新型1,4-二氢吡啶基尾式卟啉的合成及其抗菌活性研究

以乙酰乙酸乙酯、4-羟基苯甲醛、碳酸氢铵和二溴烷烃为原料,经两步反应合成溴烷氧基1,4-二氢吡啶;再将其与5-对羟基苯基-10,15,20-三苯基卟啉缩合,得到了12种新型的卟啉-二氢吡啶及其金属锌配合物,结构通过NMR,IR和HRMS进行详细表征.研究中测试了这些复杂的卟啉-二氢吡啶化合物对金黄色葡萄球菌(Staphylococcus aureus,ATCC 25923)和大肠杆菌(Escherichia coli,ATCC 25922)的抑菌活性,实验结果显示这12种化合物都有很好的抑菌活性,其中对金黄色葡萄球菌抑菌效果较好,且卟啉-二氢吡啶二元化合物的抑菌效果优于两种单体.     

3-氰基-1,4-二氢吡啶衍生物的合成

1,4-二氢吡啶类化合物具有多种生物活性,在临床上受到广泛应用,普遍用于各类心脑血管疾病的治疗。以3-氰基吡啶和含不同取代基的溴化苄为原料在加热回流15h的条件下合成中间体盐;以硼氢化钾(KBH₄)作为还原剂,在冰水浴搅拌的情况下,与中间体盐反应,合成了15个结构新颖的1,4-二氢吡啶衍生物(a～o),产率可达85%～90%,其结构经¹H NMR、¹³C NMR和质谱进行表征。该方法具有成本低、环境友好、操作简单、产率高的特点。     

含有薁类结构的1,4-二氢吡啶衍生物的合成

在对甲基苯磺酸作用下,以1-甲酰基奠-3-甲酸甲酯、乙酰乙酸酯、醋酸铵或3-氨基巴豆酸酯为原料,进行三组分一锅法缩合,以较优的收率制备了含有薁类结构的新的1,4-二氢吡啶类衍生物,该反应收率良好、操作简单、条件温和.产物的结构经1H NMR,IR及元素分析等得以证实.     

联萘酚多氢键硫脲催化合成1,4-二氢吡啶衍生物

本文合成了三种具有多氢键的联萘酚轴手性硫脲催化剂,并将其用于催化合成1,4-二氢吡啶衍生物。结果显示,所合成的新型多氢键硫脲均表现出较好的催化作用,能有效地提高1,4-二氢吡啶衍生物的收率和对映选择性。所有新化合物结构均经过¹H NMR、¹³C NMR、IR、熔点等表征所确认。     

吡咯烷类有机小分子催化合成 1,4-二氢吡啶衍生物

对以芳香醛、乙酰丙酮及碳酸氢铵为原料,苯甲酰胺吡咯烷为催化剂,合成1,4-二氢吡啶的反应进行了研究。考察了催化剂、溶剂、温度、时间和氮源对产率的影响。结果表明,反应温度70℃,芳香醛、乙酰丙酮和碳酸氢铵的摩尔比0.5∶1∶0.5,催化剂Ⅳ的用量10(mol)%时,产率最高,可达93%。催化剂循环使用3次,产率基本不变。该反应具有催化剂经济易得、反应条件温和、环境友好和操作简单等优点。     

无溶剂一锅法合成1,4-二氢吡啶

碳酸氢铵、醛和1, 3-二羰基化合物于70 ℃无溶剂条件下缩合以86～97%的产率得到1, 4-二氢吡啶.     

微波辐射下4-胡椒基-2,6-二甲基-3,5-乙氧羰基-1,4-二氢吡啶的合成、芳构化及产物的晶体结构

用胡椒醛、乙酰乙酸乙酯和醋酸铵在微波辐射下干反应得4-胡椒基-2,6-二甲基-3,5-乙氧羰基-1,4-二氢吡啶 1(C20H23NO6),4-胡椒基-2,6-二甲基-3,5-乙氧羰基-1,4-二氢吡啶在NDC (烟酸三氧化铬) 存在下经微波辐射得到4-胡椒基-2,6-二甲基-3,5-乙氧羰基吡啶 2 (C20H21NO6)。产物的结构通过单晶X-射线衍射法确定, 1 属单斜晶系, 空间群P21/c, a = 14.864(3), b = 9.830(1), c = 14.517(3)? b = 115.25(1), V = 1918.6(6)?, Z = 4, Mr = 373.39, Dc = 1.293g/cm3, m(MoKa)=0.096mm-1, F(000)=792。最终的偏离因子为R = 0.0496, wR = 0.1368。2 属三斜晶系,空间群Pī, a = 8.915(1), b = 10.575(1), c = 11.904(1)?α = 102.19(1),b = 109.43(1),γ=108.94(1), V=934.79(16) 3, Z = 2, Mr = 371.38, Dc = 1.319g/cm3 , m(MoKa) = 0.098mm-1, F(000) = 392。最终的偏离因子为R=0.0412, wR=0.1011。1 的二氢吡啶环为信封式结构, 2的吡啶环为平面结构。     

水相条件下1,4-二氢吡啶衍生物的合成与芳构化

将醛、乙酰乙酸乙酯和醋酸铵的多组分反应引入到水相回流条件下, 合成了一系列具有生物和药物活性的1,4-二氢吡啶化合物. 在此基础之上, 向反应体系中直接加入氧化剂MnO2, “一锅法”生成了芳构化的吡啶衍生物, 将原来Hantzsch酯的合成与芳构化在“一锅”里实现, 缩减了反应步骤, 提高了反应效率.     

