CN113173884B - 二氯二茂钛催化汉斯酯1,4-二氢吡啶类化合物合成吡啶及其衍生物的方法 - Google Patents

二氯二茂钛催化汉斯酯1,4-二氢吡啶类化合物合成吡啶及其衍生物的方法 Download PDF

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CN113173884B
CN113173884B CN202110490253.1A CN202110490253A CN113173884B CN 113173884 B CN113173884 B CN 113173884B CN 202110490253 A CN202110490253 A CN 202110490253A CN 113173884 B CN113173884 B CN 113173884B
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高子伟
罗点
孙华明
孙晓
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Shaanxi Normal University
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Abstract

本发明公开了一种二氯二茂钛催化汉斯酯1,4‑二氢吡啶类化合物合成吡啶及其衍生物的方法，汉斯酯1,4‑二氢吡啶类化合物的二氢吡啶结构具有一定的芳环驱动力，容易氧化成吡啶结构，在二氯二茂钛作为催化剂，汉斯酯1,4‑二氢吡啶及其衍生物进行氧化转化生成吡啶及其衍生物，成为制备吡啶及其衍生物的一条简易途径。本发明反应条件温和，操作简单，反应时间短，反应产物单一，原子经济性高，反应结束后只需将产物经过简单的柱层析分离即可。本发明得到的汉斯酯1,4‑二氢吡啶以及衍生物具有广泛的生物活性和药用价值。

Description

二氯二茂钛催化汉斯酯1,4-二氢吡啶类化合物合成吡啶及其 衍生物的方法
技术领域
本发明属于汉斯酯1,4-二氢吡啶类化合物合成吡啶及其衍生物的的合成技术领域，具体涉及一种二氯二茂钛催化汉斯酯1,4-二氢吡啶类化合物芳构化合成吡啶及其衍生物的方法。
背景技术
1,4-二氢吡啶衍生物具有丰富的药理和生物学特性，广泛存在于天然产物中，此外，它们还是有机化学中有用的、用途广泛的合成中间体。因此，对于1,4-二氢吡啶衍生物的合成就有了广泛的研究。有关1,4-二氢吡啶的芳构化已有很多的文献报道，但是通常存在需要使用化学当量氧化剂、后处理麻烦、不能实现循环利用且严重污染环境等问题。近年来，金属、非金属及光催化氧化1,4-二氢吡啶，因反应条件温和、高效、选择性高和“绿色”等特点而备受关注。固载的硝酸铜和最近报道的溴化铜已经被用来实现汉斯酯1,4-二氢吡啶的氧化转化，但仍需要化学剂量的氧化剂。钛作为地壳中含量第二丰富的过渡金属元素，通常无毒，价格相对便宜，二茂钛的出现为钛的金属有机配合物开辟了新纪元。茂环的引入为茂钛类配合物赋予了独特结构，它不仅强化了化合物的稳定性，而且在性质方面表现出许多特殊性。且其己经被广泛应用于催化稀烃聚合、不饱和烃加氢还原、有机合成以及抗癌活性等方面，成为国内外研究的热点领域之一。以二氯二茂钛作为催化剂，该反应体系简单、条件温和、底物适用范围较广、目标产物收率较高，为制备取代吡啶及其衍生物提供了一种新方法。
发明内容
本发明的目的是提供一种条件温和、操作简单、反应时间短，反应产物单一、底物适用性好、高效合成吡啶及其衍生物的方法。
针对上述目的，本发明所采用的技术方案是：将式I或III或V或VII所示的汉斯酯1,4-二氢吡啶类化合物加入到溶剂中，并加入二氯二茂钛作为催化剂，在25～60℃的条件下反应2～12小时，分离纯化，相应的得到式II或IV或VI或VIII所示的吡啶及其衍生物；
式中，R、R1和R2各自独立的代表H、C1～C4烷基、C1～C4烷氧基中的任意一种。
上述合成方法中，优选在50℃下反应12小时。
