一种连续流动合成4-吡啶酮及其衍生物的方法
阅读说明：本技术 一种连续流动合成4-吡啶酮及其衍生物的方法 (Method for synthesizing 4-pyridone and derivatives thereof by continuous flow ) 是由 黄超 刘腾 李伟强 于 2021-10-13 设计创作，主要内容包括：本发明公开了一种连续流动合成4-吡啶酮及其衍生物的方法,包括以下步骤：1)将反应原料以烷氧基甲叉-3-氧代羧酸酯、炔和胺类化合物分别溶于有机溶剂中得到物料a、物料b和物料c；2)将物料a和物料c经单元泵连续流动下混合得到物料d；3)物料d再与物料b在催化剂条件下进行流动反应得到反应液e；4)将反应液e经除去溶剂、层析分离、洗脱、干燥得到目标产物4-吡啶酮及其衍生物。本发明提供了一种通过简单易得的原料乙氧基甲叉丙二酸二乙酯、乙炔二羧酸二乙酯和胺类在流动条件下制得4-吡啶酮及其衍生物,为后续工业生产提供一种简单易行的方法。(The invention discloses a method for synthesizing 4-pyridone and derivatives thereof by continuous flow, which comprises the following steps: 1) respectively dissolving alkoxy methylene-3-oxocarboxylate, alkyne and amine compounds serving as reaction raw materials in an organic solvent to obtain a material a, a material b and a material c; 2) continuously flowing and mixing the material a and the material c through a unit pump to obtain a material d; 3) carrying out flow reaction on the material d and the material b under the condition of a catalyst to obtain a reaction liquid e; 4) and removing the solvent from the reaction liquid e, carrying out chromatographic separation, eluting and drying to obtain the target product 4-pyridone and the derivative thereof. The invention provides a simple and easily-obtained method for preparing 4-pyridone and derivatives thereof by using simple and easily-obtained raw materials of diethyl ethoxymethylene malonate, diethyl acetylenedicarboxylate and amines under a flowing condition, and provides a simple and easy method for subsequent industrial production.)
技术领域
本发明属于化学技术领域，具体涉及一种连续流动合成4-吡啶酮及其衍生物的方法。
背景技术
4-吡啶酮是一类重要的广泛存在于药物分子中的骨架化合物，由于不易氧化或甲基化，往往表现出不同的生物学特性，如抗纤维化、抗癫痫和抗炎等生物活性可做为多种药物的核心模块，如下所示：
由于吡啶酮类化合物具有广泛的生物活性，同时具有合成药物分子的应用价值。在过去的几十年里，N -芳基/烷基-2-吡啶类化合物的合成取得了长足的进展，而N -芳基/烷基-4-吡啶类化合物的合成却很少。目前为止对于N -芳基/烷基-4-吡啶酮，已经确定了几种合成路线，包括p-TSA催化N -芳基乙酰乙酰胺的自缩合后与双烯酮反应，过硫酸钠介导的酰基迁移反应，3-氨基环丁烯酮与缺电子炔烃的 [4+2] 环加成反应，钌催化的C-H活化苯与吡啶环反应等。然而，目前所报道的方法经常需要使用强酸，强氧化剂，致癌溶剂(苯)，过渡金属催化(Ru, Rh)，而且通常选择性差和低产率，反应慢且底物普适性有限。为了解决这些限制，探索一种高效和通用的方法来获取N -芳基/烷基-4-吡啶仍然是一个艰巨的挑战。
发明内容
本发明的目的在于提供一种连续流动合成4-吡啶酮及其衍生物的方法。
本发明的目的是这样实现的，所述的连续流动合成4-吡啶酮及其衍生物的方法是以烷氧基甲叉-3-氧代羧酸酯、炔和胺类化合物为反应原料，在催化剂条件下流动反应得到4-吡啶酮及其衍生物，其合成路线如下：
。
近年来，连续流动化学受到了合成工作者和工艺生产者的广泛关注，连续流动微反应器与传统的间歇式反应器相比，具有高比表面积，高效传热效率，高效传质效率，可以进行精确控制等优点，易于放大工业生产。同时在有机合成中得到了迅速的发展，成为替代传统操作的有效方法。
基于以上原因，本发明提供了一种通过简单易得的原料乙氧基甲叉丙二酸二乙酯、乙炔二羧酸二乙酯和胺类在流动条件下制得4-吡啶酮及其衍生物，为后续工业生产提供一种简单易行的方法。
本发明是将胺类和乙氧基甲叉丙二酸二乙酯或甲氧基甲基戊烯酸二甲酯在反应线圈中流动下进行反应，反应之后不进入收集装置，再与炔酯和催化剂DABCO在另一个反应线圈中进行反应，最终通过产物收集器在线收集流出反应液，经后处理，得到产物4-吡啶酮及其衍生物。
有益效果主要体现为：
1）原料简单易得市场可以买到且价格便宜；
2）中间不需要分离操作，反应高效省力；
3）绿色的反应过程、副产物只有乙醇、原子经济性高；
4）产率高，可在流动合成仪上大批量生产，为工艺化生产4-吡啶酮及其衍生物提供了简单易行的方法。
附图说明
图1为本发明实施例1中4a化合物核磁谱图；
