CN103910682A - 一种基于邻苯二胺环化的苯并咪唑类化合物制备方法 - Google Patents
一种基于邻苯二胺环化的苯并咪唑类化合物制备方法 Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
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Abstract
本发明属于精细化工领域，涉及一种苯并咪唑化合物的合成方法改进及相关化学技术。其特征在于：使用邻苯二胺和1,3-二羰基化合物为原料，在质子酸催化下合成苯并咪唑化合物。本发明主要是提供一种新的合成苯并咪唑化合物的方法，该方法具有反应条件温和、方法步骤简单、原料易得、官能团兼容性好等优点。由于苯并咪唑是一种重要的生物活性基团，在药学领域有着非常广泛的应用；因此，本发明具有较大的使用价值和社会经济效益。
Description
技术领域
本发明涉及医药化工中间体的制备方法，尤其是苯并咪唑类化合物的制备方法。
背景技术
苯并咪唑类化合物是一类重要的生物活性分子或有机合成中间体，在多个领域有着非常广泛的应用。关于苯并咪唑化合物的合成，通常采用如下两种方法：
（1）邻笨二胺类化合物与羧酸或醛的缩合反应
该方法的反应条件非常苛刻，如需要强酸、高温反应条件，或者需要强氧化剂，且原料醛不易制备和储存[参见：(a)Chhanda,M.;Pradip,K.T.Tetrahedron Lett.2008,49,6237–6240.(b)Suleman,M.I.;Vinod,K.M.;Sisir,K.M.Tetrahedron Lett.2013,54,579–583.]。
（2）铜催化C–N键交叉偶联反应
该方法的反应体系较复杂，如不仅需要铜盐催化剂，还需要配体、碱等添加剂，且反应温度较高[参见(a)Yang,D.;Fu,H.;Hu,L.;Jiang,Y.;Zhao,Y.J.Org.Chem.2009,74,8719–8725.(b)Peng,J.;Ye,M.;Zong,C.;Hu,F.;Feng,L.;Wang,X.;Wang,Y.;Chen,C.J.Org.Chem.2011,76,716–719.]。
发明目的
本发明的目的是提供一种步骤简单、原料易得、反应条件温和的苯并咪唑化合物的合成方法。
发明内容
本发明以邻苯二胺和1,3-二羰基化合物为原料，以质子酸为催化剂，加热反应，合成一系列苯并咪唑类化合物。合成路线如下：
在上述合成方法的反应中，所用的质子酸催化剂选自脂肪羧酸、芳香羧酸、脂肪基磺酸或芳基磺酸；其中，邻苯二胺与质子酸催化剂的物质的量比为1:0.05-0.5。
在上述合成方法的反应中，所用的有机溶剂包括苯、甲苯、1,4-二氧六环、二甲基亚砜、乙醇、甲醇、叔丁醇、异丙醇、二氯甲烷、三氯甲烷、正丁醚、四氯化碳、己二酸二甲酯、乙酸乙酯、石油醚、甲基叔丁基醚、四氢呋喃、丙酮、乙腈、环己烷或正己烷中一种或两种以上的混合溶剂，所述有机溶剂的加入量为邻苯二胺质量的10-100倍。
在上述合成方法的反应中，反应温度为20-150℃。
附图说明
图1为化合物3a的1H-NMR。
图2为化合物3a的13C-NMR。
图3为化合物3b的1H-NMR。
图4为化合物3b的13C-NMR。
图5为化合物3c的1H-NMR。
图6为化合物3c的13C-NMR。
图7为化合物3d的1H-NMR。
图8为化合物3d的13C-NMR。
图9为化合物3e的1H-NMR。
图10为化合物3e的13C-NMR。
图11为化合物3f的1H-NMR。
图12为化合物3f的13C-NMR。
具体实施方式
下面结合实施例子进一步说明本发明以及本发明方法进行的方式。这些实施例子仅是为了进一步阐述本发明而非本发明的保护仅限于此。
实施例1：2-甲基苯并咪唑(3a)的合成
准确称取邻苯二胺（54.0mg,0.5mmol）、乙酰丙酮（50.1mg,0.5mmol）和苯甲酸（3.1mg,0.025mmol），并依次加入到25mL的Schlenk瓶中，加入乙醇(5.0mL)，置于20℃油浴中反应24h。反应结束后，减压除去溶剂，使用石油醚/乙酸乙酯作为洗脱剂，经硅胶柱分离，2-甲基苯并咪唑收率为88%。 1H NMR(400MHz,d6-DMSO)δ2.50(s,3H),7.12(dd,J=3.2,6.0Hz,2H),7.55(d,J=3.2Hz,1H),7.56(d,J=3.2Hz,1H),9.25(s,1H),;13C NMR(100MHz,d6-DMSO)δ14.7,114.3,121.1,139.0,151.5.
