不对称Hantzsch 1,4-二氢吡啶类化合物的合成研究
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摘要
1,4-二氢吡啶(1,4-dihydropyridines, 1,4-DHPs)是一类重要的含氮杂环化合物,大多具有生理活性,在药物合成与应用等领域得到广泛研究。二氢吡啶类钙离子(Ca~(2+))拮抗剂是近30年来临床应用最广泛的一类治疗心脑血管疾病的药物。硝苯地平(Nifedipine)作为第一代二氢吡啶类钙离子(Ca~(2+))拮抗剂主要作为冠脉舒张药。第二代二氢吡啶类钙离子(Ca~(2+))拮抗剂尼莫地平(Nimodipine)、尼群地平(Nitrendipine)、尼卡地平(Nicardipine)、尼索地平(Nisoldipine)、非洛地平(Felodipine)、伊拉地平(Isradipine)和第三代二氢吡啶类钙离子(Ca~(2+))拮抗剂拉西地平(Lecidipine)、马尼地平(Manidipine)、氨氯地平(Amlodipine)、西尼地平(Cilnidipine)也相继被广泛应用于心脑血管疾病。二氢吡啶类钙离子(Ca~(2+))拮抗剂具有调节钙离子通道及降血压等作用,同时还具有抗病毒、抗菌和消炎的作用。此类化合物及其衍生物在抗癌等领域也具有广阔的前景。
除硝苯地平外,这一类药物分子中大多具有一个或多个手性中心。目前此类化合物一般都以外消旋体的形式应用。
Hantzsch 1,4-二氢吡啶合成法广泛应用于1,4-二氢吡啶类化合物的合成,但该方法反应时间较长、产率较低。关于Hantzsch 1,4-二氢吡啶类化合物合成方法的改良已有很多报道,但是仍存在着溶剂毒性较高、催化剂昂贵、合成步骤繁琐等缺点,不符合绿色化学的要求。
本工作旨在进行不对称取代的1,4-二氢吡啶类化合物的合成研究。
1.在无溶剂、无催化、微波照射条件下,以芳香醛、乙酰乙酸甲(乙、丁)酯、苯甲酰乙酸乙酯、乙酸铵为原料,通过改良的Hantzsch反应,一锅法两步合成了不对称取代的1,4-二氢吡啶类化合物50个,其中45个新化合物。
2.从反应温度、微波功率、溶剂、催化剂、投料比、反应时间等方面优化了反应条件。
3.目标化合物已经核磁共振氢谱(1H NMR)、核磁共振碳谱(13C NMR)、红外光谱(IR)、质谱(MS)和元素分析(EA)等表征,其中两个化合物的结构通过单晶X-射线衍射分析得以确证。
本工作较系统地研究了三个系列不对称取代的1,4-二氢吡啶类化合物的合成方法。我们在无溶剂、无催化、微波照射的条件下,通过改良的Hantzsch合成法,实现了一锅法两步合成不对称取代的1,4-二氢吡啶类化合物。我们通过对反应原料的选择、合成路线的设计、反应条件的优化以及对目标产物的结构表征系统地证明了该方法的有效性。此外,该方法具有反应环境友好、条件温和、操作简便、产率高、经济、无毒、无污染、省时高效等优点。
我们希望这种以绿色、环境友好的方式合成不对称取代的1,4-二氢吡啶类化合物,以此够完善Hantzsch合成法在二氢吡啶类化合物合成中的应用,为建立此类化合物库并筛选新的药物提供理论基础。
1,4-Dihydropyridines (1,4-DHPs) are a kind of important nitrogen-containing heterocyclic compounds, mostly with physiological activities, which also have a wide range of applications in biology and medicine. In recent 30 years, DHPs calcium channel blockers have found broad clinical applications in the treatment of cardiovascular diseases. Nifedipine, the first generation of DHPs calcium channel blocker, is primarily used as coronary diastolic medicine. The second generation of DHPs calcium channel blockers such as Nimodipine, Nitrendipine, Nisoldipine, Nicardipine, Isradipine and the third generation of DHPs calcium channel blockers, for example, Amlodipine Lacidipine, Manidipine, Cilnidipine are also used constantly as cardiovascular drugs. Most of them can regulate calcium ion channels and lower blood pressure. Moreover, they have the functions of antivirus, antibacterial and antiphlogistic. Noteworthly, such compounds and the derivatives also have broad prospects in the field of anti-cancer.