图2为本发明实施例1中4c化合物核磁谱图；
图3为本发明实施例1中4o化合物核磁谱图；
图4为本发明实施例1中4j化合物核磁谱图；
图5为本发明实施例1中4l化合物核磁谱图；
图6为本发明实施例2中5i化合物核磁谱图。
具体实施方式
下面结合实施例对本发明作进一步的说明，但不以任何方式对本发明加以限制，基于本发明教导所作的任何变换或替换，均属于本发明的保护范围。
本发明所述的所述的连续流动合成4-吡啶酮及其衍生物的方法是以烷氧基甲叉-3-氧代羧酸酯、炔和胺类化合物为反应原料，在催化剂条件下流动反应得到4-吡啶酮及其衍生物，其合成路线如下：
。
所述的连续流动合成4-吡啶酮及其衍生物的方法包括以下步骤：
1）将反应原料以烷氧基甲叉-3-氧代羧酸酯、炔和胺类化合物分别溶于有机溶剂中得到物料a、物料b和物料c；
2）将物料a和物料c经单元泵连续流动下混合得到物料d；
3）物料d再与物料b在催化剂条件下进行流动反应得到反应液e；
4）将反应液e经除去溶剂、层析分离、洗脱、干燥得到目标产物4-吡啶酮及其衍生物。
所述的烷氧基甲叉-3-氧代羧酸酯、炔和胺类化合物得摩尔比为（0.9~1.3）：（0.9~1.1）：（0.9~1.1）。
所述的烷氧基甲叉-3-氧代羧酸酯为乙氧基甲叉丙二酸二乙酯或甲氧基甲基戊烯酸二甲酯。
所述的炔为乙炔二羧酸或丁炔二酸二甲酯。
所述的胺类化合物为苯胺、吡啶胺或烷基胺。
所述的催化剂为碱性催化剂。
所述得碱性催化剂为三乙烯二胺（DABCO）。
1）步骤中所述的有机溶剂为乙腈。
4）步骤中所述的洗脱是以体积比3:1的石油醚-乙酸乙酯混合液进行洗脱。
本发明提供的连续流动合成4-吡啶酮及其衍生物的方法，所用的单体为乙氧基甲叉丙二酸二乙酯或甲氧基甲基戊烯酸二甲酯中的一种，炔酯类为乙炔二羧酸二乙酯或丁炔二酸二甲酯中的一种，胺类为常见的各种取代的芳胺、苄胺或脂肪胺中的一种，催化剂为有机碱DABCO，在加热的条件下对流动管道中的反应物进行加热，制备所需的4-吡啶酮。合成所用装置包括单元泵、透明管道线圈、加热装置及收集装置。具体步骤如下：
以乙腈为反应溶剂、苯胺、乙氧基甲叉丙二酸二乙酯和乙炔二羧酸二乙酯为原料，DABCO为催化剂。将原料苯胺和乙氧基甲叉丙二酸二乙酯各自用溶剂溶解后分别置于A、B两试管中，将乙炔二羧酸二乙酯和催化剂DABCO用溶剂溶解混合后置于C试管中。在蠕动泵的推动下试管A、B中的苯胺和乙氧基甲叉丙二酸二乙酯连续通入反应线圈1中进行反应，控制温度为25~80 oC（优选50 oC），反应液在反应通道1内连续流动的反应时间为10~50min（优选25min），精确控制反应时间使其苯胺和乙氧基甲叉丙二酸二乙酯反应产物在流出反应通道1后将C试管中的乙炔二羧酸二乙酯和催化剂DABCO泵入，使其苯胺和乙氧基甲叉丙二酸二乙酯反应产物和C试管中的乙炔二羧酸二乙酯和催化剂DABCO在反应线圈2中经行反应，控制温度为25~80 oC（优选55 oC），反应液在反应通道2内连续流动的反应时间为10~50min（优选30min），通过产物收集器在线收集流出反应液，经后处理，得到产物4-吡啶酮产物。
所述的苯胺、乙氧基甲叉丙二酸二乙酯和乙炔二羧酸二乙酯各自用乙腈溶解后，所得的溶液浓度推荐在1.0 mol/L。
所述的DABCO为三乙烯二胺，是一种有机碱类催化剂，所使用的量为反应底物量的2~15%，特别优选10%。
所述后处理的方法具体例如：将反应液减压蒸馏除去溶剂，进行硅胶柱层析分离，用200-300目硅胶干法装柱，洗脱试剂为石油醚：乙酸乙酯体积比＝3：1的混合液，TLC跟踪洗脱进程，收集含目标化合物的洗脱液，蒸除溶剂并干燥，得到产物4-吡啶酮及其衍生物。
其反应原理如下：
。
下面以具体实施案例对本发明做进一步说明：
实施例1
该制备方法包括以下步骤：
以乙腈为系统溶剂、苯胺、乙氧基甲叉丙二酸二乙酯和乙炔二羧酸二乙酯为原料，DABCO为催化剂。将原料苯胺、乙氧基甲叉丙二酸二乙酯和乙炔二羧酸二乙酯各自用乙腈稀释至1.0 mol/L后分别置于A、B和C两试管中，将DABCO按10%的当量置于C试管中。在蠕动泵的推动下试管A、B中的苯胺和乙氧基甲叉丙二酸二乙酯连续通入反应线圈1中进行反应，控制温度为50 oC，反应液在反应通道1内连续流动的反应时间为25 min，精确控制反应时间使其苯胺和乙氧基甲叉丙二酸二乙酯反应产物在流出反应通道1后不进入收集装置而直接进入下一反应线圈，将C试管中的乙炔二羧酸二乙酯和催化剂DABCO泵入，使其苯胺和乙氧基甲叉丙二酸二乙酯反应产物和C试管中的乙炔二羧酸二乙酯和催化剂DABCO在反应线圈2中经行反应，控制温度为55 oC，反应液在反应通道2内连续流动的反应时间为30min，通过产物收集器在线收集流出反应液，经后处理，得到产物4-吡啶酮产物。
实施例中供电子基胺类化合物及酯基变化制备得到4-吡啶酮类化合物的得率情况如下：
上述化合物数据如下：
Triethyl 4-oxo-1-phenyl-1,4-dihydropyridine-2,3,5-tricarboxylate (4a)：Yellow oil; yield 90%; 1H NMR (400 MHz, CDCl3) δ 7.50–7.42 (m, 3H, Ph-H),7.24 (dd, J = 4.7, 1.7 Hz, 2H, Ph-H), 6.80 (s, 1H, CH), 4.36 (q, J = 7.2 Hz,2H, OCH2), 4.25 (q, J = 7.1 Hz, 2H, OCH2), 3.92 (q, J = 7.2 Hz, 2H, OCH2),1.36 (t, J = 7.2 Hz, 3H, CH3), 1.28 (t, J = 7.2 Hz, 3H), 0.93 (t, J = 7.2 Hz,3H, CH3); 13C NMR (100 MHz, CDCl3) δ 165.4, 163.4, 161.0, 145.7, 143.8, 136.6,130.1, 129.5, 128.5, 121.4, 107.2, 62.9, 62.5, 62.3, 14.2, 14.0, 13.5; HRMS(ESI-TOF+) m/z: calcd for C20H22NO7 + [(M + H)+], 388.1391; found, 388.1387.