实施例2：2-乙基苯并咪唑(3b)的合成
准确称取邻苯二胺（54.0mg,0.5mmol）、3,5-二庚酮（256.0mg,2.0mmol）和苯甲酸（30.5mg,0.25mmol），并依次加入到25mL的Schlenk瓶中，加入1,4-二氧六环(3.0mL)，置于150℃油浴中反应36h。反应结束后，减压除去溶剂，使用石油醚/乙酸乙酯作为洗脱剂，经硅胶柱分离，2-乙基苯并咪唑收率为65%。 1H NMR(400MHz,CDCl3)δ1.45(t,J=7.6Hz,3H),3.03(q,J=7.5Hz,2H),7.21(dd,J=2.8,5.6Hz,2H),7.56(d,J=2.8Hz,2H),11.49(s,1H);13C NMR(100MHz,CDCl3)δ12.9,23.0,114.9,122.4,138.9,157.2.
实施例3：2-乙基-5-氯苯并咪唑(3c)的合成
准确称取4-氯邻苯二胺（71.0mg,0.5mmol）、3,5-二庚酮（64.0mg,0.5mmol）和对甲苯磺酸（9.5mg,0.05mmol），并依次加入到25mL的Schlenk瓶中，加入甲苯(4.0mL)，置于60℃油浴中反应24h。反应结束后，减压除去溶剂，使用石油醚/乙酸乙酯作为洗脱剂，经硅胶柱分离，2-乙基-5-氯苯并咪唑收率为95%。1H NMR(400MHz,d6-DMSO)δ1.30(t,J=7.5Hz,3H),2.82(q,J=7.5Hz,2H),7.12(d,J=8.2Hz,1H),7.46(bs,2H),12.39(s,1H);13C NMR(100MHz,d6-DMSO)δ12.1,22.1,110.6,112.0,117.6,119.3,121.3,125.4,157.8.
实施例4：2-乙基-5-甲氧基苯并咪唑(3d)的合成
准确称取4-甲氧基邻苯二胺（69.0mg,0.5mmol）、3,5-二庚酮（64.0mg,0.5mmol）和乙酸（3.0mg,0.05mmol），并依次加入到25mL的Schlenk瓶中，加入甲苯(4.0mL)，置于90℃油浴中反应36h。反应结束后，减压除去溶剂，使用石油醚/乙酸乙酯作为洗脱剂，经硅胶柱分离，2-乙基-5-甲氧基苯并咪唑收率为65%。1H NMR(400MHz,CDCl3)δ1.41(t,J=7.6Hz,3H),2.96(q,J=7.6Hz,2H),3.79(s,3H),6.85(dd,J=2.0,8.8Hz,1H),7.02(d,J=2.0Hz,1H),7.43(d,J=8.8Hz,1H);13C NMR(100MHz,CDCl3)δ12.8,22.9,56.1,97.8,111.5,115.6,133.8,139.0,156.3,156.7.
