CN104892495B - 一种新的合成含吡啶类化合物的方法 - Google Patents

一种新的合成含吡啶类化合物的方法 Download PDF

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CN104892495B
CN104892495B CN201510305043.5A CN201510305043A CN104892495B CN 104892495 B CN104892495 B CN 104892495B CN 201510305043 A CN201510305043 A CN 201510305043A CN 104892495 B CN104892495 B CN 104892495B
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CN104892495A (zh
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王祖利
董道青
张雪燕
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Qingdao Agricultural University
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    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms

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Abstract

本发明公布了一种含吡啶单元的化合物的合成方法，以硝基取代的苯乙酸，甲基吡啶或甲基喹啉为反应物，CuBr为催化剂，反应温度为120℃，氧气氛围下反应24‑36小时。反应完毕，对反应液进行萃取，合并有机相，柱色谱分离，获得含吡啶单元的产物。本发明制备方法用羧酸类化合物代替传统的醛类化合物参与反应，具有很好的应用前景。

Description

一种新的合成含吡啶类化合物的方法
技术领域
本发明涉及化合物的合成属于有机合成领域。
背景技术
吡啶类化合物在天然产物及药物活性分子中广泛存在，具有重要的研究意义（Bagley, M. C.; Glover, C.; Merritt, E. A. Synlett, 2007, 2459; G. D. Henry,Tetrahedron, 2004, 60, 6043; J. P. Michael, Nat. Prod. Rep. 2005, 22, 627;Baxter, P. N. W.; Lehn, J. M.; Fischerand, J.; Youinou, M. T. Angew. Chem.Int. Ed. Engl., 1994, 33, 2284; Lehn, J. M. Science, 2002, 295, 2400; Henry,D. Tetrahedron 2004, 60, 6043; J. P. Michael, Nat. Prod. Rep., 2005, 22, 627;Bagley, M. C.; Gloverand, C.; Merritt, E. A. Synlett, 2007, 2459.）。利用2-甲基吡啶类化合物与醛的加成反应合成此类含吡啶单元的化合物已有几例文献报道（J.-J.Jin, H.-Y. Niu, G.-R. Qu, H. M. Guo and J. S. Fossey, RSC Adv., 2012, 2,5968; F. F. Wang, C.-P. Luo, Y. Wang, G. Deng and Yang, L. Org. Biomol. Chem.2012, 10, 8605; X.-Y. Zhang, D.-Q.Dong, T. Yue, S.-H. Hao and Z.-L. Wang,Tetrahedron Lett, 2014, 55, 5462; N. N. Rao and H. M. Meshram, TetrahedronLett. 2013, 54, 5087; ）。从已报道的文献来看，反应中使用的醛类化合物的范围还有待进一步拓展，产率有待提高。因此，发展新的合成含吡啶单元化合物的方法还有待开发。
发明内容
本发明提供一种新的合成含吡啶单元化合物的方法。本发明不直接使用醛类化合物与甲基吡啶类化合物反应，而是用羧酸类化合物与甲基吡啶类化合物反应生成含吡啶单位的化合物，大大拓展了合成含吡啶单元化合物的方法，具有广阔的应用前景。
本发明的反应方程式如下：
其中，所用的CuBr催化剂的量20%—30%，反应时间为24—36小时。反应结束后经过萃取，洗涤，干燥，浓缩和纯化的步骤可以得到所需要的目标产物。
其中，萃取所用的溶剂为乙醚或乙酸乙酯；洗涤用饱和食盐水洗涤；干燥用无水硫酸镁或者无水硫酸钠干燥；浓缩使用旋转蒸发的方法将溶剂蒸干；纯化采用硅胶柱层析进行分离纯化。
本发明具有如下优点：反应底物使用的是廉价易得的羧酸类化合物，而不是文献报道中使用的醛类化合物，大大拓展了此类反应的底物范围，为人们合成含吡啶类化合物提供了一种崭新的方法，具有很好的应用前景。