Triethyl 4-oxo-1-(o-tolyl)-1,4-dihydropyridine-2,3,5-tricarboxylate (4b)：Pale yellow oil; yield 89%; 1H NMR (400 MHz, CDCl3) δ 7.33–7.28 (m, 1H,Ph-H), 7.25 (d, J = 6.5 Hz, 1H, Ph-H), 7.24–7.18 (m, 1H, Ph-H), 7.11–6.99 (m,1H, Ph-H), 6.76 (s, 1H, CH), 4.32 (q, J = 7.2 Hz, 2H, OCH2), 4.20 (dd, J =7.1, 2.3 Hz, 2H, OCH2), 3.88–3.83 (m, 2H, OCH2), 2.11 (s, 3H, CH3), 1.32 (t, J= 7.2 Hz, 3H, CH3), 1.22 (t, J = 7.2 Hz, 3H, CH3), 0.88 (t, J = 7.2 Hz, 3H,CH3); 13C NMR (100 MHz, CDCl3) δ 165.6, 163.3, 160.9, 160.3, 145.9, 144.1,137.0, 135.8, 131.2, 130.4, 128.5, 127.0, 121.1, 106.9, 62.8, 62.6, 62.3,17.7, 14.2, 14.0, 13.4; HRMS (ESI-TOF+) m/z: calcd for C21H24NO7 + [(M + H)+],402.1547; found, 402.1544.
Triethyl 4-oxo-1-(m-tolyl)-1,4-dihydropyridine-2,3,5-tricarboxylate (4c)：Drak yellow oil; yield 90%; 1H NMR (400 MHz, CDCl3) δ 7.34 (t, J = 7.8Hz, 1H, Ph-H), 7.25 (d, J = 5.9 Hz, 1H, Ph-H), 7.09–6.98 (m, 2H, Ph-H), 6.81(d, J = 11.9 Hz, 1H, CH), 4.36 (q, J = 7.2 Hz, 2H, OCH2), 4.25 (q, J = 7.1Hz, 2H, OCH2), 3.97–3.92 (m, 2H, OCH2), 2.37 (s, 3H, CH3), 1.36 (t, J = 7.2Hz, 3H, CH3), 1.28 (d, J = 7.1 Hz, 3H, CH3), 0.94 (t, J = 7.2 Hz, 3H, CH3); 13CNMR (100 MHz, CDCl3) δ 164.3, 162.2, 159.8, 144.6, 142.6, 138.4, 135.3,129.6, 128.1, 127.8, 124.3, 120.2, 106.0, 61.6, 61.3, 61.1, 20.2, 13.0, 12.8,12.3; HRMS (ESI-TOF+) m/z: calcd for C21H25NO7 + [(M + H)+], 402.1547; found,402.1549.
Triethyl 4-oxo-1-(p-tolyl)-1,4-dihydropyridine-2,3,5-tricarboxylate (4d)：Pale yellow oil; yield 93%; 1H NMR (400 MHz, CDCl3) δ 7.27 (s, 1H, Ph-H),7.25 (s, 1H, Ph-H), 7.12 (d, J = 8.3 Hz, 2H, Ph-H), 6.82 (s, 1H, CH), 4.36(q, J = 7.1 Hz, 2H, OCH2), 4.25 (q, J = 7.1 Hz, 2H, OCH2), 3.96 (q, J = 7.2Hz, 2H, OCH2), 2.40 (d, J = 10.0 Hz, 3H, CH3), 1.36 (t, J = 7.2 Hz, 3H, CH3),1.28 (t, J = 7.2 Hz, 3H, CH3), 0.98 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (100MHz, CDCl3) δ 165.5, 163.5, 161.1, 145.9, 143.8, 140.3, 133.9, 130.1, 128.2,121.3, 107.1, 62.8, 62.5, 62.3, 21.4, 14.2, 14.0, 13.5; HRMS (ESI-TOF+) m/z:calcd for C21H24NO7 + [(M + H)+], 402.1547; found, 402.1544.
Triethyl 1-(2-methoxyphenyl)-4-oxo-1,4-dihydropyridine-2,3,5- tricarboxylate (4e)：Pale yellow oil; yield 89%; 1H NMR (400 MHz, CDCl3) δ7.44–7.38 (m, 1H, Ph-H), 7.16–7.14 (m, 1H, Ph-H), 7.02–6.97 (m, 2H, Ph-H),6.78 (d, J = 1.6 Hz, 1H, CH), 4.38–4.33 (m, 2H, OCH2), 4.23 (d, J = 7.2 Hz,2H, OCH2), 3.94–3.91 (m, 2H, OCH2), 3.79 (d, J = 1.6 Hz, 3H, OCH3), 1.38–1.34(m, 3H, CH3), 1.26 (dd, J = 7.2, 5.7 Hz, 3H, CH3), 0.96–0.92 (m, 3H, CH3); 13CNMR (100 MHz, CDCl3) δ 165.7, 163.4, 161.0, 160.5, 155.4, 146.5, 143.9,131.8, 129.7, 125.5, 121.1, 120.7, 112.3, 106.8, 62.6, 62.5, 62.2, 56.1,14.2, 14.0, 13.6; HRMS (ESI-TOF+) m/z: calcd for C21H24NO8 + [(M + H)+],418.1496; found, 418.1494.
