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CN113214106A - 一种高效合成伯酰胺、n-甲基仲酰胺类化合物的方法 - Google Patents

一种高效合成伯酰胺、n-甲基仲酰胺类化合物的方法 Download PDF

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CN113214106A
CN113214106A CN202110390372.XA CN202110390372A CN113214106A CN 113214106 A CN113214106 A CN 113214106A CN 202110390372 A CN202110390372 A CN 202110390372A CN 113214106 A CN113214106 A CN 113214106A
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陈学年
郭宇
陈西孟
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    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
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    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

本发明公开了一种高效合成伯酰胺、N‑甲基仲酰胺类化合物的方法，其具体过程为：在无水无氧的条件下将金属胺硼烷MRNHBH3加入到装有无水THF的反应容器中，其中M=Na或K，R=H或Me，再加入酯类化合物R’CO2R’’，其中R’为烷基或芳基，R’’为烷基或芳基，于室温条件下搅拌反应并经后处理得到纯净的目标产物伯酰胺类化合物或N‑甲基仲酰胺类化合物。本发明操作简单，低毒无害，安全可靠，适合规模化生产。

Description

一种高效合成伯酰胺、N-甲基仲酰胺类化合物的方法
技术领域
本发明属于酰胺类化合物的合成技术领域，具体涉及一种高效合成伯酰胺、N-甲基仲酰胺类化合物的方法。
背景技术
酰胺键是一种典型的基本化学键，广泛存在于天然和人造产品中，如多肽蛋白质、农药、高分子材料和药物。目前最常见的合成酰胺键的方法几乎完全依赖于羧酸和胺的脱水，这个过程通常是需要催化剂先将羧酸转化为活化羧酸盐，因为羧酸的直接酰胺化是一个热力学上不利的过程。此外，酯是目标化合物中常见的合成中间体。在无催化剂、无任何添加物的条件下，酯与胺反应直接酰胺化是一个非常理想的方法。然而，由于反应条件苛刻，反应时间长，化学计量试剂或催化剂的使用限制了该方法的实际应用。
除了这些传统方法外，还开发了创新的酰胺合成的替代方法，包括新型的C-N连接方式：Staudinger连接、天然化学连接、化学选择性酰胺连接、硝基烷烃-胺偶联，叠氮炔偶联等，这些起始于不同的材料，如醇、醛或炔烃和腈。虽然这些替代酰胺形成的方法在许多应用中取得了显著成功，但由于大量使用超化学计量的偶联剂和添加剂，它们的效率受到了不利影响。因此，酰胺类化合物的合成方法一直被认为是有机化学面临的最大挑战。因此，设计一种简便新颖且绿色的方法高效合成酰胺是非常有必要的。
发明内容
本发明解决的技术问题是提供了一种操作简单、安全可靠且低毒无害的高效合成伯酰胺、N-甲基仲酰胺类化合物的方法。
本发明为解决上述技术问题采用如下技术方案，一种高效合成伯酰胺、N-甲基仲酰胺类化合物的方法，其特征在于具体过程为：在无水无氧的条件下将金属胺硼烷MRNHBH3加入到装有无水THF的反应容器中，其中M=Na或K，R=H或Me，再加入酯类化合物R’CO2R’’，其中R’为烷基或芳基，R’’为烷基或芳基，于室温条件下搅拌反应并经后处理得到纯净的目标产物伯酰胺类化合物或N-甲基仲酰胺类化合物。
本发明所述的高效合成伯酰胺、N-甲基仲酰胺类化合物的方法，其特征在于具体步骤为：将装有1.2mmol金属胺硼烷MRNHBH3的10mL烧瓶连接到Schlenk线上，再添加5mLTHF，然后添加0.5mmol底物酯类化合物R’CO2R’’，反应混合物在室温下搅拌反应，并通过1HNMR核磁共振光谱或TLC进行监测，5分钟后底物酯类化合物被消耗完，然后移走溶剂，接着，加入体积比为10:1的CH2Cl2与n-hexane的混合溶剂萃取NH3BH3，再在烧瓶中加入15mL水，搅拌15分钟后加入体积比为1:1的水和乙酸乙酯的混合溶剂萃取产物，重复7-8次，收集有机相并干燥即得到纯度高、收率高的伯酰胺类化合物或N-甲基仲酰胺类化合物。
本发明所述的高效合成伯酰胺、N-甲基仲酰胺类化合物的方法的反应方程式为：
Figure 3216DEST_PATH_IMAGE002
。
本发明与现有技术相比具有以下有益效果：本发明操作简单，低毒无害，安全可靠，适合规模化生产。
附图说明
图1是本发明实施例1制得苯甲酰胺在氘代乙腈中的1H NMR，由图可知制得的目标产物为纯净的苯甲酰胺(伯酰胺)。
具体实施方式
以下通过实施例对本发明的上述内容做进一步详细说明，但不应该将此理解为本发明上述主题的范围仅限于以下的实施例，凡基于本发明上述内容实现的技术均属于本发明的范围。
实施例1
合成伯酰胺、N-甲基仲酰胺的方法以NaNH2BH3与苯甲酸甲酯的反应(目标产物是苯甲酰胺)为例。将一个含有0.0636g (1.20mmol) NaNH2BH3的10mL烧瓶连接到Schlenk线，然后依次添加5mL THF和0.5mmol苯甲酸甲酯。反应混合物在室温下搅拌，并通过1H NMR或TLC进行监测。苯甲酸甲酯被消耗完，反应完成仅需5分钟。反应后的主要产物Na[PhC(O)NHBH3]、NH3BH3和少量NaBH3NH2BH2NH2BH3可根据其溶解度的不同进行分离。首先，从反应混合物中泵出THF (可循环使用)，反应瓶中剩固体。NH3BH3可用溶剂为5mL CH2Cl2和0.5mL n-hexane (体积比为10:1) 从“固体混合物”中提取出来，并且可回收循环使用。然后，以1:1的比例加入水和乙酸乙酯的混合溶剂，提取NaBH3NH2BH2NH2BH3 (水相) 和苯甲酰胺 (Na[PhC(O)NHBH3]水解后的产物；乙酸乙酯相)。收集有机相，旋干得到纯苯甲酰胺，产率高达91%。同时，将底物苯甲酸甲酯换成其他的酯，例如，4-X1-苯甲酸甲酯 (X1 = Me, MeO, F,Cl, Br, I, CN, NO2, CF3 )、3-X2-苯甲酸甲酯 (X2 = Me，F)、2-X3-苯甲酸甲酯 (X3 = Me，F)、1-萘甲酸甲酯、2-萘甲酸甲酯、烟酸甲酯、2-噻吩甲酸甲酯、2-呋喃甲酸甲酯、环己甲酸甲酯、己酸甲酯、硬脂酸甲酯、戊内酯等，上述方法同样适用。
实施例2
合成伯酰胺、N-甲基仲酰胺的方法以NaMeNHBH3与底物苯甲酸甲酯的反应 (目标产物是N-甲基苯甲酰胺)为例。将一个含有0.0804g (1.20mmol) NaMeNHBH3的10mL烧瓶连接到Schlenk线，然后依次添加5mL THF和0.5mmol苯甲酸甲酯。反应混合物在室温下搅拌，并通过1H NMR或TLC进行监测。苯甲酸甲酯被消耗完，反应在5分钟内完成。该反应后的主要产物Na[PhC(O)NMeBH3]、MeNH2BH3和少量NaBH3NH(Me)BH2NH(Me)BH3，可根据其溶解度的不同进行分离。首先，从反应混合物中泵出THF (可循环使用)，反应瓶中剩固体。其中MeNH2BH3可用溶剂为5mL CH2Cl2和0.5mL n-hexane (体积比为10:1) 从“固体混合物”中提取出来，并且可回收循环使用。然后，以1:1的比例加入水和乙酸乙酯的混合溶剂，提取NaBH3NH(Me)BH2NH(Me)BH3 (水相) 和N-甲基苯甲酰胺 (Na[PhC(O)NMeBH3]水解后的产物；乙酸乙酯相）。收集有机相，旋干得到纯N-甲基苯甲酰胺，产率高达99%。上述方法适用于其他多样的底物酯类化合物，例如， 4-X1-苯甲酸甲酯(X1 = Me, MeO, F, Cl, Br, I, CN, NO2,CF3)、3-X2-苯甲酸甲酯 (X2 = Me，F)、2-X3-苯甲酸甲酯 (X3 = Me，F)、1-萘甲酸甲酯、2-萘甲酸甲酯、烟酸甲酯、2-噻吩甲酸甲酯、2-呋喃甲酸甲酯、环己甲酸甲酯、己酸甲酯、硬脂酸甲酯、戊内酯等。
以上实施例描述了本发明的基本原理、主要特征及优点，本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。

