1-(3-芳亚甲基氨基)丙基-2,8,9-三氧杂-5-氮杂-1-硅杂双环[3,3,3]十一烷金属络合物的合成及其抗肿瘤活性研究

我们曾对1-亚甲基氨基烷基-2,8,9-三氧杂-5-氮杂-1-硅杂双环[3,3,3]十一烷的合成及其抗肿瘤活性作过研究,发现1-[3-(2-羟基苯亚甲基氨基)丙基]-2,8,9-三氧杂-5-氮杂-1-硅杂双环[3,3,3]十一烷和1-[3-(2,4-二羟基苯亚甲基氨基)丙基]-2,8,9-三氧杂-5-氮杂-1-硅杂双环[3,3,3]十一烷具有较好的抗肿瘤活性。已知亚甲胺类(Schiff碱)化合物与某些金属离子形成络合物后,能提高它们的抗肿瘤活性。为此,我们进一步研究了这两种亚甲胺衍生物的合成及其抗肿瘤活性。     

1-(3-氨基丙基)-2,8,9-三氧杂-5-氮杂-1-硅杂双环[3,3,3]十一烷衍生物的合成及其抗肿瘤活性研究

通过1-(3-氨基丙基)-2,8,9-三氧杂-5-氮杂-1-硅杂双环[3,3,3]十一烷与酸反应或1-(3-氯丙基)-2,8,9-三氧杂-5-氮杂-1-硅杂双环[3,3,3]十一烷与胺反应,合成了14种1-(3-氨基丙基)-2,8,9-三氧杂-5-氮杂-1-硅杂双环[3,3,3]十一烷衍生物.体外细胞培养试验结果表明,某些1-(3-氨基丙基)-2,8,9-三氧杂-5-氮杂-1-硅杂双环[3,3,3]十一烷衍生物对艾氏腹水癌细胞具有较好的杀伤活性.     

新型树形化合物1,3,5-三-[7-(7-甲基-2,2-二-(2,2-二羟甲基-3-羟基丙氧基羰基)-6,8-二氧杂螺[3.5]-壬基)]苯的合成

以丙酮和甲酸乙酯为原料, 在醇钠的作用下合成了1,3,5-三乙酰基苯(1). 1与二溴新戊二醇在酸的作用下发生缩酮化反应, 制成1,3,5-三-(1-甲基-2,6-二氧杂-4,4-二溴甲基环己基)苯(2). 2与5,5-二甲基-4,6-二氧杂-1,3-环己二酮在乙醇钠的作用下合成了1,3,5-三-[7-(7-甲基-2,2-二-乙氧羰基-6,8-二氧杂螺[3.5]-壬基)]苯(3). 将3在氯仿中与季戊四醇进行酯交换反应得到产物1,3,5-三-[7-(7-甲基-2,2-二-(2,2-二羟甲基-3-羟基丙氧基羰基)-6,8-二氧杂螺[3.5]-壬基)]苯(4). 收率为47.7%. 标题化合物及中间产物使用IR, ¹H NMR和MS或元素分析进行了表征.     

2,8-二甲基-1,7-二氧杂螺[5,5]十一烷的合成

果蝇 ( Tephritidae)对水果生产有严重的危害 .热带果蝇寿命较长 ,具有很强的迁徙能力和繁殖能力 .因此开展果蝇生物防治和控制措施的相关研究具有重要的意义 [1,2 ] .Baker等 [3]发现性成熟的雌B.dorsalis果蝇 ,性腺分泌物中包含有螺环缩酮化合物 2 ,8-二甲基 - 1 ,7-二氧杂螺 [5 ,5 ]十一烷 ( 1 ) .Bactrocera Latifrons( Hendel)果蝇的雄性腺体分泌物中也存在螺环缩酮 1 [4 ] ,另外在 rove甲虫腹梢分泌物中也分离出 1 [5] ,螺环缩酮不仅作为性信息素组分存在于许多果蝇腺体中 ,而且作为结构单元存在于许多复杂的有强烈生理活性的天然…     

新型三环系稠杂环[1,2,4]-三唑并[1,5-a][1]-苯并氮杂及[1,2,4]-三唑并[1,5-a]-喹啉的合成

α-四氢萘酮的乙氧羰基腙(1)经LTA氧化,得到α-偶氮-α-乙酰氧基化合物2.在A lC l3作用下,化合物2脱去乙酰氧基产生重氮正离子中间体3,再经与腈的1,3-偶极环加成、[1,2]-迁移扩环、碱性水解和与苦味酸作用,得到新型[1,2,4]-三唑并[1,5-a][1]苯并氮杂苦味酸盐6a~6c.以2,3-二氢-1-茚酮为底物,采用相同的合成路线,合成了1,2,4-三唑并[1,5-a]-二氢喹啉苦味酸盐12a~12c.     