Triethyl 1-(3-methoxyphenyl)-4-oxo-1,4-dihydropyridine-2,3,5- tricarboxylate (4f)：Pale yellow oil; yield 92%; 1H NMR (400 MHz, CDCl3) δ 7.36(t, J = 8.1 Hz, 1H, Ph-H), 7.03–6.94 (m, 1H, Ph-H), 6.87–6.78 (m, 2H, Ph-H),6.77 (t, J = 2.2 Hz, 1H, CH), 4.36 (q, J = 7.2 Hz, 2H, OCH2), 4.25 (q, J =7.1 Hz, 2H, OCH2), 4.00–3.94 (m, 2H, OCH2), 3.78 (s, 3H, OCH3), 1.36 (t, J =7.2 Hz, 3H, CH3), 1.27 (t, J = 7.1 Hz, 3H, CH3), 0.97 (t, J = 7.2 Hz, 3H,CH3); 13C NMR (100 MHz, CDCl3) δ 165.4, 163.4, 161.0, 160.8, 160.3, 145.6,143.7, 137.4, 130.2, 121.5, 120.6, 116.2, 114.0, 107.3, 62.9, 62.5, 62.3,55.7, 14.2, 14.0, 13.5; HRMS (ESI-TOF+) m/z: calcd for C21H24NO8 + [(M + H)+],418.1496; found, 418.1498.
Triethyl 1-(2-(tert-butyl)phenyl)-4-oxo-1,4-dihydropyridine-2,3,5- tricarboxylate (4g)：Pale yellow oil; yield 88%; 1H NMR (400 MHz, CDCl3) δ 7.59(dd, J = 8.2, 1.3 Hz, 1H, Ph-H), 7.44–7.35 (m, 1H, Ph-H), 7.24–7.18 (m, 1H,Ph-H), 6.92 (dd, J = 7.9, 1.4 Hz, 1H, Ph-H), 6.78 (s, 1H, CH), 4.37 (q, J =7.2 Hz, 2H, OCH2), 4.28–4.22 (m, 2H, OCH2), 3.98–3.92 (m, 2H, OCH2), 1.37 (t,J = 7.2 Hz, 3H, CH3), 1.30 (d, J = 2.1 Hz, 9H, CH3), 1.28 (d, J = 7.2 Hz, 3H,CH3), 0.95 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 165.6, 163.5,162.1, 161.1, 147.7, 146.4, 144.2, 133.4, 130.7, 130.6, 130.2, 126.8, 121.0,106.9, 62.9, 62.6, 62.3, 37.1, 31.7, 14.2, 14.0, 13.5; HRMS (ESI-TOF+) m/z:calcd for C24H30NO7 + [(M + H)+], 444.2017; found, 444.2019.
Triethyl 1-(3,4-dimethylphenyl)-4-oxo-1,4-dihydropyridine-2,3,5- tricarboxylate (4h)：Drak yellow solid; yield 95%; 1H NMR (400 MHz, CDCl3) δ7.21 (d, J = 8.0 Hz, 1H, Ph-H), 7.04–6.93 (m, 2H, Ph-H), 6.81 (s, 1H, CH),4.35 (q, J = 7.2 Hz, 2H, OCH2), 4.25 (q, J = 7.1 Hz, 2H, OCH2), 3.96 (dd, J =7.2, 5.2 Hz, 2H, OCH2), 2.26 (d, J = 5.3 Hz, 6H, CH3), 1.36 (t, J = 7.2 Hz,3H, CH3), 1.27 (t, J = 7.2 Hz, 3H, CH3), 0.96 (t, J = 7.2 Hz, 3H, CH3); 13C NMR(100 MHz, CDCl3) δ 165.5, 163.4, 161.1, 161.1, 145.9, 143.7, 138.9, 138.0,134.0, 130.5, 129.2, 125.5, 121.3, 106.9, 62.7, 62.5, 62.2, 19.9, 19.7, 14.1,14.0, 13.5; HRMS (ESI-TOF+) m/z: calcd for C21H27NO7 + [(M + H)+], 416.1704;found, 416.1700.
Triethyl 1-(naphthalen-1-yl)-4-oxo-1,4-dihydropyridine-2,3,5- tricarboxylate (4i)：Pale yellow oil; yield 95%; 1H NMR (400 MHz, CDCl3) δ 7.97(d, J = 8.2 Hz, 1H, Ph-H), 7.93–7.87 (m, 1H, Ph-H), 7.55–7.55 (m, 4H, Ph-H),7.39 (dd, J = 7.3, 1.0 Hz, 1H, Ph-H), 6.91 (s, 1H, CH), 4.41 (q, J = 7.2 Hz,2H, OCH2), 4.26 (dd, J = 7.1, 2.5 Hz, 2H, OCH2), 3.67 (dd, J = 7.2, 4.4 Hz,2H, OCH2), 1.40 (t, J = 7.2 Hz, 3H, CH3), 1.28 (d, J = 7.1 Hz, 3H, CH3), 0.46(t, J = 7.2 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 165.6, 163.4, 160.9,160.9, 146.5, 144.2, 134.2, 133.4, 130.9, 130.0, 128.5, 127.9, 127.1, 127.0,125.2, 122.7, 121.3, 107.3, 62.7, 62.6, 62.4, 14.2, 14.0, 13.0; HRMS (ESI-TOF+) m/z: calcd for C24H24NO7 + [(M + H)+], 438.1547; found, 438.1543.
