CN104892336B - 一种仲胺类化合物的制备方法 - Google Patents
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Abstract
本发明属于医药化工中间体及相关化学技术领域，涉及到一种仲胺类化合物的制备方法。其特征是以亚胺及其衍生物为原料，以AuNPore为催化剂、在一定氢气压力下，选择性加氢得到对应的仲胺类化合物产物。该体系采用的催化剂是一种新型的异相催化剂，该催化剂结构稳定，多次使用后活性几乎没有减少，也没有催化剂流失现象。不仅如此，该方法还具有选择性还原C＝N双键的特点。由于是异相催化剂，该方法又具有产物易于分离的优点。
Description
技术领域
本发明属于医药化工中间体及相关化学技术领域，涉及到一种仲胺类化合物的制备方法。
背景技术
胺类是有机化合物中十分重要的一类化合物，存在于许多天然产物的结构中，也是合成一些医药及生物活性大分子的中间体。长期以来，人们对胺的合成有过大量的研究，主要以变换催化剂的种类，以及氢源来提高反应的性能。早在100年前就出现了有关胺的合成方法的报道,[R.Leuckart；Ber.Dtsch,Chem.Ges.1905,18,2341-2342]。之后又涌现出了大量的文献，这些方法主要归类为：催化加氢以及金属的氢化物作为氢源如硼氢化钠，氢化锂铝等还原性很强的还原剂作为还原手段，但是存在选择性不好，氢化锂铝反应剧烈，对条件要求苛刻的缺点[M.R.Saidia；R.Stan Brownb,J.Iran.Chem.Soc.2007,4,194-198.]。一些均相催化剂也能催化还原亚胺，但是由于金属污染，而不太适合在药物合成中广泛应用[Renat Kadyrov et al.J.Org.Chem.2003,68,4067-4070]。而以Pd等贵金属催化剂催化加氢还原亚胺，则存在催化剂流失、重复利用率低的问题，而且由于钯催化的高活性，导致C-X键也常常被破坏掉，而卤素经常存在于一些药物分子结构中[Marcelo E.Dominea etal.Catalysis Today 2011,159,2–11]。为了克服以上这些传统方法的不足，我们研发出了一种新的亚胺化合物的加氢还原方法。即以纳米骨架金为催化剂，在一定的氢气压力和温度下，适合的溶剂中进行还原反应。该体系的特点之一为催化剂是一种新型的异相催化剂，该催化剂结构稳定，多次使用后未见活性降低。不仅如此，该方法还具有选择性还原C＝N双键的特点。由于是异相催化剂，该方法又具有产物易于分离的优点。
发明内容
本发明提供了一种亚胺及其衍生物的催化加氢还原方法，该方法最高选择性达到100％，选用催化剂催化反应重现性好，且重复利用多次催化效果没有明显降低。
本发明是以亚胺及其衍生物为原料，以AuNPore为催化剂、氢气为氢源选择性加氢得到亚胺还原产物，合成路线如下：
该方法采用的技术方案如下：
在AuNPore为催化剂、氢气为氢源、碱作为添加剂，能够选择性加氢得到仲胺的产物。
反应温度在10℃～150℃范围。反应时间为12h～36h；
R1选自芳基、烷基、甲氧基、羟基、卤素、三氟甲基；
R2选自芳基、烷基；
金属催化剂为纳米多孔金催化剂；
亚胺及其衍生物与所用催化剂摩尔比为1:0.01～1:0.1；
H2为氢源，压力为0.1MPa～50MPa；
亚胺及其衍生物与碱的摩尔比为1:0.1～1:15；
亚胺及其衍生物在有机溶剂中的的摩尔浓度为0.01mmol/mL～2mmol/mL；
溶剂包括：四氢呋喃、甲苯、乙二醇二甲醚、三氯甲烷、二氯甲烷、乙醚、乙腈、二甲基亚砜、四氯化碳、丙酮、N,N-二甲基甲酰胺、环己烷、正己烷、甲醇、乙醇、正庚烷中的一种或两种以上混合。
碱包括：氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸氢钠、乙二胺、三乙胺、二乙胺、吡啶、哌啶、三苯胺、三正丁胺。
分离方法包括：重结晶、柱层析等。重结晶方法使用的溶剂如，苯、甲苯、乙醇、石油醚、乙腈、四氢呋喃、氯仿、环己烷、二氧六环、乙酸乙酯、N,N-二甲基甲酰胺；用柱层析方法，可以使用硅胶或氧化铝作为固定相，展开剂一般为极性与非极性的的混合溶剂，如乙酸乙酯-石油醚、乙酸乙酯-正己烷、二氯甲烷-石油醚、甲醇-石油醚。
本发明的有益效果是该产物选择性高，催化剂重现性好，且重复利用多次催化效果没有没有明显降低，为其实现工业化提供可能。
附图说明
图1为实施例1、2中产物4-甲氧基-N-(4-甲基苯)苯胺的1H核磁谱图。
图2为实施例3、4中产物4-甲氧基-N-(4-甲氧苯基)苯胺的1H核磁谱图。
图3为实施例5、6中产物N-(4-氯苯基)苯胺的1H核磁谱图。
图4为实施例7、8中产物N-苯基-4-甲氧基苯胺的1H核磁谱图。
具体实施方式