1,4-二氢吡啶的微波合成新方法

研究了微波作用下1,4-二氢吡啶-3,5-二甲酸乙酯（3）的合成,结果表明,在微波的作用下,用简单易得的原料如（HCHO）n,HCHO／H2O,（CH2）6N4,NH4OAc,NH3／H2O,NH4HCO3,（NH4）2CO3等就可以得到3,收率在50％左右。微波可以很容易地由甲醛水溶液和氨水为反应物得到3,传统方法根本得不到。反应中只使用少量乙醇,而用甲醛水溶液的反应是无溶剂合成。     

1,4-二氢吡啶衍生物的合成及其与牛血清白蛋白的相互作用

以对甲苯磺酸为催化剂,一锅法合成了一系列1,4-二氢吡啶衍生物,并对其进行了红外光谱、质谱和核磁共振表征。采用荧光光谱法、紫外光谱法对2,6-二甲基-4-苯乙烯-1,4-二氢吡啶-3,5-二甲酸乙酯(1a)与BSA在不同温度的相互作用进行了研究。在298K时,Kq为2.43×10~(12)L·mol~(-1)·s~(-1),Ka为4.15×10~3L·mol~(-1),n为0.82,ΔS为65.12J·mol~(-1)·K~(-1),ΔH为-1.24k J·mol~(-1)。研究表明,1a对BSA具有荧光猝灭作用,且1a与BSA的主要作用力可能是疏水作用力(ΔS0)。     

Synthesis and Electrochemical Oxidation of Nitriles of 4-Aryl-2-carbamoylmethylthio-5-ethoxycarbonyl-1,4-dihydropyridine-3-carboxylic Acids

Nitriles of 4-aryl-2-carbamoylmethylthio-5-ethoxycarbonyl-6-hydroxy-1,4,5,6-tetrahydropyridine-3-carboxylic acids were obtained by the alkylation of 1,4,5,6-tetrahydropyridine-2-thiolate with iodoacetamide or by a three-component synthesis by condensing 2-arylmethylene-1,3-dicarbonyl compounds with 2-cyanothioacetamide in the presence of piperidine with subsequent reaction with iodoacetamide. Nitriles of 4-aryl-2-carbamoylmethylthio-5-ethoxycarbonyl-1,4-dihydropyridine-3-carboxylic acids were obtained by the dehydration of 6-hydroxy-1,4,5,6-tetrahydropyridines or with a one-reactor three-component system from 2-cyano-3-(4-methoxyphenyl)thioacrylamide, 1,3-dicarbonyl compounds, and iodoacetamide. The electrochemical oxidation of the synthesized nitriles was investigated and it was established that derivatives of 1,4,5,6-tetrahydropyridine as a rule are oxidized readily to the corresponding 1,4-dihydropyridines. A comparative analysis has been carried out of the ability of hydrogenated pyridines to be oxidized electrochemically depending on the electron-withdrawing properties of the substituents in the heterocycle.     

Synthesis of 7-Bromo/5,6-Dimethyl-4 H -1,4-Benzothiazines and Their Conversion into Sulfones

The synthesis of 7-bromo/5,6-dimethyl-4 H -1,4-benzothiazines and their conversion into sulfones is reported. The 7-bromo/5,6-dimethyl-4 H -1,4-benzothiazines were synthesized by the condensation and oxidative cyclization of 2-amino-5-bromo/3,4-dimethylbenzenethiol with g -diketones in dimethyl sulfoxide. The reaction is believed to proceed via an enaminoketone system. 4 H -1,4-Benzothiazine sulfones have been synthesized by the oxidation of 4 H -1,4-benzothiazines using 30% H 2 O 2 in glacial acetic acid. The structures of all newly synthesized compounds have been confirmed by elemental analysis and spectral studies.     

Synthesis and study of novel fulleropyrrolidines bearing biologically active 1,4-dihydropyridines

New fulleropyrrolidines endowed with chlorine-containing biological active 1,4-dihydropyridines (1,4-DHPs) have been synthesised from the respective formyl substituted 1,4-DHPs by following Prato's procedure. The presence of the chlorine atom on C2 of the 1,4-DHP ring brings about important spectroscopical and structural differences in compounds 10a-f related to the parent hydrogen-containing 11a. The mass spectroscopy study reveals different fragmentation patterns for fulleropyrrolidines 10a-f and their precursors 1,4-DHPs, as well as with 11a. Semiempirical calculations (AM1 and PM3) predict a most stable stereoisomer in all cases (RS for 10a-f) and the same RR for 11a. The presence of chlorine atom in 10a-f is responsible for the higher calculated conformational energy barriers in comparison with 11a. The geometry of the 1,4-DHP shows that the presence of fullerene unit does not significantly alter the required conformation for biological activity.     