上述合成方法中，优选二氯二茂钛的加入量为汉斯酯1,4-二氢吡啶类化合物摩尔量的5％～10％。
上述合成方法中，优选溶剂为乙醇、四氢呋喃、甲醇中任意一种。
本发明的有益效果如下：
本发明在二氯二茂钛作为催化剂，将汉斯酯1,4-二氢吡啶类化合物转化成吡啶及其衍生物的。本发明反应条件温和，操作简单，反应时间短，反应产物单一，原子经济性高，反应结束后只需将产物经过简单的柱层析分离即可。得到的吡啶类化合物具有广泛的生物活性和药用价值。
具体实施方式
下面结合实施例对本发明进一步详细说明，但本发明所要保护的范围不仅限于这些实施例。
实施例1
合成结构式如下的3,3,6,6-四甲基-3,4,6,7-四氢吡啶-1,8-(2H,5H)-二酮
向20mL反应瓶中加入0.253g(1mmol)3,3,6,6-四甲基-3,4,6,7,9,10-六氢吡啶-1,8-(2H,5H)-二酮、0.0124g(0.05mmol)二氯二茂钛、3mL乙醇，在50℃下搅拌反应12小时，停止反应，自然降至室温，旋转蒸发除去乙醇，用硅胶柱分离(洗脱剂是乙酸乙酯与石油醚的体积比为1:10的混合液)，得到3,3,6,6-四甲基-3,4,6,7-四氢吡啶-1,8-(2H,5H)-二酮，其产率为94％。
所得产物用Bruker Avance型超导傅立叶数字化核磁共振谱仪进行表征，表征数据为：1H NMR(600MHz,Chloroform-d)δ8.78(s,1H),3.03(s,4H),2.54(s,4H),1.10(s,12H)；13C NMR(151MHz,CDCl3)δ195.79,165.35,132.57,125.25,76.24,76.03,75.87,75.82,50.92,45.84,31.77,28.67,27.30.
实施例2
合成结构式如下的2,7,7-三甲基-5-氧代-5,6,7,8-四氢喹啉-3-羧酸甲酯
在实施例1中，所用的3,3,6,6-四甲基-3,4,6,7,9,10-六氢吡啶-1,8-(2H,5H)-二酮用等摩尔的2-甲氧基-3,6,6-三甲基-3,4,6,7,9,10-六氢吡啶-1,8-(2H,5H)-二酮替换，其它步骤与实施例1相同，得到2,7,7-三甲基-5-氧代-5,6,7,8-四氢喹啉-3-羧酸甲酯，其产率为91％。
所得产物用Bruker Avance型超导傅立叶数字化核磁共振谱仪进行表征，表征数据为：1H NMR(600MHz,Chloroform-d)δ8.66(s,1H),3.86(s,3H),2.97(s,2H),2.81(s,3H),2.50(s,2H),1.05(s,6H)；13C NMR(151MHz,CDCl3)δ195.99,165.12,163.67,163.40,136.06,123.84,123.06,76.30,76.09,75.88,51.29,50.85,45.44,31.86,28.65,27.25,24.16.
实施例3
合成结构式如下的3-乙酰基-2,7,7-三甲基-7,8-二氢喹啉-5(6H)-酮
在实施例1中，所用的3,3,6,6-四甲基-3,4,6,7,9,10-六氢吡啶-1,8-(2H,5H)-二酮用等摩尔的3-乙酰基-2,7,7-三甲基-4,6,7,8-四氢喹啉-5-(1H)-酮替换，其它步骤与实施例1相同，得到3-乙酰基-2,7,7-三甲基-7,8-二氢喹啉-5(6H)-酮，其产率为85％。
所得产物用Bruker Avance型超导傅立叶数字化核磁共振谱仪进行表征，表征数据为：1H NMR(600MHz,Chloroform-d)δ8.44(s,1H),2.99(s,2H),2.75(s,3H),2.58(s,3H),2.53(s,2H),1.07(s,6H)；13C NMR(151MHz,CDCl3)δ198.32,196.22,163.00,162.57,134.35,130.08,123.58,76.27,76.06,75.84,50.84,45.43,31.92,28.17,27.26,24.36.
