2-甲氧羰基-3-(4-羟苯基)丙酸甲酯的合成

4-苄氧基苯甲醛(Ⅱ)与丙二酸二甲酯脱水缩合,产生2-甲氧羰基-3-(4-羟苯基)丙烯酸甲酯(Ⅲ),收率为88%,化合物(Ⅲ)经过催化氢化,以95%的收率得到中间体2-甲氧羰基-3-(4-羟苯基)丙酸甲酯(Ⅰ),(Ⅰ)的合成总收率达到73.6%。产品的结构经过IR、ESI-MS1、H NMR确证。     

1-(3,4-二甲氧基苯基)环丁烷甲腈的合成

以2-(3,4-二甲氧基苯基)乙腈和1,3-二溴丙烷为原料,在KOH碱性条件下,经过两次亲核取代反应,合成得到目标化合物1-(3,4-二甲氧基苯基)环丁烷甲腈,收率59.3％.产物结构经1H NMR和ESI-MS确证.并对影响产物收率的主要因素进行了考察,确定适宜的反应条件为:物料比n3∶n2=1.2∶1;KOH用量n...     

(S)-4-苄氧基取代苯丙胺醇衍生物的制备

采用以L-N-Boc酪氨酸甲酯为原料，经苄基保护4位酚羟基、LiAlH4还原甲酯、脱苄基保护、醚化反应、脱Boc保护基等反应，合成了中间体3和(S)-4-苄氧基取代苯丙胺醇衍生物3个。实验过程中得到的中间体3和(S)-4-苄氧基取代苯丙胺醇衍生物分别为(S)-3-(4-羟基苯基)-2-叔丁氧甲酰氨基-1-丙醇、(S)-3-(4-苄氧苯基)-2-氨基-1-丙醇、(S)-3-[4-(3,4-二氟苄氧苯基)]-2-氨基-1-丙醇和(S)-3-[4-(2,6-二氟苄氧苯基)]-2-氨基-1-丙醇，所得化合物的化学结构经质谱和核磁共振氢谱确证。本合成路线具有操作简单、收率高的特点，其中中间体3可用于氨基醇类衍生物的合成，而(S)-4-苄氧基取代苯丙胺醇衍生物的合成提供了基础化合物和合成方法参考，以发现和研制新的活性药物。     

阿立哌唑中间体3,4-二氢-7-(4-氯丁氧基)-2-(1H)-喹啉酮的合成

3,4-二氢-7-(4-氯丁氧基)-2-(1H)-喹啉酮(DCHQ)是抗精神分裂症药物阿立哌唑的关键中间体。以间氨基苯酚为原料,经酰化,傅克烷基化,取代反应合成阿立哌唑中间体。其中3-氯-N-(3-羟基苯基)-丙酰胺(中间体1)收率95%,3,4-二氢-7-羟基-2-(1H)-喹啉酮(中间体2)收率63.2%,DCHQ收率92%。该工艺反应条件温和易于控制,反应时间短,收率高,适合工业化生产。     

L-甲基多巴的合成工艺改进

以3,4-二甲氧基苯丙酮为原料,经Strecker 反应得到(3',4'-二甲氧基苯基)-2-氨基-2-甲基丙腈,然后用L-酒石酸拆分得到L-(3',4'-二甲氧基苯基)-2-氨基-2-甲基丙腈盐酸盐,再经水解、脱甲基得到目标产物L-甲基多巴,收率为50.4%.     