Claims (3)

1.一种高效合成伯酰胺、N-甲基仲酰胺类化合物的方法，其特征在于具体过程为：在无水无氧的条件下将金属胺硼烷MRNHBH3加入到装有无水THF的反应容器中，其中M=Na或K，R=H或Me，再加入酯类化合物R’CO2R’’，其中R’为烷基或芳基，R’’为烷基或芳基，于室温条件下搅拌反应并经后处理得到纯净的目标产物伯酰胺类化合物或N-甲基仲酰胺类化合物。
2. 根据权利要求1所述的高效合成伯酰胺、N-甲基仲酰胺类化合物的方法，其特征在于具体步骤为：将装有1.2mmol金属胺硼烷MRNHBH3的10mL烧瓶连接到Schlenk线上，再添加5mL THF，然后添加0.5mmol底物酯类化合物R’CO2R’’，反应混合物在室温下搅拌反应，并通过1H NMR核磁共振光谱或TLC进行监测，5分钟后底物酯类化合物被消耗完，然后移走溶剂，接着，加入体积比为10:1的CH2Cl2与n-hexane的混合溶剂萃取NH3BH3，再在烧瓶中加入15mL水，搅拌15分钟后加入体积比为1:1的水和乙酸乙酯的混合溶剂萃取产物，重复7-8次，收集有机相并干燥即得到纯度高、收率高的伯酰胺类化合物或N-甲基仲酰胺类化合物。
3.根据权利要求1或2所述的高效合成伯酰胺、N-甲基仲酰胺类化合物的方法，其特征在于：所述酯类化合物R’CO2R’’适用于多样的酯类化合物。
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