新型3-芳甲基-5-芳氧甲基丁内酯的合成及其抑制肺癌细胞生长活性评价

通过2-芳氧甲基环氧烷与α-芳甲基丙二酸二乙酯在乙醇钠条件下反应, 合成了8个新型3-芳甲基-5-芳氧甲基丁内酯, 收率为13%～81%. 由IR, ¹H NMR和MS波谱数据进行了结构表征. 所得化合物均具有抑制A549肺癌细胞生长的活性, 其抑制效果具有浓度依赖性.     

(±)-6,7-丙酮缩二醇-3-酮-庚酸乙酯合成研究

用对甲苯磺酸-2,3-丙酮缩甘油酯(2)与乙酰乙酸乙酯盐、碳酸二乙酯反应, 制备β-酮酯类衍生物1. 以(±)-1,2-丙酮缩甘油为起始物, 经对甲苯磺酰化、亲核取代、脱羧等反应, 方便、高产率地合成了6,7-丙酮缩二醇-3-酮-庚酸乙酯(1). 试图通过对甲苯磺酸-2,3-丙酮缩甘油酯(2)和乙酰乙酸乙酯双阴离子反应制备6,7-丙酮缩二醇-3-酮-庚酸乙酯(1)未获成功. 所合成的化合物经元素分析, IR, ¹H NMR, ¹³C NMR和MS光谱表征.     

2-取代氨基-6-甲基-5-氧代-4-正丁基-4,5-二氢-1,2,4-三氮唑并[1,5-a]嘧啶类衍生物的合成

以2-溴丙酸甲酯、α,α-二氯甲基甲醚和胍唑为原料, 经缩合以及环化反应制得2-氨基-6-甲基-5-氧代-4,5-二氢-1,2,4-三氮唑并[1,5-a]嘧啶. 为了提高其在有机溶剂中的溶解性, 该化合物再同1-溴丁烷发生亲核取代反应得到了2-氨基-6-甲基-5-氧代-4-正丁基-4,5-二氢-1,2,4-三氮唑并[1,5-a]嘧啶, 然后与芳基醛和叔丁基异氰发生Ugi多组分反应, 合成了一系列具有潜在催吐活性的2-取代氨基-6-甲基-5-氧代-4-正丁基-4,5-二氢-1,2,4-三氮唑并[1,5-a]嘧啶类衍生物, 产品结构经质谱、核磁共振谱及元素分析确认.     

N-{4-{N-甲基-N-[2-羟基-3-(2,4-二氧代-1,2,3,4-四氢嘧啶-5-基)氨基]丙基}氨基-3-溴}苯甲酰基-L-谷氨酸二乙酯及其衍生物的合成

报道了N-{4-{N-甲基-N-[2-羟基-3-(2,4-二氧代-1,2,3,4-四氢嘧啶-5-基)氨基]丙基}氨基-3-溴}苯甲酰基-L-谷氨酸二乙酯及其衍生物的简便合成方法. 分别以4-氨基苯甲酸乙酯和4-氨基苯甲酰基-L-谷氨酸二乙酯为起始物, 经甲基化、烯丙基化、溴羟基化、环氧化、开环、脱保护等反应首次合成了6个新型5-取代氨基嘧啶类化合物, 并通过¹H NMR, ¹³C NMR 和MS对其化学结构进行了表征. 初步生物活性结果表明, 苯环侧链的L-谷氨酸酯部分是此类化合物抑制人重组二氢叶酸还原酶的必需结构.     

2-取代硫醚-5-(5,7-二甲基-1,2,4-三唑并[1,5-a]嘧啶基)-1,3,4-噁二唑/噻二唑类化合物的合成及生物活性

以5-氨基-1H-1,2,4-三唑-3-羧酸乙酯为起始原料, 设计合成了11个新型的2-取代硫醚-5-(5,7-二甲基-1,2,4-三唑并[1,5-a]嘧啶基)-1,3,4-噁二唑类化合物(5)和6个新型的2-取代硫醚-5-(5,7-二甲基-1,2,4-三唑并[1,5-a]嘧啶基)-1,3,4-噻二唑类化合物(8). 通过¹H NMR, MS和元素分析对所合成的化合物进行了结构表征. 初步的生物活性测试结果表明, 所合成的化合物均表现出不同程度的除草及杀菌活性, 其中化合物5k和8f的活性最好, 在50 mg/L浓度下对水稻纹枯病菌的抑制率达90%以上.     

