新型5-取代吲哚-3-甲酰胺化合物的合成

以5-取代吲哚为原料,经维尔斯迈尔-哈克反应制得5-取代吲哚-3-甲醛(2a~2e);2a~2e在DMF催化下,与盐酸羟胺反应制得5-取代吲哚-3-甲腈(3a~3e);3a~3e在H2O2和Na OH溶液中水解合成了5-取代吲哚-3-甲酰胺(4a~4e,4b~4e为新化合物),产率62.0%~75.0%,其结构经1H NMR,13C NMR和ESI-MS表征。     

新型取代吲哚-3-甲醇类衍生物的合成

以取代吲哚为原料,经维尔斯迈尔-哈克反应制得取代吲哚-3-甲醛,再通过DMSO/NaOH体系制得N-取代吲哚-3-甲醛(3a~3g);3a~3g经Na BH4还原合成了7个未见文献报道的取代吲哚-3-甲醇类衍生物(4a~4g),其结构经~1H NMR,~(13)C NMR和MS表征。     

5-乙基-2-吲哚酮的合成及其酰基化和N上烃基化反应研究

以4-乙基苯胺1为原料,经Sandmeyer反应得5-乙基靛红2;2经水合肼还原得到5-乙基-2-吲哚酮3;N,N-二甲基甲酰胺与三氯氧磷先形成Vilsmeier-Haack试剂,再与化合物3反应,合成2-氯-5-乙基-3-乙酰吲哚4;以丙酮为溶剂,对化合物4烃基化,以78.5%-95.6%的收率得到N-取代-2-氯-5-乙基-3-乙酰吲哚5a-5e。其中化合物4、5a-5e均未见文献报道,它们的结构均通过红外光谱、核磁共振氢谱(碳谱),质谱等确认。     

3-(2-二唑啉基)-色酮类化合物的合成研究

报道了取代的邻羟基苯乙酮(1a～1e)经Vilsmeier-Haack反应一步制得3-醛基色酮(2a～2e),2a～2e与取代的芳酰肼(3a～3c)缩合制得15个酰腙类化合物(4a～4o),4a～4o在醋酸酐作用下关环得15个3-(2-苝二唑啉基)-色酮(5a～5o),并通过元素分析,IR,~1H NMR和MS诺数据确证了上述化合物的结构。     

3-(2-卓二唑啉基) - 色酮类化合物的合成研究

报道了取代的邻羟基苯乙酮(1a～1e)经Vilsmeier-Haack反应一步制得3－醛基色酮(2a～2e),2a～2e与取代的芳酰肼(3a～3c)缩合制得15个酰腙类化合物(4a～4o),4a～4o在醋酸酐作用下关环得15个3-(2-卓二唑啉基)-色酮(5a～5o),并通过元素分析,IR,^1^HNMR和MS谱数据确证了上述化合物的结构。     

尼达尼布的合成新方法

以N-甲基-4-硝基苯胺作为起始原料,依次经氯乙酰化、取代及氢化还原反应制得关键中间体N-(4-氨基苯基)-甲基-2-(4-甲基-1-哌嗪基)乙酰胺(4);以4-氯-3-硝基苯甲酸为原料,依次经酯化、取代、氢化还原及环合反应制得6-甲氧羰基-2-吲哚酮(8);8与原苯甲酸三乙酯和乙酸酐经"一锅煮"反应制得中间体1-乙酰基-3-甲氧基(苯基)亚甲烯基-2-氧代吲哚环-6-羧酸甲酯(9);4和9进行取代反应的同时脱除保护,经"一锅煮"反应合成尼达尼布,总收率57.2%,其结构经~1H NMR,~(13)C NMR和MS(ESI)确证。     

