(s,3H),1.99(s,2H),1.67(s,6H),1.06(s,9H);13C NMR(101MHz,CDCl3,δppm)189.3,168.7,161.9,144.2,144.1,137.3,130.5,129.9,129.5,129.2,126.8,57.6,52.1,31.8,31.5,28.9,22.0,21.4.HRMS(ESI)m/z:calcd for C25H33N4[M+H]+389.2705;found389.2701.
4bcc:顺-N-(金刚烷-1-基)-4-((4-甲氧基苯基)亚胺基)-2-(对甲苯基)-4氢-咪唑-5-胺
红色固体,产率:71%.1H NMR(400MHz,CDCl3,δppm)8.40(d,J=7.9Hz,2H),8.02(d,J=8.7Hz,2H),7.30(d,J=7.9Hz,2H),6.96(d,J=8.8Hz,2H),3.85(s,3H),2.45(s,3H),2.27(s,6H),2.20(s,3H),1.77(s,6H);13C NMR(101MHz,CDCl3,δppm)188.5,168.8,160.7,159.1,144.0,140.1,130.4,129.9,129.2,129.0,114.1,55.5,54.2,41.4,36.2,29.5,22.0.HRMS(ESI)m/z:calcd for C27H31N4O[M+H]+427.2498;found 427.2496.
实施例2:目标化合物4aaa(R1=苯基,R2=叔丁基,R3=苯基)的合成
重复实施例1,不同的是,不加三苯基膦。
最后所得红色固体经核磁共振氢谱、碳谱以及高分辨质谱确证为目标化合物4aaa。产率为31%。
实施例3:目标化合物4aaa(R1=苯基,R2=叔丁基,R3=苯基)的合成
重复实施例1,不同的是,反应改在40℃条件下进行。
最后所得红色固体经核磁共振氢谱、碳谱以及高分辨质谱确证为目标化合物4aaa。产率为13%。
实施例4:目标化合物4aaa(R1=苯基,R2=叔丁基,R3=苯基)的合成
重复实施例1,不同的是,用四(三苯基膦)钯替代醋酸钯,用三环己基膦替代三苯基膦,用甲苯替代二甲基亚砜。
最后所得红色固体经核磁共振氢谱、碳谱以及高分辨质谱确证为目标化合物4aaa。产率为72%。
实施例5:目标化合物4baa(R1=4-甲基苯基,R2=叔丁基,R3=苯基)的合成
重复实施例1,不同的是,用氯化钯和二溴化钯的组合物(摩尔比为1:1)替代醋酸钯,用三丁基膦替代三苯基膦,用N-甲基吡咯烷酮和1,4二氧六环的组合物(体积比为1:1)替代二甲基亚砜,反应改在120℃条件下进行。
最后所得红色固体经核磁共振氢谱、碳谱以及高分辨质谱确证为目标化合物4baa。产率为22%。
实施例6:目标化合物4iac(R1=萘-2-基,R2=叔丁基,R3=4-甲氧基苯基)的合成
重复实施例1,不同的是,用二(三苯基膦)氯化钯替代醋酸钯,用1,3-双(二苯基膦)丙烷替代三苯基膦,用乙腈替代二甲基亚砜,反应改在50℃条件下进行。
最后所得红色固体经核磁共振氢谱、碳谱以及高分辨质谱确证为目标化合物4iac。产率为11%。
实施例7:目标化合物4jab(R1=噻吩-2-基,R2=叔丁基,R3=4-甲基苯基)的合成
重复实施例1,不同的是,用二(氰基苯)二氯化钯替代醋酸钯,用环己基二苯基膦替代三苯基膦,用N,N-二甲基甲酰胺替代二甲基亚砜,反应改在80℃条件下进行。
最后所得红色固体经核磁共振氢谱、碳谱以及高分辨质谱确证为目标化合物4jab。产率为37%。
Claims (10)
2.根据权利要求1所述的化合物,其特征是,
R1表示苯基、4-氯苯基、4-氟苯基、4-溴苯基、2-甲基苯基、4-甲基苯基、2,3-二甲基苯基、3,4-二甲基苯基、4-甲氧基苯基、4-三氟甲基苯基、萘基或噻吩基;
R2表示叔丁基、金刚烷基或1,1,3,3-四甲基丁烷基;
R3表示苯基、4-氯苯基、4-氟苯基、4-溴苯基、4-甲基苯基、4-甲氧基苯基、4-三氟甲基苯基或萘基。
4.根据权利要求3所述的合成方法,其特征是,在反应之前加入还原剂。
5.根据权利要求4所述的合成方法,其特征是,所述的还原剂为选自三苯基膦、三环己基膦、三丁基膦、1,3-双(二苯基膦)丙烷和环己基二苯基膦中的一种或两种以上的组合。
6.根据权利要求3~5中任一项所述的合成方法,其特征是,所述的钯催化剂为选自四(三苯基膦)钯、氯化钯、醋酸钯、二(三苯基膦)氯化钯、二(氰基苯)二氯化钯和二溴化钯中的一种或两种以上的组合。
7.根据权利要求3~5中任一项所述的合成方法,其特征是,所述的有机溶剂为选自甲苯、二甲基亚砜、乙腈、N,N-二甲基甲酰胺、N-甲基吡咯烷酮、苯甲腈和1,4二氧六环中一种或两种以上的组合。
8.根据权利要求3~5中任一项所述的合成方法,其特征是,所述反应在50~120℃条件下进行。
9.根据权利要求3~5中任一项所述的合成方法,其特征是,还包括对制得的目标化合物粗品进行纯化的步骤。
10.根据权利要求9所述的合成方法,其特征是,所述纯化的步骤是将制得的目标化合物粗品进行硅胶柱层析,得到纯化后的目标化合物。
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