基于硼氢化钾-三氟化硼乙醚还原体系的3,4-二甲氧基苯乙胺合成新方法

以邻苯二酚为原料,经醚化、Vilsmeier反应制得藜芦醛,收率95.2%,藜芦醛与硝基甲烷反应制得了3,4-二甲氧基苯基-β-硝基乙烯,收率高达93.6%,然后利用硼氢化钾-三氟化硼乙醚体系(KBH4/BF3-Et2O)催化还原3,4-二甲氧基苯基-β-硝基乙烯合成3,4-二甲氧基苯乙胺。该方法使用KBH4/F3B-Et2O还原体系,具有反应条件温和、后处理容易、产率较高等特点,适于工业化生产。     

二烷基苯基不饱和羧酸钠盐双尾表面活性剂的合成及性能研究

以邻二氯苯、1-溴己烷和1-溴辛烷为起始原料经过偶联得到邻二烷基苯,再与顺丁烯二酸酐经Friedel-Crafts酰基化反应,合成了两种不饱和羧酸——4-(3,4-二正己基苯基)-4-氧代-2-丁烯酸和4-(3,4-二正辛基苯基)-4-氧代-2-丁烯酸,总收率分别为59%和42%,经过核磁共振谱、红外光谱和高分辨质谱对产物结构进行了确认。然后用氢氧化钠中和得到两种不饱和羧酸钠盐,并测量了它们不同浓度的表面张力。     

六芳基二咪唑的合成研究

为开发六芳基二咪唑类光致变色材料 ,以联苯甲酰、对甲氧基苯甲醛及乙酸铵为原料 ,经过环合、氧化合成了光致变色化合物 2 ,2′-二对甲氧苯基 - 4,4′,5 ,5′-四苯基 - 1 ,2′-二咪唑。研究了多种因素对反应收率的影响 ,得到最佳工艺条件 :在冰乙酸中 ,联苯甲酰、对甲氧基苯甲醛及醋酸铵物质的量之比为 1∶ 1∶ 8,回流 3 h后生成 2 -对甲氧苯基 - 4,5 -二苯基咪唑 ,收率为 93 .6 % ;以乙二醇 -乙醚为溶剂 ,2 -对甲氧苯基 - 4,5 -二苯基咪唑与氧化剂 K3 [Fe(CN) 6]的物质的量之比为 1∶ 2 ,在 0～1 5°C下反应 5 h,得到产品 2 ,2′-二对甲氧苯基 - 4,4′,5 ,5′-四苯基 - 1 ,2′-二咪唑 ,收率为 87.5 %。     

微波辐射下合成2,6-二甲基-3-芳基-4(1H)-喹啉酮

研究了在微波促进下N-对甲苯基乙酰胺与取代苯乙酸经酰化和环化反应合成2,6-二甲基-3-芳基-4(1H)-喹啉酮化合物的方法,反应时间短,产物收率高,操作简便。在微波辐射下,以BF3·Et2O为催化剂,N-对甲苯基乙酰胺与取代苯乙酸发生酰化,80℃下反应15 min,以85.7%~91.3%的收率得到中间产物N-[4-甲基-2-(2-芳基乙酰基)苯基]乙酰胺;中间产物在叔丁醇钠/叔丁醇存在下进行环化,微波辐射下回流反应20 min,得到目标产物2,6-二甲基-3-芳基-4(1H)-喹啉酮,收率89.2%~94.3%。用IR、1HNMR和元素分析确证了目标产物的结构。     

中试规模合成青霉烯和碳青霉烯类抗生素关键中间体4-AA

该文研究了青霉烯和碳青霉烯关键中间体4-AA的生产工艺。在-5℃,L-苏氨酸与亚硝酸钠、盐酸、氢氧化钠发生重氮化、分子内亲核取代反应生成(2R,3R)-2,3-环氧丁酸(中间体A),收率74.5%。A再与对甲氧苯氨基乙酸乙酯(中间体B)反应5～6 h制得(2R,3R)-N-乙氧羰甲基-N-(4-甲氧基苯基)-2,3-环氧丁酰胺(中间体C),收率94.3%。中间体C在六甲基二硅氮烷、氨基锂作用下环合成(3S,4S)-3-[(1R)-1-羟乙基]-4-乙氧羰基-1-对甲氧苯基-2-氮杂环丁酮(中间体D),收率72.1%。最后中间体D经羟基保护、水解、氧化脱羧、臭氧化脱保护基制得4-AA{(3R,4R)-3-[(1R)-叔丁基二甲基硅氧乙基]-4-乙酰氧基-2-氮杂环丁酮}。总收率达到34.5%,4-AA液相色谱纯度达到99.34%。     