具体实施方式
实施例1、化合物3a的合成
向反应器中依次加入溶剂，对硝基苯乙酸（0.25 mmol），2,6-二甲基吡啶（0.75mmol），催化剂CuBr（0.075 mmol），二甲基亚砜作溶剂，氧气氛围下，120℃反应24小时。反应体系冷却后，用乙醚（2 ml）萃取6次，合并有机相，有机相用无水硫酸镁干燥，旋转蒸发有机相得到粗产品。粗产品用石油醚：乙酸乙酯=3：1（v/v）为洗脱剂，硅胶为吸附相柱层析分离，得到固体产物3a，产率50%。
该化合物的核磁数据如下：1H NMR (300 MHz, CDCl3, TMS) δ 8.18 (s, 1H),8.16 (s, 1H), 7.57 (d, J =5.7 Hz, 2H), 7.50 (t, J =8.0 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 6.87 (d, J =8.0 Hz, 1H), 5.22 (d, J =4.8 Hz, 1H), 3.11-2.98 (m,2H), 2.54 (s, 3H); 13C NMR (75 MHz, CDCl3, TMS) δ 158.2, 157.7, 151.7, 147.1,137.5, 126.6, 123.6, 121.7, 120.7, 72.6, 44.5, 24.3 ;
证明所合成的化合物结构正确。
实施例2、化合物3b的合成
向反应器中依次加入溶剂，间硝基苯乙酸（0.25 mmol），2,6-二甲基吡啶（0.75mmol），催化剂CuBr（0.075 mmol），二甲基亚砜作溶剂，氧气氛围下，120℃反应24小时。反应体系冷却后，用乙醚（2 ml）萃取6次，合并有机相，有机相用无水硫酸镁干燥，旋转蒸发有机相得到粗产品。粗产品用石油醚：乙酸乙酯=3：1（v/v）为洗脱剂，硅胶为吸附相柱层析分离，得到固体产物3b，产率40%。
该化合物的核磁数据如下：1H NMR (400 MHz, CDCl3, TMS) δ 8.28 (s, 1H),8.09 (d, J =8.0 Hz, 1H), 7.76 (d, J =7.6 Hz, 1H), 7.47-7.53 (m, 2H), 7.05 (d,J =8.0 Hz, 1H), 6.89 (d, J =8.4 Hz, 1H), 5.21 (dd, J =3.2, 8.8 Hz, 1H), 3.01-3.12 (m, 2H), 2.55 (s, 3H); 13C NMR (100 MHz, CDCl3, TMS) δ 158.3, 157.5,148.3, 146.5, 137.5, 132.1, 129.3, 122.2, 121.7, 121.0, 120.7, 72.5, 44.6,24.4;
证明所合成的化合物结构正确。
实施例3、化合物3c的合成
向反应器中依次加入溶剂，对硝基苯乙酸（0.25 mmol），2-甲基喹啉（0.75 mmol），催化剂CuBr（0.075 mmol），二甲基亚砜作溶剂，氧气氛围下，120℃反应24小时。反应体系冷却后，用乙醚（2 ml）萃取6次，合并有机相，有机相用无水硫酸镁干燥，旋转蒸发有机相得到粗产品。粗产品用石油醚：乙酸乙酯=3：1（v/v）为洗脱剂，硅胶为吸附相柱层析分离，得到固体产物3c，产率56%。
该化合物的核磁数据如下：1H NMR (300 MHz, CDCl3): δ 8.22 (d, J = 8.7Hz, 2H), 8.12 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 8.7 Hz, 1H), 7.82 (d, J = 8.1Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.64 (d, J = 8.6 Hz, 2H), 7.55 (t, J = 7.5Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 5.44 (dd, J = 3.3 Hz, J = 8.4 Hz, 1H),3.23-3.38 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 159.7, 151.5, 147.2, 146.9,137.3, 130.2, 128.6, 127.7, 126.7, 126.6, 123.7, 121.9, 72.1, 45.1;
证明所合成的化合物结构正确。

Claims (2)

1.一种合成含吡啶类化合物的方法，其合成步骤如下：向反应器中依次加入溶剂，苯乙酸类化合物，甲基吡啶类或甲基喹啉类化合物，催化剂CuBr，二甲基亚砜做溶剂，氧气氛围下，120℃反应24-36小时，反应体系冷却后，用乙醚或者乙酸乙酯萃取6次，合并有机相，有机相用无水硫酸镁干燥，粗产品用石油醚/乙酸乙酯为洗脱剂，硅胶为吸附相的柱层析分离，得到固体产物：
所述的方法如式(1)所示。
2.如权利要求1所述的合成含吡啶类化合物的方法，其特征在于：反应所使用的底物为苯乙酸类化合物，苯乙酸类化合物包括对硝基苯乙酸，间硝基苯乙酸。
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