实施例4
合成结构式如下的2,7,7-三甲基-5-氧代-5,6,7,8-四氢喹啉-3-羧酸异丙酯
在实施例1中，所用的3,3,6,6-四甲基-3,4,6,7,9,10-六氢吡啶-1,8-(2H,5H)-二酮用等摩尔的2,7,7-三甲基-5-氧代-1,4,5,6,7,8-六氢喹啉-3-羧酸异丙酯替换，其它步骤与实施例1相同，得到2,7,7-三甲基-5-氧代-5,6,7,8-四氢喹啉-3-羧酸异丙酯，其产率为97％。
所得产物用Bruker Avance型超导傅立叶数字化核磁共振谱仪进行表征，表征数据为：1H NMR(600MHz,Chloroform-d)δ8.65(s,1H),5.23(p,J＝6.3Hz,1H),2.99(s,2H),2.84(s,3H),2.52(s,2H),1.35(d,J＝6.3Hz,6H),1.08(s,6H)；13C NMR(151MHz,CDCl3)δ196.15,164.38,163.45,163.10,135.81,124.00,123.85,76.25,76.10,76.04,75.82,68.13,50.93,45.48,31.87,28.67,27.25,24.17,20.87.
实施例5
合成结构式如下的2,7,7-三甲基-5-氧代-5,6,7,8-四氢喹啉-3-羧酸乙酯
在实施例1中，所用的3,3,6,6-四甲基-3,4,6,7,9,10-六氢吡啶-1,8-(2H,5H)-二酮用等摩尔的2,7,7-三甲基-5-氧代-1,4,5,6,7,8-六氢喹啉-3-羧酸乙酯替换，其它步骤与实施例1相同，得到2,7,7-三甲基-5-氧代-5,6,7,8-四氢喹啉-3-羧酸乙酯，其产率为91％。
所得产物用Bruker Avance型超导傅立叶数字化核磁共振谱仪进行表征，表征数据为：1H NMR(600MHz,Chloroform-d)δ8.67(s,1H),4.33(q,J＝7.1Hz,2H),2.97(s,2H),2.82(s,3H),2.51(s,2H),1.35(d,J＝7.1Hz,3H),1.06(s,6H)；13C NMR(151MHz,CDCl3)δ197.10,197.08,165.73,164.59,164.24,136.93,124.82,124.45,77.27,77.06,76.85,61.39,51.87,46.44,32.85,29.65,28.23,25.17,25.16,14.24,0.99.
实施例6
合成结构式如下的5-乙酰基-2,6-二甲基烟酸甲酯
在实施例1中，所用的3,3,6,6-四甲基-3,4,6,7,9,10-六氢吡啶-1,8-(2H,5H)-二酮用等摩尔的5-乙酰基-2,6-二甲基-1,4-二氢吡啶-3-羧酸甲酯替换，其它步骤与实施例1相同，得到5-乙酰基-2,6-二甲基烟酸甲酯，其产率为93％。
所得产物用Bruker Avance型超导傅立叶数字化核磁共振谱仪进行表征，表征数据为：1H NMR(600MHz,Chloroform-d)δ8.49(s,1H),3.93(s,3H),2.83(s,3H),2.76(s,3H),2.60(s,3H)；13C NMR(151MHz,CDCl3)δ198.12,165.24,161.07,160.20,138.56,128.89,121.37,76.23,76.02,75.80,51.36,28.68,28.16,24.01,23.99.