3,4-二甲氧基苯乙腈及其杂质的气相色谱分析

采用GC-FID,采用内标法测定了3,4-二甲氧基苯乙腈含量,外标法测定了杂质邻苯二酚、藜芦醇含量,对3,4-二甲氧基苯乙腈、邻苯二酚和藜芦醇的色谱分离条件进行了优化。3,4-二甲氧基苯乙腈的添加平均回收率为99.8%～100.1%,RSD 0.96%,准确度和精密度均能满足常量分析的要求;邻苯二酚和藜芦醇的检出限分别为100 mg/kg和50 mg/kg。     

发酵新鲜鸢尾香气成分分析

采用同时蒸馏萃取装置提取挥发油并用气相色谱-质谱联用仪对经发酵的新鲜鸢尾根茎挥发性香味化合物进行了分离和鉴定,分离并鉴定出 69个组分,占峰面积的 84 .24%,并用面积归一化法测定了各种成分的质量分数,其主要香气成分为:w( 3- 甲基 -2 -丁烯醛 ) =0. 14%、w〔(Z) 3 -己烯醛〕=0. 09%、w〔(Z)- 2 庚烯醛〕=0.07%、w〔(E) 2- 癸烯醛〕=0 .08%、w〔(E,E) -2, 4 -癸二烯醛〕=0 .06%、w(辛酸 ) =0. 52%、w(癸酸 ) =0 66%、w(十二酸) =0. 57%、w(2, 4 二羟基 3, 6 -二甲基苯甲酸) =0. 13%、w(十四酸) =7 .76%、w(十五酸 ) =0 .19%、w(1, 2- 苯二甲酸) =0 .14%、w(9- 十六碳烯酸) =0. 37%、w(十六酸 ) =11. 25%、w(十七酸 ) =0 .21%、w-〔(Z,Z) 9, 12 -十八碳二烯酸〕=26. 09%、w〔(E) 9 十八碳烯酸〕=9. 58%、w(蒿醇) =0. 20%、w(环橙花叔醇 ) =0 88%、w(1- 二十二醇) =0 .20%、w(2- 十四烷氧乙醇 ) =0. 15%、w(3, 7, 11 -三甲基- 2, 6- 十二碳二烯 1 醇 ) = 0 08%、w(蒿酮) =0 .04%、w〔1 ( 4 -羟基- 3- 甲氧苯基 )乙酮〕= 2 .69%、w〔4- ( 2, 5, 6, 6 -四甲基环己 1 烯基 )丁- 2- 酮〕=0. 12%、w(5 甲基α 紫罗兰酮) =1 .22%、w〔1- (3, 4- 二甲氧苯基) 乙酮〕=0. 47%、w(3, 5, 5- 三甲基 -2- 环己烯-     

新型(6-氯喹喔啉-2-基氧基)苯基丙烯酸酯和丙烯腈衍生物的设计、合成及生物活性

以2,6-二氯喹喔啉为起始原料、经Baylis—Hillman反应设计并合成了4个结构新颖的（6-氯喹喔啉-2-基氧基）苯基丙烯酸酯和丙烯腈衍生物,其结构经红外、核磁、元素分析确认。生物活性测定结果表明2-（（3-（6-氯喹喔啉-2-基氧）苯基）（羟基）甲基）丙烯酸甲酯（3a）和2-（（4-（6-氯喹喔啉-2．基氧）苯基）（羟基）甲基）丙烯腈（3d）具有有效的杀菌活性,在400ga．i．／hm^2的剂量下对黄瓜霜霉病的防效分别为100％和75％。     