Triethyl 4-oxo-1-(quinolin-3-yl)-1,4-dihydropyridine-2,3,5- tricarboxylate (4j)：Yellow solid; yield 92%; 1H NMR (400 MHz, CDCl3) δ 8.77(d, J = 2.4 Hz, 1H, Ph-H), 8.16 (d, J = 8.5 Hz, 1H, Ph-H), 8.09 (d, J = 2.4Hz, 1H, Ph-H), 7.88–7.75 (m, 2H, Ph-H), 7.62 (dd, J = 8.0, 7.1 Hz, 1H, Ph-H),6.89 (d, J = 0.5 Hz, 1H, CH), 4.38 (q, J = 7.1 Hz, 2H, OCH2), 4.27 (q, J =7.1 Hz, 2H, OCH2), 3.92–3.82 (m, 2H, OCH2), 1.38 (t, J = 7.2 Hz, 3H, CH3),1.28 (t, J = 7.1 Hz, 3H, CH3), 0.80 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (100MHz, CDCl3) δ 164.0, 162.0, 159.8, 159.6, 148.1, 146.8, 144.2, 142.9, 134.2,130.1, 129.1, 128.5, 127.2, 126.8, 126.1, 120.4, 106.9, 62.0, 61.5, 61.3,13.0, 12.8, 12.2; HRMS (ESI-TOF+) m/z: calcd for C23H23N2O7 + [(M + H)+],439.1500; found, 439.1503.
Triethyl 1-isopropyl-4-oxo-1,4-dihydropyridine-2,3,5-tricarboxylate (4k)：Pale yellow oil; yield 83%; 1H NMR (400 MHz, CDCl3) δ 6.62 (s, 1H, CH),4.46–4.40 (m, 2H, OCH2), 4.35–4.29 (m, 2H, OCH2), 4.26–4.21 (m, 2H, OCH2),4.19–4.10 (m, 1H, CH), 1.61 (s, 3H, CH3), 1.60 (s, 3H, CH3), 1.41–1.38 (m, 3H,CH3), 1.35–1.32 (m, 3H, CH3), 1.30–1.26 (m, 3H, CH3); 13C NMR (100 MHz, CDCl3)δ 164.5, 162.6, 161.3, 160.1, 144.7, 141.3, 120.8, 105.7, 62.2, 61.2, 61.0,55.9, 18.3, 13.0, 12.9 12.7; HRMS (ESI-TOF+) m/z: calcd for C17H24NO7 + [(M + H)+],354.1547; found, 354.1543.
Triethyl 1-cyclopropyl-4-oxo-1,4-dihydropyridine-2,3,5-tricarboxylate (4l)：Pale yellow oil; yield 85%; 1H NMR (400 MHz, CDCl3) δ 6.76 (s, 1H, CH),4.40 (q, J = 7.2 Hz, 2H, OCH2), 4.30 (q, J = 7.1 Hz, 1H, OCH2), 4.24 (q, J =7.2 Hz, 1H, OCH2), 3.18–2.99 (m, 1H, CH), 1.39 (t, J = 7.2 Hz, 3H, CH3), 1.32(t, J = 6.7 Hz, 3H, CH3), 1.28 (d, J = 7.2 Hz, 3H, CH3), 1.13 (d, J = 7.0 Hz,2H, CH2), 0.91–0.84 (m, 1H, CH2); 13C NMR (100 MHz, CDCl3) δ 165.0, 164.1,162.0, 161.4, 145.6, 141.6, 122.1, 109.4, 63.2, 62.5, 62.3, 31.2, 14.2, 14.0,14.0, 9.0; HRMS (ESI-TOF+) m/z: calcd for C17H22NO7 + [(M + H)+], 352.1391;found, 352.1394.
Triethyl 1-cyclohexyl-4-oxo-1,4-dihydropyridine-2,3,5-tricarboxylate (4m)：Pale yellow oil; yield 90%; 1H NMR (400 MHz, CDCl3) δ 6.60 (s, 1H, CH),4.44 (q, J = 7.2 Hz, 2H, OCH2), 4.31 (q, J = 7.2 Hz, 2H, OCH2), 4.23 (q, J =7.2 Hz, 2H, OCH2), 3.63 (s, 1H, CH), 2.62 (d, J = 11.5 Hz, 2H, CH2), 1.86 (d,J = 12.0 Hz, 2H, CH2), 1.72 (d, J = 10.8 Hz, 2H, CH2), 1.62 (d, J = 8.7 Hz,2H, CH2), 1.41 (t, J = 7.2 Hz, 3H, CH3), 1.33 (t, J = 7.2 Hz, 3H, CH3), 1.28(d, J = 7.2 Hz, 3H, CH3), 1.25–1.09 (m, 4H, CH2).13C NMR (100 MHz, CDCl3) δ164.6, 162.5, 161.4, 160.2, 145.1, 141.3, 120.8, 62.1, 61.1, 61.0, 27.3,25.3, 23.8, 13.0, 12.9; HRMS (ESI-TOF+) m/z: calcd for C20H27NO7 + [(M + H)+],393.1788; found, 393.1790.