无溶剂条件下合成顺/反3-芳基亚甲基-2,3-二氢-吲哚-2-酮类化合物

无溶剂条件下, 芳香醛与2-吲哚酮在碱性条件下通过研磨, 方便有效地合成了一系列3-芳基亚甲基-2,3-二氢- 吲哚-2-酮类化合物, 该反应条件温和, 时间短, 产率高, 对环境友好. 产物的结构得到¹H NMR, IR, HRMS的表征, 其中(Z)-3e和(Z)-3j的结构得到了X单晶衍射的进一步确证.     

2-甲硫基-7(5)-取代-3-吡唑并[1,5-a]嘧啶甲酸乙酯的区域选择性合成与2D NMR 研究

利用3-甲硫基-4-乙氧羰基-5-氨基-1H-吡唑分别与甲基/芳基烯胺酮反应, 合成了8种新的化合物2-甲硫基-7-取代-3-吡唑并[1,5-a]嘧啶甲酸乙酯(3a～3g)和2-甲硫基-5-甲基-3-吡唑并[1,5-a]嘧啶甲酸乙酯(4a). 化合物的结构均经元素分析, IR, ¹H NMR, MS所证实, 异构体3a和4a的结构进一步由¹³C NMR, HMQC和HMBC确认. 同时, 探讨了区域选择性合成吡唑并[1,5-a]嘧啶类化合物可能的反应机理, 并对部分化合物杀菌活性进行了测试.     

1,3-二(乙氧基甲基)-5-N,N-二甲氨基-6-甲基尿嘧啶的合成

报道了1,3-二(乙氧基甲基)-5-N,N-二甲氨基-6-甲基尿嘧啶方便、高产率的合成方法. 以6-甲基尿嘧啶(1)为起始物, 经硝化、嘧啶N¹,N ³-烷基化、还原及氨基甲基化, 首次高产率合成了1,3-二(乙氧基甲基)-5- N,N -二甲氨基-6-甲基尿嘧啶(5), 并对其化学结构进行了表征.     

N-(4,6-二取代嘧啶-2-基)-N'-[1-(杂芳基)甲基-5-甲基-1H-1,2,3-三唑基-4- 甲酰基]硫脲的合成与除草活性研究

采用2-氯-5-(氯甲基)吡啶和2-氯-5-(氯甲基)噻唑为原料, 经过叠氮化, 与乙酰乙酸乙酯环化, 水解, 酰氯化, 然后与异硫氰酸钾反应生成相应的异硫氰酸酯5, 最后与2-氨基-4,6-二取代嘧啶加成, 合成了10种未见文献报道的目标化合物, 其结构经IR, ¹H NMR, MS和元素分析确证, 初步的生物活性测定结果表明, 部分目标化合物在100 mg/L浓度下显示出良好的除草活性.     

α-(1,3,4-噻二唑-5-基)氨基烃基膦酸酯的合成及生物活性

以5-氨基-2-巯基的席夫碱与亚磷酸二乙酯反应, 合成了15个新的α-(1,3,4-噻二唑-5-基)氨基烃基膦酸酯, 初步的生物活性测试表明部分目标化合物具有较好的植物生长调节活性, 其中2,4-二氯苯甲醛、呋喃甲醛和吲哚甲醛的席夫碱生成的α-氨基烃基膦酸酯具有较好的生长素活性.     

Reduction and diazotization of ethyl 7-amino-3-<Emphasis Type="Italic">tert</Emphasis>-butyl-4-oxo-4,6-dihydropyrazolo[5,1-<Emphasis Type="Italic">c</Emphasis>][1,2,4]triazine-8-carboxylate

The ester group in ethyl 7-amino-3-tert-butyl-4-oxo-4,6-dihydropyrazolo[5,1-c][1,2,4]triazine-8-carboxylate was converted for the first time to methyl by the action of lithium tetrahydridoborate in the presence of boron trifluoride–diethyl ether complex. This reaction has almost no analogies among other classes of organic compounds. New difficultly accessible 7-chloro and 7-azido derivatives were synthesized via diazotization of the reduction product, and treatment of the latter with acetic anhydride afforded the exhaustively acetylated derivative. Diazotization of ethyl 7-amino-3-tert-butyl-4-oxo-4,6-dihydropyrazolo-[5,1-c][1,2,4]triazine-8-carboxylate, followed by reaction with sodium azide, gave the corresponding azide, and the product of azo coupling with ethyl acetoacetate failed to undergo intramolecular cyclization to tricyclic pyrazolo[3,2-c: 5,1-c′]bis[1,2,4]triazine system.     