Dichlorophenylacrylonitriles as AhR Ligands That Display Selective Breast Cancer Cytotoxicity in vitro

Knoevenagel condensation of 3,4‐dichloro‐ and 2,6‐dichlorophenylacetonitriles gave a library of dichlorophenylacrylonitriles. Our leads (Z)‐2‐(3,4‐dichlorophenyl)‐3‐(1H‐pyrrol‐2‐yl)acrylonitrile ( 5 ) and (Z)‐2‐(3,4‐dichlorophenyl)‐3‐(4‐nitrophenyl)acrylonitrile ( 6 ) displayed 0.56±0.03 and 0.127±0.04 μm growth inhibition (GI₅₀) and 260‐fold selectivity for the MCF‐7 breast cancer cell line. A 2,6‐dichlorophenyl moiety saw a 10‐fold decrease in potency; additional nitrogen moieties (‐NO₂) enhanced activity (Z)‐2‐(2,6‐dichloro‐3‐nitrophenyl)‐3‐(2‐nitrophenyl)acrylonitrile ( 26 ) and (Z)‐2‐(2,6‐dichloro‐3‐nitrophenyl)‐3‐(3‐nitrophenyl)acrylonitrile ( 27 ), with the corresponding ‐NH₂ analogues (Z)‐2‐(3‐amino‐2,6‐dichlorophenyl)‐3‐(2‐aminophenyl)acrylonitrile ( 29 ) and (Z)‐2‐(3‐amino‐2,6‐dichlorophenyl)‐3‐(3‐aminophenyl)acrylonitrile ( 30 ) being more potent. Despite this, both 29 (2.8±0.03 μm ) and 30 (2.8±0.03 μm ) were found to be 10‐fold less cytotoxic than 6 . A bromine moiety effected a 3‐fold enhancement in solubility with (Z)‐3‐(5‐bromo‐1H‐pyrrol‐2‐yl)‐2‐(3,4‐dichlorophenyl)acrylonitrile 18 relative to 5 at 211 μg mL^?1. Modeling‐guided synthesis saw the introduction of 4‐aminophenyl substituents (Z)‐3‐(4‐aminophenyl)‐2‐(3,4‐dichlorophenyl)acrylonitrile ( 35 ) and (Z)‐N‐(4‐(2‐cyano‐2‐(3,4‐dichlorophenyl)vinyl)phenyl)acetamide ( 38 ), with respective GI₅₀ values of 0.030±0.014 and 0.034±0.01 μm . Other analogues such as 35 and 36 were found to have sub‐micromolar potency against our panel of cancer cell lines (HT29, colon; U87 and SJ‐G2, glioblastoma; A2780, ovarian; H460, lung; A431, skin; Du145, prostate; BE2‐C, neuroblastoma; MIA, pancreas; and SMA, murine glioblastoma), except compound 38 against the U87 cell line. A more extensive evaluation of 38 ((Z)‐N‐(4‐(2‐cyano‐2‐(3,4‐dichlorophenyl)vinyl)phenyl)acetamide) in a panel of drug‐resistant breast carcinoma cell lines showed 10–206 nm potency against MDAMB468, T47D, ZR‐75‐1, SKBR3, and BT474. Molecular Operating Environment docking scores showed a good correlation between predicted binding efficiencies and observed MCF‐7 cytotoxicity. This supports the use of this model in the development of breast‐cancer‐specific drugs.     