2,3-Diethyl 5-methyl 4-oxo-1-phenyl-1,4-dihydropyridine-2,3,5- tricarboxylate (4n)：Pale yellow oil; yield 87%; 1H NMR (400 MHz, CDCl3) δ7.50–7.44 (m, 3H, Ph-H), 7.28–7.22 (m, 2H, Ph-H), 6.82 (s, 1H, CH), 4.25 (q,J = 7.2 Hz, 2H, OCH2), 3.97–3.91 (m, 2H, OCH2), 3.91 (d, J = 2.8 Hz, 3H,OCH3), 1.28 (t, J = 7.2 Hz, 3H, CH3), 0.94 (t, J = 7.2 Hz, 3H, CH3); 13C NMR(100 MHz, CDCl3) δ 164.8, 162.1, 159.8, 159.7, 144.7, 142.4, 135.3, 128.9,128.3, 127.4, 120.2, 105.8, 61.7, 61.2, 52.1, 12.8, 12.3; HRMS (ESI-TOF+) m/ z: calcd for C19H20NO7 + [(M + H)+], 374.1234; found, 374.1231.
5-Ethyl 2,3-dimethyl 4-oxo-1-phenyl-1,4-dihydropyridine-2,3,5- tricarboxylate (4o)：Pale yellow oil; yield 91%; 1H NMR (400 MHz, CDCl3) δ7.49–7.39 (m, 3H, Ph-H), 7.24–7.16 (m, 2H, Ph-H), 6.86–6.74 (m, 1H, CH), 4.33(q, J = 7.1 Hz, 2H, OCH2), 3.75 (s, 3H, OCH3), 3.44 (s, 3H, OCH3), 1.32 (t, J= 7.2 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 165.2, 163.7, 161.3, 160.6,145.5, 143.5, 136.3, 129.9, 129.4, 128.1, 121.4, 106.8, 62.5, 53.1, 52.8,14.0; HRMS (ESI-TOF+) m/z: calcd for C18H18NO7 + [(M + H)+], 360.1078; found,360.1075.
Trimethyl 4-oxo-1-phenyl-1,4-dihydropyridine-2,3,5-tricarboxylate (4p)：Pale yellow oil; yield 96%; 1H NMR (400 MHz, CDCl3) δ 7.52–7.45 (m, 3H,Ph-H),7.25–7.23 (m, 2H, Ph-H), 6.83 (s, 1H, CH), 3.91 (s, 3H, CH3), 3.80 (s,3H, CH3), 3.48 (s, 3H, CH3).13C NMR (100 MHz, CDCl3) δ 164.7, 162.6, 160.3,159.6, 144.6, 142.2, 135.3, 129.0, 128.4, 127.1, 120.5, 105.7, 52.2, 52.1,51.9; HRMS (ESI-TOF+) m/z: calcd for C17H15NO7 + [(M + H)+], 345.0849; found,345.0846.
实施例2
该制备方法包括以下步骤：
以乙腈为系统溶剂、苯胺、乙氧基甲叉丙二酸二乙酯和乙炔二羧酸二乙酯为原料，DABCO为催化剂。将原料苯胺、乙氧基甲叉丙二酸二乙酯和乙炔二羧酸二乙酯各自用乙腈稀释至1.0mol/L后分别置于A、B和C两试管中，将DABCO按10%的当量置于C试管中。在蠕动泵的推动下试管A、B中的苯胺和乙氧基甲叉丙二酸二乙酯连续通入反应线圈1中进行反应，控制温度为50℃，反应液在反应通道1内连续流动的反应时间为25min，精确控制反应时间使其苯胺和乙氧基甲叉丙二酸二乙酯反应产物在流出反应通道1后不进入收集装置而直接进入下一反应线圈，将C试管中的乙炔二羧酸二乙酯和催化剂DABCO泵入，使其苯胺和乙氧基甲叉丙二酸二乙酯反应产物和C试管中的乙炔二羧酸二乙酯和催化剂DABCO在反应线圈2中经行反应，控制温度为55℃，反应液在反应通道2内连续流动的反应时间为30min，通过产物收集器在线收集流出反应液，经后处理，得到产物4-吡啶酮产物。
实施例中吸电子基胺类化合物变化制备得到4-吡啶酮类化合物的得率情况如下：
上述化合物数据如下：
Triethyl 1-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-2,3,5- tricarboxylate (5a)：Yellow oil; yield 83%; 1H NMR (400 MHz, CDCl3) δ 7.26–7.19(m, 2H, Ph-H), 7.14 (t, J = 8.5 Hz, 2H, Ph-H), 6.79 (d, J = 2.5 Hz, 1H, CH),4.34 (q, J = 7.1 Hz, 2H, OCH2), 4.24 (q, J = 7.1 Hz, 2H, OCH2), 3.96 (q, J =7.2 Hz, 2H, OCH2), 1.34 (t, J = 7.2 Hz, 3H, CH3), 1.26 (t, J = 7.2 Hz, 3H,CH3), 0.98 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 165.2, 164.4,163.2, 161.9, 160.8, 145.6, 143.8, 132.3, 130.5, 121.3, 116.6, 116.4, 107.3,62.9, 62.5, 62.3, 14.1, 13.9, 13.5; 19F NMR (311 MHz, CDCl3) δ -110.1 (s, 1F);HRMS (ESI-TOF+) m/z: calcd for C20H21FNO7 + [(M + H)+], 406.1297; found,406.1295.
Triethyl 1-(4-chlorophenyl)-4-oxo-1,4-dihydropyridine-2,3,5- tricarboxylate (5b)：Pale yellow oil; yield 85%; 1H NMR (400 MHz, CDCl3) δ 7.45(d, J = 8.5 Hz, 2H, Ph-H), 7.20 (d, J = 8.5 Hz, 2H, Ph-H), 6.83 (s, 1H, CH),4.36 (q, J = 7.1 Hz, 2H, OCH2), 4.26 (q, J = 7.2 Hz, 2H, OCH2), 3.99 (q, J =7.1 Hz, 2H, OCH2), 1.36 (t, J = 7.2 Hz, 3H, CH3), 1.29 (d, J = 7.1 Hz, 3H,CH3), 1.01 (t, J = 7.1 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 164.1, 162.1,159.7, 159.6, 144.2, 142.7, 135.1, 133.8, 128.8, 128.6, 120.3, 106.4, 61.9,61.4, 61.2, 13.0, 12.8, 12.4; HRMS (ESI-TOF+) m/z: calcd for C20H21ClNO7 + [(M +H)+], 422.1001; found, 422.1005.