实施例7
合成结构式如下的2,6-二甲基吡啶-3,5-二甲酸二甲酯
在实施例1中，所用的3,3,6,6-四甲基-3,4,6,7,9,10-六氢吡啶-1,8-(2H,5H)-二酮用等摩尔的2,6-二甲基-1,4-二氢吡啶-3,5-二甲酸二甲酯替换，其它步骤与实施例1相同，得到2,6-二甲基吡啶-3,5-二甲酸二甲酯，其产率为95％。
所得产物用Bruker Avance型超导傅立叶数字化核磁共振谱仪进行表征，表征数据为：1H NMR(600MHz,Chloroform-d)δ8.67(s,1H),3.91(s,6H),2.83(s,6H)；13CNMR(151MHz,CDCl3)δ165.18,161.59,140.00,121.59,76.24,76.02,75.81,51.28,51.26,23.93,23.91.
实施例8
合成结构式如下的1,1'-(2,6-二甲基吡啶-3,5-二基)双(乙-1-酮)
在实施例1中，所用的3,3,6,6-四甲基-3,4,6,7,9,10-六氢吡啶-1,8-(2H,5H)-二酮用等摩尔的1,1'-(2,6-二甲基-1,4-二氢吡啶-3,5-二酰基)双(乙烷-1-酮)替换，其它步骤与实施例1相同，得到1,1'-(2,6-二甲基吡啶-3,5-二基)双(乙-1-酮)，其产率为62％。
所得产物用Bruker Avance型超导傅立叶数字化核磁共振谱仪进行表征，表征数据为：1H NMR(600MHz,Chloroform-d)δ8.21(s,1H),2.74(s,6H),2.58(s,6H)；13CNMR(151MHz,CDCl3)δ198.17,159.23,136.74,136.72,129.13,76.25,76.04,75.83,28.34,23.98,23.96.
实施例9
合成结构式如下的2,6-二甲基吡啶-3,5-二羧酸二叔丁酯
在实施例1中，所用的3,3,6,6-四甲基-3,4,6,7,9,10-六氢吡啶-1,8-(2H,5H)-二酮用等摩尔的2,6-二甲基-1,4-二氢吡啶-3,5-二羧酸二叔丁酯替换，其它步骤与实施例1相同，得到2,6-二甲基吡啶-3,5-二羧酸二叔丁酯，其产率为75％。
所得产物用Bruker Avance型超导傅立叶数字化核磁共振谱仪进行表征，表征数据为：1H NMR(600MHz,Chloroform-d)δ8.51(s,1H),2.79(s,6H),1.59(s,18H)；13CNMR(151MHz,CDCl3)δ164.44,160.09,139.70,123.63,81.07,76.21,76.00,75.88,75.79,27.24,27.20,23.94,23.92.
实施例10
合成结构式如下的2,7,7-三甲基-5-氧代-5,6,7,8-四氢喹啉-3-羧酸叔丁酯
在实施例1中，所用的3,3,6,6-四甲基-3,4,6,7,9,10-六氢吡啶-1,8-(2H,5H)-二酮用等摩尔的叔丁基2,7,7-三甲基-5-氧基-1,4,5,6,7,8-六氢喹啉-3-羧酸盐替换，其它步骤与实施例1相同，得到2,7,7-三甲基-5-氧代-5,6,7,8-四氢喹啉-3-羧酸叔丁酯，其产率为65％。
所得产物用Bruker Avance型超导傅立叶数字化核磁共振谱仪进行表征，表征数据为：1H NMR(600MHz,Chloroform-d)δ8.59(s,1H),3.00(s,2H),2.82(s,3H),2.53(s,2H),1.59(s,9H),1.10(s,6H)；13C NMR(151MHz,CDCl3)δ197.22,165.30,164.01,163.71,136.63,126.32,124.82,82.32,77.22,77.01,76.80,51.96,46.47,32.88,28.25,28.19,25.12,1.00.