1/2,5-二取代吲唑-3-甲酰胺衍生物的合成及其抗肿瘤活性

以吲唑-3-羧酸为原料,依次经溴代和酯化反应制得中间体5-溴吲唑-3-羧酸甲酯(2);2经N-烷基化并原位水解生成1/2-取代-5-溴吲唑-3-羧酸(3);3与吡啶酮甲胺类化合物经缩合反应制得酰胺(4);4与芳基频哪醇硼酸酯发生Suzuki偶联反应合成了14个新型二取代吲唑-3-甲酰吡啶酮甲胺衍生物(5a~5n),收率26%~32%,其结构经~1H NMR,~(13)C NMR和HR-MS(ESI-TOF)表征。通过NOE差谱确证了取代基在吲唑氮原子上的取代位置。采用MTT法研究了5a~5n对人B淋巴瘤细胞(Ramos)、人黑色素瘤细胞(CHL-1,WM-266-4)和乳腺癌细胞(BT-474)的体外抗肿瘤活性。结果表明:5a,5b,5m对Ramos细胞、5a,5b,5l对WM-266-4细胞、5a,5b,5d,5e,5h,5j,5m,5n对CHL-1细胞和5a,5b,5d,5h,5m对BT-474细胞具有较好的抑制活性(IC5010.0μmol.L-1)。     

三联噻吩-吡唑啉类化合物的合成

以2-溴噻吩为原料,经溴代反应和格氏试剂反应制得2,2':5',5'-三联噻吩(1);1乙酰化后与4-取代苯甲醛发生亲核加成反应得到α,β-不饱和酮(3a～3e);3与80%水合肼发生关环反应,合成了5个α-三联噻吩-毗唑啉类化合物(4a～4e),收率74.3%～89.7%.其结构经H NMR,IR和元素分析表征.3和4均为新化合物.     

4-(5-喹啉-3-基-四氮唑-2-基)丁胺的合成

三苯基膦钯催化3-溴喹啉完成氰化取代制得3-氰喹啉(1);1与叠氮化钠经[2+3]环加成合成了3-(2H-四氮唑-5-基)喹啉(2);2与N-(4-溴丁基)邻苯二甲酰亚胺反应制得2-[4-(5-喹啉-3-基-四氮唑-2-基)丁基]异吲哚-1,3-二酮(3);3经肼解合成了4-(5-喹啉-3-基-四氮唑-2-基)丁胺(4...     

取代吲哚-3-甲酸类化合物的合成

吲哚-3-甲酸是一种重要的有机中间体,被广泛应用于医药与农药的合成.以取代邻硝基甲苯为原料,与N,N-二甲基甲酰胺二甲基缩醛(DMFDMA)反应制得取代2-硝基-β-二甲氨基苯乙烯,再经铁粉和冰乙酸还原环合生成取代吲哚,取代吲哚与三氟乙酸酐经酰化、碱性条件下水解制得5种取代吲哚-3-甲酸类化合物,该合成方法操作简单,条件温和,收率较高.     

2-取代的6-溴甲基-4(3H)-喹唑啉酮的合成

4(3H)-喹唑啉酮类化合物具有广泛的生物活性,如镇静催眠[1]、抗抑郁[2]、抗炎[3]、抗菌[4]、抗高血压[5]等,特别是含有4(3H)-喹唑啉酮结构的叶酸类似物显示出有效的抗肿瘤活性[6],其中ZD-1694(Raltitrexed)自1997年在英国上市后,已在40多个国家注册,成为治疗晚期结肠癌和直肠癌的主要药物[7]。我们曾以2-甲基-6-溴甲基-4(3H)-喹唑啉酮为原料,分别合成了含二硫代氨基甲酸酯、芳胺侧链的4(3H)-喹唑啉酮衍生物。生物活性测试结果表明,其中一些化合物具有显著的体外抗肿瘤活性[8,9]。为合成并筛选活性更强的抗肿瘤化合物,同时考察C2位上不同…     

Preparation of 5-sulfonylpyrimidines from β-keto, β-cyano-, and β-ethoxycarbonyl-β-sulfonylenamines

β-Keto-β-sulfonylenamines 2a,b reacted with benzamidine or guanidines to give 2,4-disubstituted 5-methanesulfonylpyrimidines 3a-d , whose methanesulfonyl groups were substituted by n-butyllithium or alkylmagnesium bromides to yield 2,4-disubstitued 5-alkylpyrimidines 6a-d. 2-Substituted 4-amino-5-sulfonylpyrimidines 7a,b, 8 and 2-substituted 5-benzenesulfonylpyrimidin-4-ones 9a,b were similarly obtained from β-cyano-β-sulfonylenamines 2c,d and β-ethoxycarbonyl-β-sulfonylenamine ( 2e ), respectively.     