Triethyl 1-(4-bromophenyl)-4-oxo-1,4-dihydropyridine-2,3,5- tricarboxylate (5c)：Yellow oil; yield 84%;1H NMR (400 MHz, CDCl3) δ 7.61 (d, J= 8.7 Hz, 2H, Ph-H), 7.13 (d, J = 8.7 Hz, 2H, Ph-H), 6.83 (s, 1H, CH), 4.36(q, J = 7.1 Hz, 2H, OCH2), 4.26 (d, J = 7.2 Hz, 2H, OCH2), 3.99 (q, J = 7.2Hz, 2H, OCH2), 1.37 (t, J = 7.2 Hz, 3H, CH3), 1.28 (s, 3H, CH3), 1.01 (t, J =7.2 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 165.3, 163.4, 161.0, 160.8,145.3, 144.0, 135.6, 132.9, 130.3, 124.5, 121.6, 107.8, 63.2, 62.7, 62.5,14.3, 14.1, 13.7; HRMS (ESI-TOF+) m/z: calcd for C20H21BrNO7 + [(M + H)+],466.0496; found, 466.0493.
Triethyl 1-(4-iodophenyl)-4-oxo-1,4-dihydropyridine-2,3,5- tricarboxylate (5d)：Yellow oil; yield 87%; 1H NMR (400 MHz, CDCl3) δ 7.82 (d,J = 8.7 Hz, 2H, Ph-H), 7.00 (d, J = 8.7 Hz, 2H, Ph-H), 6.83 (s, 1H, CH), 4.37(q, J = 7.2 Hz, 2H, OCH2), 4.29–4.24 (m, 2H, OCH2), 4.00 (q, J = 7.2 Hz, 2H),OCH2, 1.37 (t, J = 7.2 Hz, 3H, CH3), 1.29 (t, J = 7.2 Hz, 3H, CH3), 1.01 (t, J= 7.2 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 165.3, 163.3, 160.9, 160.7,145.2, 143.9, 138.8, 136.3, 130.4, 121.6, 107.7, 96.1, 63.2, 62.7, 62.4,14.2, 14.0, 13.6; HRMS (ESI-TOF+) m/z: calcd for C20H21INO7 + [(M + H)+],514.0357; found, 514.0360.
Triethyl 4-oxo-1-(4-(trifluoromethyl)phenyl)-1,4-dihydropyridine-2,3, 5-tricarboxylate (5e)：Yellow oil; yield 82%; 1H NMR (400 MHz, CDCl3) δ 7.75(d, J = 8.3 Hz, 2H, Ph-H), 7.40 (d, J = 8.2 Hz, 2H, Ph-H), 6.85 (s, 1H, CH),4.37 (q, J = 7.2 Hz, 2H, OCH2), 4.26 (q, J = 7.2 Hz, 2H, OCH2), 3.96 (q, J =7.2 Hz, 2H, OCH2), 1.36 (t, J = 7.2 Hz, 3H, CH3), 1.28 (t, J = 7.2 Hz, 3H,CH3), 0.94 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 165.1, 163.3,160.8, 160.5, 144.8, 143.9, 139.7, 129.3, 126.7, 126.6, 121.7, 108.1, 63.2,62.7, 62.5, 14.1, 14.0, 13.4;19F NMR (311 MHz, CDCl3) δ -62.9 (s, 3F); HRMS(ESI-TOF+) m/z: calcd for C21H21F3NO7 + [(M + H)+], 456.1265; found, 456.1267.
Triethyl 1-(4-nitrophenyl)-4-oxo-1,4-dihydropyridine-2,3,5- tricarboxylate (5f)：Yellow oil; yield 87%; 1H NMR (400 MHz, CDCl3) δ 8.35 (d,J = 8.6 Hz, 2H, Ph-H), 7.48 (d, J = 8.8 Hz, 2H, Ph-H), 6.88 (s, 1H, CH), 4.38(q, J = 7.1 Hz, 2H, OCH2), 4.28 (q, J = 7.1 Hz, 2H, OCH2), 3.99 (q, J = 7.1Hz, 2H, OCH2), 1.38 (t, J = 7.1 Hz, 3H, CH3), 1.30 (s, 3H, CH3), 1.02 (t, J =7.1 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 163.7, 162.0, 159.5, 159.2,147.4, 143.0, 142.8, 140.8, 128.8, 123.6, 120.7, 107.4, 62.2, 61.6, 61.4,13.0, 12.8, 12.4; HRMS (ESI-TOF+) m/z: calcd for C20H21N2O9 + [(M + H)+],433.1242; found, 433.1240.
Triethyl 1-(2-chlorophenyl)-4-oxo-1,4-dihydropyridine-2,3,5- tricarboxylate (5g)：Yellow oil; yield 80%; 1H NMR (400 MHz, CDCl3) δ 7.53 (dd,J = 8.0, 1.4 Hz, 1H, Ph-H), 7.44–7.40 (m, 1H, Ph-H), 7.39–7.34 (m, 1H, Ph-H),7.28 (dd, J = 7.8, 1.6 Hz, 1H, Ph-H), 6.84 (s, 1H, CH), 4.36 (q, J = 7.2 Hz,2H, OCH2), 4.28–4.22 (m, 2H, OCH2), 3.98–3.92 (m, 2H, OCH2), 1.36 (t, J = 7.2Hz, 3H, CH3), 1.27 (t, J = 7.2 Hz, 3H, CH3), 0.96 (t, J = 7.2 Hz, 3H, CH3); 13CNMR (100 MHz, CDCl3) δ 165.3, 163.2, 160.7, 159.9, 145.3, 144.1, 134.5,133.6, 131.5, 130.5, 130.3, 127.8, 121.5, 107.6, 62.9, 62.6, 62.4, 14.1,14.0, 13.5; HRMS (ESI-TOF+) m/z: calcd for C20H21ClNO7 + [(M + H)+], 422.1001;found, 422.1002.