本发明所述的一种仲胺类化合物的制备方法，最高选择性和反应收率分别达到100％和95％，选用催化剂催化反应重现性好，且重复利用多次催化效果没有明显降低，为其工业化生产提供了有利条件。
下面结合具体实施例，进一步阐述本发明。这些实施例仅用于说明本发明而不用于限制本发明的范围。在本领域内的技术人员对本发明所做的简单替换或改进均属于本发明所保护的技术方案之内。
实施例1：制备4-甲氧基-N-(4-甲基苯)苯胺
向一只25mL的高压反应釜中分别加入催化剂AuNPore(5.0mg,5mol％)，乙醇(5mL)，底物4-甲氧基-N-(4-甲基苯)亚胺(103mg,0.5mmol)、三乙胺(0.25mL,5mmol)，充入氢气10MPa，置于磁力搅拌器上100℃下反应20h，柱层析(硅胶，200-300目；展开剂，石油醚：乙酸乙酯＝20:1)得到产物4-甲氧基-N-(4-甲基苯)苯胺92mg，产率91％。
4-甲氧基-N-(4-甲基苯)苯胺
黄色液体；1H NMR(400MHz,CDCl3)δ:7.26(t,J＝4.0Hz,2H),7.14(d,J＝7.9Hz,2H),6.88–6.72(m,2H),6.68–6.56(m,2H),4.23(s,2H),3.83(s,1H),3.74(s,3H),2.34(s,3H),1.55(s,1H).
实施例2：制备4-甲氧基-N-(4-甲基苯)苯胺
向一只25mL的高压反应釜中分别加入催化剂AuNPore(5.0mg,5mol％)，正己烷(5mL)，底物4-甲氧基-N-(4-甲基苯)亚胺(103.07mg,0.5mmol)、二乙胺(0.25mL,5mmol)，充入氢气10MPa，置于磁力搅拌器上90℃下反应24h，柱层析(硅胶，200-300目；展开剂，石油醚：乙酸乙酯＝20:1)得到产物4-甲氧基-N-(4-甲基苯)苯胺93.7mg，产率91％。
4-甲氧基-N-(4-甲基苯)苯胺
黄色液体；1H NMR(400MHz,CDCl3)δ:7.26(t,J＝4.0Hz,2H),7.14(d,J＝7.9Hz,2H),6.88–6.72(m,2H),6.68–6.56(m,2H),4.23(s,2H),3.83(s,1H),3.74(s,3H),2.34(s,3H),1.55(s,1H).
实施例3：制备4-甲氧基-N-(4-甲氧苯基)苯胺
向一只25mL的高压反应釜中分别加入催化剂AuNPore(5.0mg,5mol％)，乙醇(5mL)，底物4-甲氧基-N-(4-甲氧基苯)亚胺(120.5mg,0.5mmol)、乙二胺(0.28mL,5mmol)，充入氢气10MPa，置于磁力搅拌器上80℃下反应22h，柱层析(硅胶，200-300目；展开剂，石油醚：乙酸乙酯＝20:1)得到产物4-甲氧基-N-(4-甲氧苯基)苯胺114.7mg,收率95％。
4-甲氧基-N-(4-甲氧苯基)苯胺
黄色固体；1H NMR(400MHz,CDCl3)δ:7.27(dd,J＝9.7,6.9Hz,2H),6.93–6.84(m,2H),6.81–6.73(m,2H),6.68–6.58(m,2H),4.21(s,2H),3.80(s,3H),3.74(s,3H)。
实施例4：制备4-甲氧基-N-(4-甲氧苯基)苯胺
向一只25mL的高压反应釜中分别加入催化剂AuNPore(5.0mg,5mol％)，甲醇(5mL)，底物4-甲氧基-N-(4-甲氧基苯)亚胺(120.5mg,0.5mmol)、乙二胺(0.28mL,5mmol)，充入氢气10MPa，置于磁力搅拌器上50℃下反应26h，柱层析(硅胶，200-300目；展开剂，石油醚：乙酸乙酯＝20:1)得到产物4-甲氧基-N-(4-甲氧苯基)苯胺112mg,收率93％。
4-甲氧基-N-(4-甲氧苯基)苯胺
黄色固体；1H NMR(400MHz,CDCl3)δ:7.27(dd,J＝9.7,6.9Hz,2H),6.93–6.84(m,2H),6.81–6.73(m,2H),6.68–6.58(m,2H),4.21(s,2H),3.80(s,3H),3.74(s,3H)。
实施例5：制备N-(4-氯苯基)苯胺
向一只25mL的高压反应釜中分别加入催化剂AuNPore(5.0mg,5mol％)，环己烷(7mL)，底物N-(4-氯苯基)亚苯胺(100.5mg,0.5mmol)、三乙胺(0.25mL,5mmol)，充入氢气10MPa，置于磁力搅拌器上90℃下反应18h，柱层析(硅胶，200-300目；展开剂，石油醚：乙酸乙酯＝20:1)得到产物4-甲氧基-N-(4-甲氧苯基)苯胺94mg,收率93％。
N-(4-氯苯基)苯胺
无色液体；1H NMR(400MHz,CDCl3)δ:7.43–7.25(m,2H),7.24–7.10(m,2H),7.06–6.95(m,2H),6.76–6.67(m,2H),6.60(dt,J＝3.2,1.6Hz,1H),4.27(s,2H),3.99(s,1H).