基于[3+2]环加成反应的氮杂螺[3,4]环辛烷的合成

哌嗪、吗啉是小分子药物中常见的结构片段,2,6-二氮杂螺[3,4]环辛烷和2-氧-6-氮杂螺[3,4]环辛烷等四元螺环化合物作为其类似物,在药物化学领域具有良好的应用前景.本研究以廉价易得的丙二酸二乙酯或丙烯酸乙酯为起始原料,经[3+2]环加成反应,可便捷高效地完成6-苄基-2,6-二氮杂螺[3,4]环辛烷和2-氧-6-氮杂螺[3,4]环辛烷克级水平的合成.     

2-(烃基胺磺酰基)-5,6-二氢-二苯并[b,e]氮杂-6,11-二酮的合成与杀菌活性

以蒽醌为原料,经Schmidt重排为5,6-二氢-二苯并[b,e]氮杂-6,11-二酮,再经氯磺酰化和胺化合成了一系列新颖的2-(烃基胺磺酰基)-5,6-二氢-二苯并[b,e]氮杂-6,11-二酮.结构经1H NMR,13C NMR和高分辨质谱确证.初步的生测结果表明,它们对棉花立枯病菌、油菜菌核病菌和芦笋茎枯病菌具有一定的杀菌活性.其中,2-(3-三氟甲基-4-溴苯基胺磺酰基)-5,6-二氢-二苯并[b,e]氮杂-6,11二酮(4u)对芦笋茎枯病菌有良好的杀菌活性,在50μg/m L浓度下抑制率达96.3%,与对照药剂百菌清基本相当(在50μg/m L浓度下的抑制率为98.8%).初步的构效关系分析指出,氟原子的引入有利于杀菌活性的提高.     

新型1,2,4-三唑并[3,2-d][1,5]苯并氧氮杂(艹卓)-2-酮的合成

取代苯并二氢吡喃-4-酮(1)的芳腙在冰醋酸中与KNCO发生[3 2]环加成反应,加成产物经KMnO4氧化开环得偕偶氮异氰酸酯(3).3在HBF4的催化下发生环化-重排反应,合成得到一系列新型6-7-5三环系1,2,4-三唑并[3,2-d][1,5]苯并氧氮杂(艹卓)2-酮(5a～5g).由X单晶衍射测定了化合物5a的晶体结构.     

含1,2,3-三氮唑结构的1,5-苯并硫氮杂[艹卓]的合成及其抑真菌活性

设计合成了三类含1,2,3-三氮唑结构的1,5-苯并硫氮杂[艹卓]化合物3-(1H-1,2,3-三氮唑)-4-芳基-2,5-二氢-1,5-苯并硫氮杂[艹卓](5a^5f)、3-(2H-1,2,3-三氮唑)-4-芳基-2,3-二氢-1,5-苯并硫氮杂[艹卓](6a^6f)和3-(1H-1,2,3-三氮唑)-4-芳基-2,3,4,5-四氢-1,5-苯并硫氮杂[艹卓](7a^7f).研究了中间体及目标产物的合成条件,分离出其中两个副产物并进行了结构确定.目标产物的抑真菌活性测试表明,化合物5a^5f对真菌具有良好的抑制作用,对新生隐球菌的抑制效果尤为突出.初步抑真菌构效关系研究表明, 1H-1,2,3-三氮唑环和C=C双键是化合物5a^5f抑真菌活性的关键官能团.     

新型1,2,4-三唑并[3,2-d][1,5]苯并氧氮杂-2-酮的合成

取代苯并二氢吡喃 4 酮 ( 1)的芳腙在冰醋酸中与KNCO发生 [3 2 ]环加成反应 ,加成产物经KMnO4氧化开环得偕偶氮异氰酸酯 ( 3 ) .3在HBF4的催化下发生环化 -重排反应 ,合成得到一系列新型 6 7 5三环系 1,2 ,4 三唑并 [3 ,2 d] [1,5 ]苯并氧氮杂 2 酮 ( 5a～ 5g) .由X单晶衍射测定了化合物 5a的晶体结构     

聚缩醛螺胞二醚的合成及结构表征

在I₂催化剂的作用下, 利用苯甲醛与季戊四醇反应, 制备了聚缩醛螺胞二醚的模型化合物3,9-二苯基-2,4,8,10-四氧杂螺[5.5]十一烷(1). 在此基础上, 利用1,3-苯二甲醛与不同摩尔比的季戊四醇合成了化合物1,3-二(2,6-二氧杂-4,4-二羟甲基环己基)苯(2)和2,4,8,10-四氧杂-3,9-二(3'-甲酰基苯基)螺[5.5]十一烷(3). 化合物2与化合物3反应, 制成标题化合物聚缩醛螺胞二醚4, 收率为95.4%. 用FTIR, ¹H NMR对化合物1～4的结构进行了表征. 发现在含有手性轴化合物1, 3, 4的¹H NMR谱中, 4个亚甲基中的8个氢原子裂分为4组双峰, 而不含有手性轴化合物中的4个亚甲基中的8个氢原子不裂分, 是个单峰. 这种不同不是由于化合物中刚性环所致, 而是由于有无手性轴造成的.     