实施例11
合成结构式如下的2,6-二甲基吡啶-3,5-二羧酸二异丙酯
在实施例1中，所用的3,3,6,6-四甲基-3,4,6,7,9,10-六氢吡啶-1,8-(2H,5H)-二酮用等摩尔的2,6-二甲基-1,4-二氢吡啶-3,5-二甲酸二异丙酯替换，其它步骤与实施例1相同，得到2,6-二甲基吡啶-3,5-二羧酸二异丙酯，其产率为97％。
所得产物用Bruker Avance型超导傅立叶数字化核磁共振谱仪进行表征，表征数据为：1H NMR(600MHz,Chloroform-d)δ8.56(s,1H),5.21(p,J＝6.2Hz,2H),2.78(s,6H),1.34(d,J＝6.4Hz,12H)；13C NMR(151MHz,CDCl3)δ164.59,160.72,139.74,122.54,76.29,76.13,76.08,75.87,68.06,23.92,20.87.
实施例12
合成结构式如下的5-乙酰基-2,6-二甲基烟酸乙酯
在实施例1中，所用的3,3,6,6-四甲基-3,4,6,7,9,10-六氢吡啶-1,8-(2H,5H)-二酮用等摩尔的5-乙酰基-2,6-二甲基-1,4-二氢吡啶-3-羧酸乙酯替换，其它步骤与实施例1相同，得到5-乙酰基-2,6-二甲基烟酸乙酯，其产率为73％。
所得产物用Bruker Avance型超导傅立叶数字化核磁共振谱仪进行表征，表征数据为：1H NMR(600MHz,Chloroform-d)δ8.47(s,1H),4.39(q,J＝7.1Hz,2H),2.82(s,3H),2.74(s,3H),2.60(s,3H),1.40(t,J＝7.1Hz,3H)；13C NMR(151MHz,CDCl3)δ198.20,164.90,160.87,159.96,138.52,138.50,128.93,121.79,76.24,76.03,75.82,60.48,28.67,28.17,24.04,24.03,23.99,23.97,13.27.
实施例13
合成结构式如下的2,6-二甲基吡啶-3,5-二羧酸二乙酯
在实施例1中，所用的3,3,6,6-四甲基-3,4,6,7,9,10-六氢吡啶-1,8-(2H,5H)-二酮用等摩尔的2,6-二甲基-1,4-二氢吡啶-3,5-二甲酸二乙酯替换，其它步骤与实施例1相同，得到2,6-二甲基吡啶-3,5-二羧酸二乙酯，其产率为96％。
所得产物用Bruker Avance型超导傅立叶数字化核磁共振谱仪进行表征，表征数据为：1H NMR(600MHz,Chloroform-d)δ8.63(s,1H),4.36(q,J＝7.1Hz,4H),2.81(s,6H),1.38(t,J＝7.2Hz,6H)；13C NMR(151MHz,CDCl3)δ164.90,161.18,139.86,122.02,76.26,76.05,75.84,60.35,28.67,23.93,13.25。

Claims (4)

1.一种二氯二茂钛催化汉斯酯1,4-二氢吡啶类化合物合成吡啶衍生物的方法，其特征在于：将式I或III或V或VII所示的汉斯酯1,4-二氢吡啶类化合物加入到溶剂中，并加入二氯二茂钛作为催化剂，在25～60℃的条件下反应2～12小时，分离纯化，相应的得到式 II或IV或VI或VIII所示的吡啶衍生物；
式中，R、R1和R2各自独立的代表H、C1～C4烷基、C1～C4烷氧基中的任意一种。
2.根据权利要求1所述的二氯二茂钛催化汉斯酯1,4-二氢吡啶类化合物合成吡啶衍生物的方法，其特征在于：在50℃下反应12小时。
3.根据权利要求1所述的二氯二茂钛催化汉斯酯1,4-二氢吡啶类化合物合成吡啶衍生物的方法，其特征在于：所述的二氯二茂钛的加入量为汉斯酯1,4-二氢吡啶类化合物摩尔量的5%～10%。
4.根据权利要求1或2所述的二氯二茂钛催化汉斯酯1,4-二氢吡啶类化合物合成吡啶衍生物的方法，其特征在于：所述的溶剂为乙醇、四氢呋喃、甲醇中任意一种。
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