Synthesis, Cardiovascular Activity, and Electrochemical Oxidation of Nitriles of 5-Ethoxycarbonyl-2-methylthio-1,4-dihydropyridine-3-carboxylic Acid

Nitriles of 4-aryl-5-ethoxycarbonyl-2-methylthio-1,4-dihydropyridine-3-carboxylic acid have been obtained by the methylation of 1,4-dihydropyridine-2-thiolates; of 1,4-dihydropyridine-2(3H)-thiones in the presence of a stoichiometric amount of piperidine, and of a mixture of 1,4,5,6-tetrahydro- and 1,4-dihydropyridine-2-thiolates with methyl iodide. One-pot multicomponent synthesis has also been used in the condensation of ethyl 2-arylmethyleneacetoacetate, 2-cyanothioacetamide, piperidine, and methyl iodide; of ethyl acetoacetate, 3-aryl-2-cyanothioacrylamide, piperidine, and methyl iodide; and of ethyl acetoacetate, an aromatic aldehyde, 2-cyanothioacetamide, piperidine, and methyl iodide. The latter, a five-component method, takes place rapidly and under mild conditions, it is efficient (yields of 75-96%, economy of time, labour, and resources) and green (there is no need to synthesize lachrymators, such as 3-aryl-2-cyanothioacrylamides).The cardiovascular activity and the electrochemical oxidation of the synthesized 2-methylthio-1,4-dihydropyridines have been investigated. A comparative analysis has been carried out of the ability towards electrochemical oxidation as a function of the electronic properties of the substituent at position 4 of the heterocycle.     

Candida Rugosa Lipase-catalyzed Kinetic Resolution of 3-(Isobutyryloxy)methyl 4-[2-(Difluoromethoxy)phenyl]-2-methyl-5,5-dioxo-1,4-dihydrobenzothieno[3,2-b]pyridine-3-carboxylate

The lipase-catalyzed kinetic resolution of 3-(isobutyryloxy)methyl 4-[2-(difluoromethoxy)phenyl]-2-methyl-5,5-dioxo-1,4-dihydrobenzothieno[3,2-b]pyridine-3-carboxylate has been performed. The most enantioselective reaction (E = 28) was transesterification with n-butanol in water-saturated toluene at 45°C.     

Oxidation-Reduction Conversions of Derivatives of 1,4-Dihydropyridine and 4H-pyran on Interaction of Alicyclic 1,5-Diketones wth 4-Aminoazobenzene

The interaction of 2,2'-methylenedicyclohexanone and 2,2'-methylenedicyclopentanone with 4-aminoazobenzene in acetic acid leads to reduction of the azo group of 1,4-dihydropyridine and 4H-pyran derivatives formed as intermediates. The reduction products were isolated as the corresponding pyridinium salts.     

Synthesis and Antiradical Activity of 5-Acetyl-2-alkylthio-4-aryl-6-methyl-1,4-dihydropyridine-3-carboxylic Acid Nitriles

The alkylation of 3-cyano-1,4-dihydropyridine-2(3H)-thiones or the condensation of an aromatic aldehyde, cyanothioacetamide, acetylacetone, and methyl iodide in the presence of piperidine has given a series of novel 5-acetyl-2-alkylthio-4-aryl-6-methyl-1,4-dihydropyridine-3-carboxylic acid nitriles. A compound was obtained from 3,5-di(tert-butyl)-4-hydroxybenzaldehyde in the molecule of which were combined the active part of the antioxidant ionol and a 1,4-dihydropyridine ring. It was found that, among the compounds synthesized, the highest antiradical activity occurred in a compound having two hydroxyl groups in the 4-phenyl substituent.     

A new protocol to synthesize 1,4-dihydropyridines by using 3,4,5-trifluorobenzeneboronic acid as a catalyst in ionic liquid: synthesis of novel 4-(3-carboxyl-1H-pyrazol-4-yl)-1,4-dihydropyridines

3,4,5-Trifluorobenzeneboronic acid catalysed, ionic liquid mediated facile synthesis of 4-pyrazolyl 1,4-dihydropyridines at room temperature by the cyclocondensation of ethyl 3-aminocrotonate, pyrazole aldehyde and a β-keto ester is reported. The procedure adopted was found to be eco-benign, facile at room temperature and better than the conventional, [bmim]Cl mediated and InCl₃ catalysed, [bmim]Cl mediated 1,4-dihydropyridine syntheses.     

Methods for the Synthesis of Heteroaryl-substituted 1,4-Benzo- and 1,4-Naphthoquinones. (Review)

Methods for the synthesis of heteroaryl-substituted 1,4-benzo- and 1,4-naphthoquinones with a C-C bond between the heterocycle and quinone fragments are reviewed. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 803–833, June, 2005.