Triethyl 1-(3-chlorophenyl)-4-oxo-1,4-dihydropyridine-2,3,5- tricarboxylate (5h)：Pale yellow oil; yield 93%; 1H NMR (400 MHz, CDCl3) δ7.43–7.32 (m, 2H, Ph-H), 7.22 (t, J = 1.8 Hz, 1H, Ph-H), 7.14–7.08 (m, 1H,Ph-H), 6.77 (s, 1H, CH), 4.30 (q, J = 7.2 Hz, 2H, OCH2), 4.20 (q, J = 7.1 Hz,2H, OCH2), 3.97–3.90 (m, 2H, OCH2), 1.30 (t, J = 7.2 Hz, 3H, CH3), 1.22 (t, J= 7.2 Hz, 3H, CH3), 0.94 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ165.2, 163.2, 160.8, 160.6, 145.2, 143.9, 137.5, 135.1, 130.5, 130.4, 129.0,127.0, 121.6, 107.7, 63.1, 62.6, 62.4, 14.1, 14.0, 13.5; HRMS (ESI-TOF+) m/z:calcd for C20H21ClNO7 + [(M + H)+], 422.1001; found, 422.1003.
Triethyl 4-oxo-1-(2-(trifluoromethyl)phenyl)-1,4-dihydropyridine-2,3, 5-tricarboxylate (5i)：Yellow oil; yield 80%; 1H NMR (400 MHz, CDCl3) δ 7.80(dd, J = 7.5, 1.5 Hz, 1H, Ph-H), 7.71–7.59 (m, 2H, Ph-H), 7.31 (d, J = 7.3Hz, 1H, Ph-H), 6.86 (s, 1H, CH), 4.37 (q, J = 7.2 Hz, 2H, OCH2), 4.26 (q, J =7.1 Hz, 2H, OCH2), 3.94 (q, J = 7.1 Hz, 2H, OCH2), 1.38 (t, J = 7.2 Hz, 3H,CH3), 1.29 (t, J = 7.2 Hz, 3H, CH3), 0.95 (t, J = 7.2 Hz, 3H, CH3); 13C NMR(100 MHz, CDCl3) δ 165.2, 163.4, 160.8, 160.7, 144.8, 143.9, 133.1, 131.2,130.8, 128.2, 128.2, 121.7, 108.3, 63.0, 62.7, 62.4, 14.2, 14.0, 13.5; 19F NMR(311 MHz, CDCl3) δ -60.3 (s, 3F); HRMS (ESI-TOF+) m/z: calcd for C21H21F3NO7 +[(M + H)+], 456.1265; found, 456.1266.
Triethyl 1-(3-nitrophenyl)-4-oxo-1,4-dihydropyridine-2,3,5- tricarboxylate (5j)：Drak yellow oil; yield 85%; 1H NMR (400 MHz, CDCl3) δ8.40–8.30 (m, 1H, Ph-H), 8.18 (t, J = 2.0 Hz, 1H, Ph-H), 7.70 (t, J = 8.1 Hz,1H, Ph-H), 7.66–7.61 (m, 1H, Ph-H), 6.87 (d, J = 0.7 Hz, 1H, CH), 4.38 (q, J= 7.1 Hz, 2H, OCH2), 4.27 (q, J = 7.1 Hz, 2H, OCH2), 3.99 (q, J = 7.1 Hz, 2H,OCH2), 1.38 (t, J = 7.1 Hz, 3H, CH3), 1.30 (d, J = 7.1 Hz, 3H, CH3), 1.00 (t,J = 7.2 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 163.8, 162.0, 159.6, 159.3,147.5, 143.4, 142.9, 136.4, 133.8, 129.3, 123.8, 122.9, 120.6, 107.2, 62.2,61.6, 61.4, 13.0, 12.8, 12.4; HRMS (ESI-TOF+) m/z: calcd for C20H21N2O9 + [(M +H)+], 433.1242; found, 433.1244.
Triethyl 1-(3,4-difluorophenyl)-4-oxo-1,4-dihydropyridine-2,3,5- tricarboxylate (5k)：Yellow oil; yield 87%; 1H NMR (400 MHz, CDCl3) δ 7.27 (q,J = 9.1 Hz, 1H, Ph-H), 7.20–7.09 (m, 1H, Ph-H), 7.04–7.01 (m, 1H, Ph-H), 6.82(s, 1H, CH), 4.36 (q, J = 7.2 Hz, 2H, OCH2), 4.26 (q, J = 7.1 Hz, 2H, OCH2),4.03 (q, J = 7.2 Hz, 2H, OCH2), 1.36 (t, J = 7.2 Hz, 3H, CH3), 1.28 (t, J =7.2 Hz, 3H, CH3), 1.05 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ165.1, 163.2, 160.8, 160.6, 145.1, 144.0, 125.4, 125.3,125.3, 121.6, 118.8,118.7, 118.6, 118.1, 118.1, 118.0, 118.0, 107.8, 63.2, 62.7, 62.5, 14.2,14.0, 13.6; 19F NMR (311 MHz, CDCl3) δ -133.91 (s, 1F), -133.91 (s, 1F); HRMS(ESI-TOF+) m/z: calcd for C20H20F2NO7 + [(M + H)+], 424.1202; found, 424.1205。
- 上一篇：一种医用注射器针头装配设备
- 下一篇：一种2-氨基吡啶-3-甲酸的制备方法