Synthesis,reactions and biological evaluation of some 1,2,4-triazine derivatives

6-Substituted benzyl-4-phenyl-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazin-5-ones 3a-d were prepared and converted into their corresponding 3-methylthio derivatives 4a-d . Reaction of compounds 4a-d with hydrazine hydrate gave the corresponding 4-amino-3-anilino-4,5-dihydro-1,2,4-triazin-5-ones 5a-d . 6-Substituted benzyl-4-phenyl-2,3,4,5-tetrahydro-1,2,4-triazin-3,5-diones 9a-c were synthesized and allowed to react with hydrazine hydrate to give the corresponding 6-substituted benzyl-4-amino-2,3,4,5-tetrahydro-1,2,4-triazin-3,5-diones 10a-c . The biological evaluation of some of these triazines is described. All compounds were screened for antiviral, antibacterial, antimycobacterial, antifungal and antiyeast activity. No important biological activity was found.     

Quinolinone and pyridopyrimidinone inhibitors of DNA-dependent protein kinase

8-Substituted 2-morpholin-4-yl-quinolin-4-ones and 9-substituted 2-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-ones with selected aryl and heteroaryl groups as the substituent have been synthesised as potential inhibitors of DNA-dependent protein kinase. A multiple-parallel approach, employing Suzuki cross-coupling methodology, was utilised in the preparation of 8-substituted 2-morpholin-4-yl-quinolin-4-ones. For this purpose 8-bromo-2-morpholin-4-yl-quinolin-4-one was required as an intermediate. This compound was obtained by adapting a literature route in which thermal cyclocondensation of (2-bromoanilino)-morpholin-4-yl-5-methylene-2,2-dimethyl[1,3]dioxane-4,6-dione afforded 8-bromo-2-morpholin-4-yl-quinolin-4-one. A multiple-parallel approach, employing Suzuki cross-coupling methodology, was also utilised to prepare 9-substituted 2-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-ones using 9-hydroxy-2-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-one O-trifluoromethanesulfonate as an intermediate. 8-Substituted 2-morpholin-4-yl-quinolin-4-ones and 9-substituted 2-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-ones were both inhibitors of DNA-dependent protein kinase. When the substituent was dibenzothiophen-4-yl, dibenzofuran-4-yl or biphen-3-yl, IC50 values in the low nanomolar range were observed. Interestingly, the pyridopyrimidinones and quinolinones were essentially equipotent with the corresponding 8-substituted 2-morpholin-4-yl-chromen-4-ones previously reported (I. R. Hardcastle, X. Cockcroft, N. J. Curtin, M. Desage El-Murr, J. J. J. Leahy, M. Stockley, B. T. Golding, L. Rigoreau, C. Richardson, G. C. M. Smith and R. J. Griffin, J. Med. Chem., 2005, 48, 7829-7846).     

Some features of RuCl3-catalyzed periodate oxidation of 3-N-substituted 5-allenyl-2,5-dichloro-4,4-dimethoxycyclopent-2-en-1-ones

3-N-Substituted 5-(1Z-carboxymethylene)-2-chloro-4,4-dimethoxycyclopent-2-en-1-ones have been prepared from the corresponding 3-N-substituted 5-allenyl-2,5-dichloro-4,4-dimethoxycyclopent-2-en-1-ones using selective oxidative cleavage of their allene bond by the RuCl₃−NaIO₄ system. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1646–1648, September, 1997.     

Synthesis of new unsaturated derivatives of functionally substituted 2-imino-2,5-dihydrofurans

5,5-Substituted 2-imino-4-methyl-2,5-dihydrofuran-3-carbonitriles reacted with aromatic aldehydes to give the corresponding 5,5-substituted 2-imino-4-(2-R-vinyl)-2,5-dihydrofuran-3-carbonitriles. The latter were converted into hydrochlorides which were hydrolyzed to 3-cyano-4-(2-R-vinyl)-2,5-dihydrofuran-2-ones whose condensation with malononitrile afforded dicyanomethylidene derivatives.     