实施例6：制备N-(4-氯苯基)苯胺
向一只25mL的高压反应釜中分别加入催化剂AuNPore(5.0mg,5mol％)，乙醇(5mL)，底物N-(4-氯苯基)亚苯胺(100.5mg,0.5mmol)、二苯胺(0.45mL,5mmol)，充入氢气10MPa，置于磁力搅拌器上80℃下反应20h，柱层析(硅胶，200-300目；展开剂，石油醚：乙酸乙酯＝20:1)得到产物4-甲氧基-N-(4-甲氧苯基)苯胺91mg,收率91％。
N-(4-氯苯基)苯胺
无色液体；1H NMR(400MHz,CDCl3)δ:7.43–7.25(m,2H),7.24–7.10(m,2H),7.06–6.95(m,2H),6.76–6.67(m,2H),6.60(dt,J＝3.2,1.6Hz,1H),4.27(s,2H),3.99(s,1H).
实施例7：制备N-苯基-4-甲氧基苯胺
向一只25mL的高压反应釜中分别加入催化剂AuNPore(5.0mg,5mol％)，乙醇(6mL)，底物N-苯基-4-甲氧基亚苯胺(100.5mg,0.5mmol)、二乙胺(0.25mL,5mmol)，充入氢气10MPa，置于磁力搅拌器上60℃下反应25h，柱层析(硅胶，200-300目；展开剂，石油醚：乙酸乙酯＝20:1)得到N-苯基-4-甲氧基苯胺99mg，产率94％。
N-苯基-4-甲氧基苯胺
黄色液体；1H NMR(400MHz,CDCl3)δ:7.26(d,J＝8.6Hz,2H),7.16(dd,J＝13.0,5.6Hz,2H),6.93–6.81(m,2H),6.69(t,J＝7.3Hz,2H),6.65–6.57(m,2H),4.21(s,3H),3.83(d,J＝4.6Hz,2H),3.77(d,J＝2.6Hz,2H).
实施例8：制备N-苯基-4-甲氧基苯胺
向一只25mL的高压反应釜中分别加入催化剂AuNPore(5.0mg,5mol％)，四氢呋喃(4mL)，底物N-苯基-4-甲氧基亚苯胺(100.5mg,0.5mmol)、三乙胺(0.25mL,5mmol)，充入氢气10MPa，置于磁力搅拌器上70℃下反应23h，柱层析(硅胶，200-300目；展开剂，石油醚：乙酸乙酯＝20:1)得到N-苯基-4-甲氧基苯胺94mg，产率94％。
N-苯基-4-甲氧基苯胺
黄色液体；1H NMR(400MHz,CDCl3)δ:7.26(d,J＝8.6Hz,2H),7.16(dd,J＝13.0,5.6Hz,2H),6.93–6.81(m,2H),6.69(t,J＝7.3Hz,2H),6.65–6.57(m,2H),4.21(s,3H),3.83(d,J＝4.6Hz,2H),3.77(d,J＝2.6Hz,2H).
Claims (3)
1.一种仲胺类化合物的制备方法，其特征在于，以亚胺为原料，以纳米多孔金AuNPore为催化剂、氢气为氢源、碱作为添加剂和有机溶剂中，选择性加氢制备仲胺类化合物，合成路线如下：
反应温度在10℃～150℃；反应时间为12h～36h；
R1选自芳基；
R2选自芳基；
催化剂为纳米多孔金催化剂；
亚胺与所用催化剂摩尔比为1:0.01～1:0.1；
亚胺与碱的摩尔比为1:0.1～1:15；
亚胺在有机溶剂中的摩尔浓度为0.01mmol/mL～2mmol/mL；
所述的碱为乙二胺、三乙胺、二乙胺、三苯胺。
2.根据权利要求1所述的制备方法，其特征在于，所述的H2压力为0.1MPa～50MPa。
3.如权利要求1或2所述的一种仲胺类化合物的制备方法，其特征还在于，所述有机溶剂为四氢呋喃、甲苯、乙二醇二甲醚、三氯甲烷、二氯甲烷、乙醚、乙腈、二甲基亚砜、四氯化碳、丙酮、N,N-二甲基甲酰胺、环己烷、正己烷、甲醇、乙醇、正庚烷中的一种或两种以上混合。
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