Preparation and some reactions of 3,9-dichloro-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5] undecane-3,9-disulfide

3, 9-Dichloro-2, 4, 8, 10-tetraoxa-3, 9-diphosphaspiro[5. 5]undecane-3,9-disulfide (I), has been synthesized by treating a dimethylacetamide solution of 2, 4, 8, 10-tetraoxa-3,9-diphosphaspiro[5. 5]undecane-3, 9-disulfide (III) with carbon tetrachloride. A number of other known methods for converting dialkyl phosphorothioites to thiophosphorochloridates were also applied to III, but all failed to produce I. Chlorination of either I or III gave an acyclic product, 4, 4-bis(chloromethyl)-1, 1, 7, 7-tetrachloro-2, 6-dioxa-1, 7-di-phosphaheptane-1, 7-dioxide (IV), in nearly quantitative yield. The same compound was also obtained by the previously known method of chlorinating 3, 9-dichloro-2,4,8,10-tetraoxa-3, 9-diphosphaspiro[5.5]undecane (II). The treatment of pentaerythritol with phosphorus pentachloride gave IV in minor amount along with a 25% yield of 4,4-bis-(chloromethyl)-1-chloro-2, 6-dioxa-1-phosphacyclohexane-1-oxide (VII). The hydrolysis of I in heated aqueous sodium carbonate gave, after acidification, 3,9-dihydroxy-2,4,8,10-tetraoxa-3, 9-diphosphaspiro[5. 5]undecane-3, 9-disulfide (VIII). A number of derivatives were prepared by reaction of I with phenoxides and amines. The corresponding thio-phosphorofluoridate XI was prepared by treatment of I with potassium fluoride in dioxane.     

1,3,5-三[(4’-乙炔基苯基)乙炔基]苯的合成

设计了多种合成路线制备芳香炔基树枝状化合物中间体1,3,5-三[(4’-乙炔基苯基)乙炔基]苯,通过一系列的合成路线和反应条件的对比,发现多官能团的端基炔化合物与芳基溴化合物之间发生多重Sonogashira反应时,常会生成不同取代程度的极性相似化合物,因而难以分离.采用多官能团的端基炔化合物与芳基碘化合物反应可以避免这种情况.最终确定以1,3,5-三溴苯和2-甲基-3-丁炔-2-醇为原料,制得中间产物1,3,5-三乙炔基苯;再以对碘苯胺和三甲基硅乙炔为原料,经重氮化化、卤代反应制得4-三甲基硅乙炔基碘苯;后者与1,3,5-三乙炔苯经Sonogashira反应、裂解去保护反应,制得化合物1,3,5-三[(4’-乙炔基苯基)乙炔基]苯.用1H NMR,13C NMR,元素分析等表征手段确认了中间体及最终产物的结构.     

A new efficient route for the synthesis of 4,4′,6,6′-tetra(azido) azo- 1,3,5-triazine

A new method for the synthesis of 4,4′,6,6′-tetra(azido)azo-1,3,5-triazine(TAAT)is described.The key intermediate 4,4′,6,6′- tetra(azido)hydrazo-1,3,5-triazine(TAHT)was synthesized by nucleophilic substitution in the case of sodium azide as nacleophile. N-Bromosuccinide(NBS)was used as oxidant to oxidize TAHT by a tractable operation under mild reaction condition.The target compound TAAT was obtained with a facile process and high overall yield of 81%.The structures of TAAT and its intermediates were identified by spectroscopic methods.     