Tandem versus single C-C bond forming reaction under palladium-copper catalysis: regioselective synthesis of α-pyrones fused with thiophene

We herein report a highly convenient protocol for rapid construction of α-pyrone fused with thiophene. This includes one-pot and regioselective synthesis of 4,5-disubstituted and 5-substituted thieno[2,3-c]pyran-7-ones, 6,7-disubstituted and 6-substituted thieno[3,2-c]pyran-4-ones. The synthesis of thieno[2,3-c]pyran-7-ones involves palladium mediated cross coupling of 3-iodothiophene-2-carboxylic acid with terminal alkynes in a simple synthetic operation. The coupling-cyclization reaction was initially studied in the presence of Pd(PPh₃)₂Cl₂ and CuI in a variety of solvents. 5-Substituted 4-alkynylthieno[2,3-c]pyran-7-ones were isolated in good yields when the reaction was performed in DMF. Similarly, 6-substituted 7-alkynylthieno[3,2-c]pyran-4-ones were synthesized via palladium-catalyzed cross coupling of 2-bromothiophene-3-carboxylic acid with terminal alkynes. A tandem C-C bond forming reaction in the presence of palladium catalyst rationalizes the formation of coupled product in this apparently three-component reaction. The cyclization step of this coupling-cyclization-coupling process occurs in a regioselective fashion to furnish products containing six-membered ring only. This sequential C-C bond forming reaction however, can be restricted to the formation of single C-C bond by using 10% Pd/C-Et₃N-CuI-PPh₃ as catalyst system in the cross coupling reaction. 5-Substituted thieno[2,3-c]pyran-7-ones were obtained in good yields when the coupling reaction was performed under this condition. Some of the compounds synthesized were tested in vitro for their anticancer activities.     

新型六氢吡啶-2,3-并吲哚化合物的合成及其抗肿瘤活性

以3-取代氧化吲哚与丙烯酸酯为原料,经Michael加成反应制得中间体——3-丙酸酯取代氧化吲哚(3a~3d);3a~3d与甲胺发生酰胺化反应制得3-丙酰胺取代氧化吲哚(4a~4d);4a~4d用氢化铝锂还原-环化,合成了4个六氢吡啶-2,3-并吲哚化合物(5a~5d);5a和5b用氢化铝锂还原合成了2个六氢吡啶-2,3-并吲哚化合物(6a和6b),5a~5d,6a和6b均为新化合物,总产率42%~61%,其结构经~1H NMR,~(13)C NMR和HR-ESIMS表征。采用MTT法研究了5a~5d,6a和6b对人肺癌细胞(A549),人前列腺(PC-3)和人白血病细胞(K562)的体外抗肿瘤活性。结果表明:5b对A549,PC-3和K562的抑制活性均较好,其IC50分别为27.2μmol·L~(-1),37.5μmol·L~(-1)和21.7μmol·L~(-1)。     

3-methylthio-1,2-dithiolylium salts : Reaction with 4-hydroxy-6-methyl-2H-pyran-2-one and 4-hydroxycoumarin

The reaction of 4- and 5-aryl-3-methylthio-1,2-dithiolylium iodides with 4-hydroxy-6-methyl-2$\text{H}$-pyran-2-one and 4-hydroxycoumarin has been studied. 4-Substituted salts yielded 3-aryl-7-methyl-2-thioxo-2$\text{H}$,5$\text{H}$-pyrano [3,2-c]pyran-5-ones and 3-aryl-2-thioxo-2H,5H-pyrano[3,2-c]benzo[e]pyran-5-ones, respectively, whereas 5-substituted salts gave rise to 3-(5′-aryl-1′,2′-dithiol-3′-ylidene)-6-methyl-2$\text{H}$-pyran-2,4-diones and 3-(5′-aryl-1′,2′-dithiol-3′-ylidene)-2$\text{H}$-benzo [b]-pyran-2,4-diones.