实施例5：2-苯基苯并咪唑(3e)的合成
准确称取邻苯二胺（54.0mg,0.5mmol）、1,3-二苯基-1,3-二丙酮（134.5mg,0.6mmol）和苯甲酸（6.1mg,0.05mmol），并依次加入到25mL的Schlenk瓶中，加入乙醇(6.0mL)，置于70℃油浴中反应36h。反应结束后，减压除去溶剂，使用石油醚/乙酸乙酯作为洗脱剂，经硅胶柱分离，2-苯基苯并咪唑收率为45%。 1H NMR(400MHz,d6-DMSO)δ7.33(bs,2H),7.59-7.69(m,5H),8.31(d,J=7.3Hz,2H);13C NMR(100MHz,d6-DMSO)δ111.6,119.2,122.0,122.8,126.7,129.3,130.1,130.5,135.3,144.1,151.5.
实施例6：2-甲基-5-甲氧基苯并咪唑(3f)的合成
准确称取4-甲氧基邻苯二胺（69.0mg,0.5mmol）、乙酰丙酮（100.1mg,1.0mmol）和三氟乙酸（11.4mg,0.1mmol），并依次加入到25mL的Schlenk瓶中，加入四氢呋喃(3.0mL)，置于70℃油浴中反应12h。反应结束后，减压除去溶剂，使用石油醚/乙酸乙酯作为洗脱剂，经硅胶柱分离，2-甲基-5-甲氧基苯并咪唑收率为73%。1H NMR(400MHz,CDCl3)δ2.61(s,3H),3.80(s,3H),6.85(dd,J=2.0,8.7Hz,1H),7.02(s,1H),7.43(d,J=8.7Hz,1H),10.37(s,1H);13C NMR(100MHz,CDCl3)δ15.1,56.1,97.7,111.5,115.4,133.8,139.0,151.5,156.3。
Claims (8)
1.一种基于邻苯二胺环化的苯并咪唑类化合物制备方法，其特征在于，以邻苯二胺和1,3-二羰基化合物为原料，加入有机溶剂，通过质子酸催化环化反应，合成一系列苯并咪唑类化合物，其特征是合成路线如下：
式中：R1为氢、烷基、烯基、炔基、芳基、烃氧基、卤素；
R2为烷基、烯基、炔基、芳基。
2.根据权利要求1所述的制备方法，其特征在于，邻苯二胺与1,3-二羰基化合物的物质的量比为1:1-4。
3.根据权利要求书1或2的制备方法，其特征在于，所述质子酸催化剂选自脂肪羧酸、芳香羧酸、脂肪基磺酸或芳基磺酸；其中，邻苯二胺与质子酸催化剂的物质的量比为1:0.05-0.5。
4.根据权利要求1或2的制备方法，其特征还在于，所述有机溶剂选自苯、甲苯、1,4-二氧六环、二甲基亚砜、乙醇、甲醇、叔丁醇、异丙醇、二氯甲烷、三氯甲烷、正丁醚、四氯化碳、己二酸二甲酯、乙酸乙酯、石油醚、甲基叔丁基醚、四氢呋喃、丙酮、乙腈、环己烷或正己烷中一种或两种以上的混合溶剂，所述有机溶剂的加入量为邻苯二胺质量的10-100倍。
5.根据权利要求3的制备方法，其特征还在于，所述有机溶剂选自苯、甲苯、1,4-二氧六环、二甲基亚砜、乙醇、甲醇、叔丁醇、异丙醇、二氯甲烷、三氯甲烷、正丁醚、四氯化碳、己二酸二甲酯、乙酸乙酯、石油醚、甲基叔丁基醚、四氢呋喃、丙酮、乙腈、环己烷或正己烷中一种或两种以上的混合溶剂，所述有机溶剂的加入量为邻苯二胺质量的10-100倍。
6.根据权利要求1、2或5所述的制备方法，其特征在于，所述的反应温度为20-150℃。
7.根据权利要求3所述的制备方法，其特征在于，所述的反应温度为20-150℃。
8.根据权利要求4所述的制备方法，其特征在于，所述的反应温度为20-150℃。
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