Base-promoted rearrangement of cage α-haloketones—II : 12-oxa-3,5,9,10-tetrachlorohexacyclo[5.4.1.02,6.03,10.05,9.08,11]-dodecane-4-one

A synthesis of 12-oxa-3,5,9,10-tetrachlorohexacyclo[5.4.1.0^2,6.0^3,10.0^5,9.0^8,11]dodecane-4-one (6) from 4,4-dimethoxy-2,3,5,6-tetrachloropentacyclo [[5.4.0.0^2,6.0^3,10.0^5,9]undecane-8,11-dione (1) is described. Reaction of 6 with sodium hydroxide in refluxing benzene, toluene, or tetrahydrofuran affords 11-oxa-3,4,5-exo-6-tetrachloropentacyclo [[6.2.1.0^2,7.0^4,10.0^5,9]undecane-endo-3-carboxylic acid (7a, 80·2% yield). The corresponding reaction of 6 with refluxing aqueous sodium hydroxide solution affords 4,12-dioxa-8,11-dichlorohexacyclo-[5.4.1.0^2,6.0^3,10.0^5,9.0^8,11]dodecane-1-carboxylic acid (8a, 66·5% yield). A mechanism which accounts for the formation of 7a and 8a from 6 is presented.     

The reduction and hydrolysis of some 7,7-diethylpyrazolo[1,2-a]-pyridazine-6,8(7H)dione derivatives

The chemistry of several of the Diels-Alder adducts formed by the reaction of 4,4-diethylpyrazoline-3,5-dione ( 1 ) with conjugated dienes was studied with respect to reduction (hydride and catalytic) and reaction with base. Reaction of the 2,3-dimethyl-1,3-butadiene adduct with lithium aluminum hydride followed by hydrogenation gave 1,3,5,6,7,8-hexahydro-cis-endo-6,7-dimethyl-2,2-diethylpyrazolo[1,2-a]pyridazine ( 11 ). Attempted conversion of this compound to 3,3-diethyl-cis-7,8-dimethyl-1,5-diazacyclononane ( 12 ) gave instead a compound which has been tentatively identified as N-(2,3-dimethyl-4-aminobutyl)-2-ethyl-2-methylbutanaldimine ( 14 ). Lithium aluminum hydride reduction of 4,4-diethylpyrazolidine-3,5-dione ( 22 ) or the adducts formed from 1 and cyclopentadiene or 1,3-cyclohexadiene gave good yields of 4,4-diethylpyrazolidine ( 21 ). This later reduction gave a new and efficient synthetic route to the pyrazolidine ring system. Lithium aluminum hydride reduction of 5,6,7,8-tetrahydro-5,8-ethano-2,2-diethylpyrazolo[1,2-a]pyridazine-1,3(2H)dione ( 26 ) followed by hydrogenolysis led to a high yield of 4,4-diethyl-2,6-diazabicyclo[5.2.2]undecane ( 28 ) which is the first reported example of this ring system. Reaction of several of the adducts with ethanolic potassium hydroxide resulted in the opening of the five-membered ring.     

The composition of transformation products of 2,4,6-trinitrobenzoic acid in the aqueous-phase hydrogenation over Pd/C catalysts

Due to a detailed analysis of NMR spectra of the reaction solutions with different composition obtained by the aqueous-phase catalytic (Pd/C) hydrogenation of 2,4,6-trinitrobenzoic acid, the intermediate compounds were identified and a more substantiated mechanism was proposed for the formation of the main reaction products—1,3,5-triaminobenzene and cyclohexane-1,3,5-trione trioxime. The condensation of the 1,3,5-triaminobenzene molecules produced by a complete hydrogenation of 2,4,6-trinitrobenzoic acid was shown to result in the formation of a paramagnetic heterocyclic compound.     

An unusual reduction route of 2,4,6-trinitrobenzoic acid under conditions of aqueous-phase hydrogenation over Pd/Sibunit catalyst

For the first time it was established that the catalytic hydrogenation of 2,4,6-trinitrobenzoic acid to 1,3,5-triaminobenzene can proceed via the formation of aromatic hydroxyamines and cyclohexane-1,3,5-trione trioxime. As a result of aqueous-phase hydrogenation of sodium salt of 2,4,6-trinitrobenzoic acid in the presence of 5%Pd/Sibunit catalyst at a temperature of 323 K and pressure of 0.5 MPa, a trioxime in high yield (about 70 %) was obtained. Due to high selectivity to cyclohexane-1,3,5-trione trioxime the catalytic hydrogenation of sodium salt of 2,4,6-trinitrobenzoic acid can be considered as a new method for its synthesis.     

Synthesis of aromatic polyethers containing 2,6(7)-dihydroxy [1,3,5(6),7(8)-tetramethylanthracene] units

Friedel–Crafts copolymerization of 4,4′ bis(2,6-dimethylphenoxy-4-Phenyl)sulfone with methylene chloride used both as comonomer and solvent leads to linear and soluble aromatic polyethers containing 2,6(7)-dihydroxy[1,3,5(6),7(8)-tetramethylanthracene] units. The polymerization proceeds by multiple electrophilic substitutions that lead first to diphenylmethane and then to dihydroanthrylene units, followed by dihydrogenation.