Except for nifedipine, most of this kind of the drugs have one or more chiral center. At present, these compounds are commonly used in the form of racemic modification.
The best known procedure for the preparation of 1,4-DHPs is the classical Hantzsch reaction. However, this method involves a long reaction time and unsatisfactory yields. A number of improved procedures have been reported, but many of them suffer from drawbacks such as hazardous organic solvents, expensive catalysts and tedious work-up. These are also not acceptable in the context of green synthesis.
The present thesis is aimed at the synthesis of unsymmetrically substituted Hantzsch 1,4-dihydropyridines.
1. Under microwave irradiation and solvent- and catalyst-free conditions, 50 of unsymmetrically substituted 1,4-dihydropyridines have been synthesized via one-pot two-step modified Hantzsch condensation reaction of acromatic aldehydes, acetoacetate, ethyl benzoylacetate and ammonium acetate, of which 45 of the compounds have not been reported in the literature.
2. We have optimized the reaction conditions from reaction temperature, microwave power, solvents, catalysts, reactant ratio and reaction time.
3. The structures of the compounds prepared have been characterized by the 1H NMR, IR, 13C NMR, MS spectra and elemental analysis. Two crystals structures of the compounds have been achieved by single crystal X-ray crystallographic analysis. The molecular structures have been confirmed unambiguously and have not been reported in the literature.
In the thesis, one-pot two-step synthesis of unsymmetrically substituted Hantzsch 1,4-dihydropyridines which promoted by microwave irradiation under solvent- and catalyst-free conditions have been performed and studied comprehensively. It is the correct target products that proved the feasibility and availability of this method. Furthermore, these protocols have the advantages of environmentally benign, economy, short reaction time, high yields, and simple work-up procedure, which are acceptable in the context of green synthesis.
The present thesis improved and modified the Hantzsch synthesis of the unsymmetrically substituted 1,4-dihydropyridines, which enriched the reserch of these kind of 1,4-dihydropyridines and promoted the further studies of medicinal applications of the unsymmetrically substituted 1,4-dihydropyridine compounds.
除硝苯地平外,这一类药物分子中大多具有一个或多个手性中心。目前此类化合物一般都以外消旋体的形式应用。
Hantzsch 1,4-二氢吡啶合成法广泛应用于1,4-二氢吡啶类化合物的合成,但该方法反应时间较长、产率较低。关于Hantzsch 1,4-二氢吡啶类化合物合成方法的改良已有很多报道,但是仍存在着溶剂毒性较高、催化剂昂贵、合成步骤繁琐等缺点,不符合绿色化学的要求。
本工作旨在进行不对称取代的1,4-二氢吡啶类化合物的合成研究。
1.在无溶剂、无催化、微波照射条件下,以芳香醛、乙酰乙酸甲(乙、丁)酯、苯甲酰乙酸乙酯、乙酸铵为原料,通过改良的Hantzsch反应,一锅法两步合成了不对称取代的1,4-二氢吡啶类化合物50个,其中45个新化合物。
2.从反应温度、微波功率、溶剂、催化剂、投料比、反应时间等方面优化了反应条件。
3.目标化合物已经核磁共振氢谱(1H NMR)、核磁共振碳谱(13C NMR)、红外光谱(IR)、质谱(MS)和元素分析(EA)等表征,其中两个化合物的结构通过单晶X-射线衍射分析得以确证。
本工作较系统地研究了三个系列不对称取代的1,4-二氢吡啶类化合物的合成方法。我们在无溶剂、无催化、微波照射的条件下,通过改良的Hantzsch合成法,实现了一锅法两步合成不对称取代的1,4-二氢吡啶类化合物。我们通过对反应原料的选择、合成路线的设计、反应条件的优化以及对目标产物的结构表征系统地证明了该方法的有效性。此外,该方法具有反应环境友好、条件温和、操作简便、产率高、经济、无毒、无污染、省时高效等优点。
我们希望这种以绿色、环境友好的方式合成不对称取代的1,4-二氢吡啶类化合物,以此够完善Hantzsch合成法在二氢吡啶类化合物合成中的应用,为建立此类化合物库并筛选新的药物提供理论基础。
1,4-Dihydropyridines (1,4-DHPs) are a kind of important nitrogen-containing heterocyclic compounds, mostly with physiological activities, which also have a wide range of applications in biology and medicine. In recent 30 years, DHPs calcium channel blockers have found broad clinical applications in the treatment of cardiovascular diseases. Nifedipine, the first generation of DHPs calcium channel blocker, is primarily used as coronary diastolic medicine. The second generation of DHPs calcium channel blockers such as Nimodipine, Nitrendipine, Nisoldipine, Nicardipine, Isradipine and the third generation of DHPs calcium channel blockers, for example, Amlodipine Lacidipine, Manidipine, Cilnidipine are also used constantly as cardiovascular drugs. Most of them can regulate calcium ion channels and lower blood pressure. Moreover, they have the functions of antivirus, antibacterial and antiphlogistic. Noteworthly, such compounds and the derivatives also have broad prospects in the field of anti-cancer.