新型N-(4,6-二取代嘧啶-2-基)-1-[取代吡啶(噻唑)甲基]-5-甲基-1H-1,2,3-三唑基-4-甲酰胺的合成与除草活性

为了寻找新型低毒性的潜在除草剂, 以2-氯-5-(氯甲基)吡啶和2-氯-5-(氯甲基)噻唑为起始原料, 经过叠氮化, 然后与乙酰乙酸乙酯的环化, 水解, 卤化, 最后与2-氨基-4,6-二取代嘧啶的缩合反应, 合成了9种未见文献报道的目标化合物, 其结构经IR, ¹H NMR, MS 和元素分析确证. 初步的生物活性测试结果表明, 所测目标化合物在100 mg/L浓度下显示出良好的除草活性.     

Synthesis and antioxidant assay of new nicotinonitrile analogues clubbed thiazole,pyrazole and/or pyridine ring systems

A series of novel nicotinonitrile derivatives were synthesized by hybridization with thiazole, pyrazole, and pyridine ring systems using 4-aminobenzohydrazide as link-bridge. The synthetic strategy of nicotinonitrile-thiazole analogues involves cyclization of the precursor N-phenyl thiosemicarbazide derivative 4 with chloroacetic acid and phenacyl bromide. The reaction of hydrazide 3 with acetylacetone and/or ethyl acetoacetate was applied as a synthetic route for accessing 2-((4-(pyrazole-1-carbonyl)phenyl)amino)-nicotinonitrile derivatives 9–10 . The 2-((4-(4-thiazolylidene-pyrazole-1-carbonyl)-phenyl)amino)nicotinonitriles 14–15 were obtained via a nucleophilic addition of pyrazolone 10 to phenyl isothiocyanate followed by cyclization with chloroacetone, phenacyl chloride, and/or ethyl bromoacetate. The 6-amino-4-aryl-3,5-dicyano-2-oxo-1-(4-substitutedbenzamido)-pyridines 19 were synthesized by Knoevenagel condensation N′-(2-cyanoacetyl)-benzohydrazide derivative 16 with substituted benzaldehydes followed by heating with malononitrile. All synthesized products were evaluated for their antioxidant potentialities using of 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radical cation delcolorization assay. The nicotinonitrile-thiazole hybrid 6b was found the most promising antioxidant agent with inhibition activity 86.27%.     

Efficient Approach to the Synthesis of Ethyl 3-Amino-4,6-diarylfuro[2,3-b]pyridine-2-carboxylate

Novel ethyl 3-amino-4,6-diarylfuro[2,3-b]pyridine-2-carboxylate were synthesized by Thorpe–Ziegler cyclization using solid–liquid phase-transfer catalysis conditions.     

Synthesis, reactions and biological activity of 2-substituted 3-cyano-4,6-dimethylpyridine derivatives

The reaction of 2-chloro-4,6-dimethylpyridine-3-carbonitrile with hydrazine hydrate, hydroxylamine, and anthranilic acid afforded the corresponding pyrazolo, isoxazolo, and pyridoquinazoline derivatives. Alkylation of 2-mercapto-4,6-dimethylpyridine-3-carbonitrile with ethyl chloroacetate or phenacyl bromide followed by cyclization in NaOH gave thienopyridine derivatives. Diazotization of ethyl 3-amino-4,6-dimethylthiеno[2,3-b]pyridine-2-carboxylate followed by the reaction with thiourea, guanidine carbonate, and hydroxylamine hydrochloride gave the corresponding thienopyridine derivatives. The biological activity of some new compounds has been discussed. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 43–51, Januar, 2009.     

Experimental and theoretical studies on the reactions of 1-amino-5-benzoyl-4-phenyl-1<Emphasis Type="Italic">H</Emphasis>-pyrimidine-2-one/-thione compounds with ethyl acetoacetate

The reaction of 1-amino-5-(4-methylbenzoyl)-4-(4-methylphenyl)pyrimidin-2(1H)-one/-thione (1a,b) with ethyl acetoacetate (EA) afforded moderate to good yields (59–63%) of ethyl 2-methyl-4-(4-methylbenzoyl)-5-(4-methylphenyl)-7-oxo/-thioxo-3,3a-dihydropyrazolo[1,5-c]pyrimidine-3-carboxylate (2a,b). The newly synthesized compounds were characterized by elemental analyses, IR, ¹H and ¹³C NMR spectral data. All were compared with their previous analogues. The reaction mechanism of 1 with EA was studied by means of the B3LYP/6-31G(d,p) method. In addition, for reactants Fukui functions were performed using the data calculated with the Becke3–Lee–Yang–Parr (B3LYP) hybrid function.     