Except for nifedipine, most of this kind of the drugs have one or more chiral center. At present, these compounds are commonly used in the form of racemic modification.
The best known procedure for the preparation of 1,4-DHPs is the classical Hantzsch reaction. However, this method involves a long reaction time and unsatisfactory yields. A number of improved procedures have been reported, but many of them suffer from drawbacks such as hazardous organic solvents, expensive catalysts and tedious work-up. These are also not acceptable in the context of green synthesis.
The present thesis is aimed at the synthesis of unsymmetrically substituted Hantzsch 1,4-dihydropyridines.
1. Under microwave irradiation and solvent- and catalyst-free conditions, 50 of unsymmetrically substituted 1,4-dihydropyridines have been synthesized via one-pot two-step modified Hantzsch condensation reaction of acromatic aldehydes, acetoacetate, ethyl benzoylacetate and ammonium acetate, of which 45 of the compounds have not been reported in the literature.
2. We have optimized the reaction conditions from reaction temperature, microwave power, solvents, catalysts, reactant ratio and reaction time.
3. The structures of the compounds prepared have been characterized by the 1H NMR, IR, 13C NMR, MS spectra and elemental analysis. Two crystals structures of the compounds have been achieved by single crystal X-ray crystallographic analysis. The molecular structures have been confirmed unambiguously and have not been reported in the literature.
In the thesis, one-pot two-step synthesis of unsymmetrically substituted Hantzsch 1,4-dihydropyridines which promoted by microwave irradiation under solvent- and catalyst-free conditions have been performed and studied comprehensively. It is the correct target products that proved the feasibility and availability of this method. Furthermore, these protocols have the advantages of environmentally benign, economy, short reaction time, high yields, and simple work-up procedure, which are acceptable in the context of green synthesis.
The present thesis improved and modified the Hantzsch synthesis of the unsymmetrically substituted 1,4-dihydropyridines, which enriched the reserch of these kind of 1,4-dihydropyridines and promoted the further studies of medicinal applications of the unsymmetrically substituted 1,4-dihydropyridine compounds.
引文
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[1] Vater, W.; Kroneberg, G.; Hoffmeister, F.; Kaller, H. Zur pharmakologie van 4-(2-nitrophe- nyl)-2-6-dimethyl 1, 4-dihydropyridine-3, 5-dicarbonsaure-dimethyl ester. Arzneim-Forsch 1972, 22, 1-14.
[2] Kondo, S.; Kuchiki, A.; Tamamoto, K.; Akimoto,K. Identification of nifedipine metabolites and their determination by gas chromatography. Chem. Pharm. Bull. 1980, 28, 1-7.
[3] K. Stoepel, A. Heise, S. Kazda, Armeim. Production. of 1,4-dihydropyridine derivatives used for treating hypertension. Arzneim-Forsch 1981, 31, 2056-2064.
[4] Nyborg, N. C. B.; Mulvany, M. J. Effect of felodipine, a new dihydropyridine vasodilator, on contractile responses to potassium, noradrenaline, and calcium in mesenteric resistance vessels of the rat. J. Cardiovasc. Pharmacol. 1984, 6, 499-505.
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[11] Alexandre, F, R.; Berecibar, A.;Wriggles, R. Efficient synthesis of thiazoloquinazolinone derivatives. Tetrahedron Lett. 2003, 44, 4455-4458.
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