Synthetic utility of bifunctional thiophene derivatives and antimicrobial evaluation of the newly synthesized agents

Abstract  

The key intermediate ethyl 2-amino-5-benzoyl-4-methylthiophene-3-carboxylate was prepared by a Gewald reaction starting from benzoylacetone, sulfur, and ethyl cyanoacetate in the presence of diethylamine. This intermediate reacted with various reagents to afford different fused and polyfunctional substituted thiophenes. Antimicrobial screening of the synthesized compounds exhibited promising antimicrobial activities.     

Synthesis of New Pyrido[4″,3″:4″,5″]thieno[2″,3″:4,5]pyrimido[2,1-b][1,3,4]thiadiazine Derivatives

Ethyl 2-methyl-11-oxo-9, 10-dihydro-1 H , 11 H -pyrido[4",3":4',5']thieno[2',3':4,5]pyrimido[2,1-b][1,3,4]thiadiazine-8(7 H )-carboxylate 7 has been synthesised by the reaction of ethyl 3-amino-4-oxo-2-thioxo-1,3,4,5,6,8-hexahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidine-7(2 H )-carboxylate 2 with allylbromide followed by treatment with bromine and subsequent dehydrobromination of the brominated product 5 with ethanolic sodium hydroxide. Its isomeric ethyl 2-methyl-11-oxo-9,10-dihydro-3 H ,11 H -pyrido[4",3Prime;:4',5']thieno[2',3':4,5]pyrimido[2,1-b][1,3,4]thiadiazine-8(7 H )-carboxylate 8 has been obtained by condensation of 2 with chloroacetone followed by cyclization of the intermediate 9 with p -toulenesulfonic acid. The thiadiazino derivatives 11 , 13 , 15 were prepared through the reaction of 2 with the appropriate f -halocarbonyl compounds followed by cyclization reactions of the intermediates 10 , 12 , 14 .     

Synthesis and characterization of some new pyridines,thieno[2,3-b] pyridines and pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine-4(3H)-ones bearing styryl moiety

3-Cyano-5-ethoxycarbonyl-6-methyl-4-styrylpyridine-2(1H)-thione ( 3 ) was prepared by reaction of 2-cyano-5-phenylpenta-2,4-dienethioamide ( 2 ) with ethyl acetoacetate or by multicomponent reaction of cinnamaldehyde ( 1 ), cyanothioacetamide and ethyl acetoacetate in a moderate yield. Reaction of compound 3 with some N-aryl-2-chloroacetamides, in the presence of sodium acetate, gave the corresponding 2-(N-arylcarbamoylmethylsulfanyl)-3-cyano-5-ethoxycarbonyl-6-methyl-4-styrylpyridines 4a-f . When compounds 4a-f were subjected to Thorpe-Ziegler reaction conditions, they converted into the corresponding 3-amino-5-ethoxycarbonyl-2-(N-arylcarbamoyl)-6-methyl-4-styrylthieno[2,3-b]pyridines 5a-f . Compounds 5a,e,f were reacted, in turn, with 2,5-dimethoxytetrahydrofuran to furnish the corresponding 3-(pyrrol-1-yl)thieno-pyridines 6a,e,f . Reactions of 5a-f with triethyl orthoformate or nitrous acid were also carried out and their products were identified. Structural formulas of all synthesized compounds was characterized and confirmed on the basis of their elemental and spectral analyses.     

Novel synthesis and antitumor evaluation of polyfunctionally substituted heterocyclic compounds derived from 2-cyano-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-acetamide

The reaction of 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene with ethyl cyanoacetate gave 2-cyano-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-acetamide. The latter was used to synthesize different heterocyclic derivatives comprising thiophene, thiazole, pyrazole, pyridine, pyrimidine, and coumarin rings. The mechanistic and synthetic pathways depended on regioselective attack and/or cyclization by the cyanoacetamido moiety in the key precursor on various chemical reagents. The competition of the reaction pathways including dipolar cyclization, dinucleophilic-bielectrophilic attack, β-attack, Gewald-type attack, and condensation reactions led to the diversity of the synthesized products. The antitumor activities of the synthesized products were studied and evaluated. Most of the compounds revealed high inhibitory effects when screened in vitro for their antiproliferative activity. Three human cancer cell lines, namely, breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268) were used in the screening tests. The simplicity of the synthetic procedures which mainly involved one-pot reactions under mild reaction conditions, the convenience of yield production and the diversity of the reactive sites in the produced systems play a valuable role for further heterocyclic transformations and further biological investigations.