含三氟甲基或3,4,5-三甲氧基二苯乙烯腈衍生物的制备及其活性研究

以4-三氟甲基苯甲酸和3,4,5-三甲氧基苯甲酸为原料合成出2-(4-(三氟甲基)苯基)乙腈和2-(3,4,5-三甲氧基苯基)乙腈,将其作为中间体和几种醛类合成一系列含4-三氟甲基及3,4,5-三甲氧基二苯乙烯腈衍生物。所合成的化合物通过氢谱、碳谱与高分辨质谱进行表征后用MTT法在12种细胞上测得其细胞增殖抑制率,其中(Z)-3-(4-丙氧基苯基)-2-(3,4,5-三甲氧基苯基)丙烯腈显示最好的抗癌活性及选择性抑制活性,经进一步研究发现通过抑制细胞迁移与抑制集落形成达到抗癌效果,具有进一步开发研究的价值。     

Synthesis and spectral evaluation of some unsymmetrical mesoporphyrinic complexes

Synthesis and spectral evaluation of new zinc and copper unsymmetrical mesoporphyrinic complexes are reported. Zn(II)-5-(4-acetoxy-3-methoxyphenyl)-10,15,20- tris-(4-carboxymethylphenyl)porphyrin, Zn(II)-5-[(3,4-methylenedioxy)phenyl]-10,15,20- tris-(4-carboxymethylphenyl)porphyrin, Cu(II)-5-(4-acetoxy-3-methoxyphenyl)-10,15,20- tris-(4-carboxymethylphenyl)porphyrin and Cu(II)-5-[(3,4-methylenedioxy)phenyl]-10,15,20- tris-(4-carboxymethylphenyl)porphyrin were synthesized using microwave-assisted synthesis. The complexes were characterized by elemental analysis, FT-IR, UV-Vis, EPR and NMR spectroscopy, which fully confirmed their structure. The spectral absorption properties of the porphyrinic complexes were studied in solvents with different polarities. Fluorescence emission and singlet oxygen formation quantum yields were evaluated for the compounds under study, revealing high yields for the zinc derivatives. The copper complexes are not emissive and only display residual capacity for singlet oxygen formation.     

Study of Biological Activities and ADMET-Related Properties of Novel Chlorinated N-arylcinnamamides

A series of eighteen 4-chlorocinnamanilides and eighteen 3,4-dichlorocinnamanilides were designed, prepared and characterized. All compounds were evaluated for their activity against gram-positive bacteria and against two mycobacterial strains. Viability on both cancer and primary mammalian cell lines was also assessed. The lipophilicity of the compounds was experimentally determined and correlated together with other physicochemical properties of the prepared derivatives with biological activity. 3,4-Dichlorocinnamanilides showed a broader spectrum of action and higher antibacterial efficacy than 4-chlorocinnamanilides; however, all compounds were more effective or comparable to clinically used drugs (ampicillin, isoniazid, rifampicin). Of the thirty-six compounds, six derivatives showed submicromolar activity against Staphylococcus aureus and clinical isolates of methicillin-resistant S. aureus (MRSA). (2E)-N-[3,5-bis(trifluoromethyl)phenyl]- 3-(4-chlorophenyl)prop-2-enamide was the most potent in series 1. (2E)-N-[3,5-bis(Trifluoromethyl)phenyl]-3-(3,4-dichlorophenyl)prop-2-enamide, (2E)-3-(3,4-dichlorophenyl)-N-[3-(trifluoromethyl)phenyl]prop-2-enamide, (2E)-3-(3,4-dichloro- phenyl)-N-[4-(trifluoromethyl)phenyl]prop-2-enamide and (2E)-3-(3,4-dichlorophenyl)- N-[4-(trifluoromethoxy)phenyl]prop-2-enamide were the most active in series 2 and in addition to activity against S. aureus and MRSA were highly active against Enterococcus faecalis and vancomycin-resistant E. faecalis isolates and against fast-growing Mycobacterium smegmatis and against slow-growing M. marinum, M. tuberculosis non-hazardous test models. In addition, the last three compounds of the above-mentioned showed insignificant cytotoxicity to primary porcine monocyte-derived macrophages.     

The synthesis,absorption and fluorescence of polar diketo-pyrrolo-pyrroles

The effect of electron-donor (piperidino) and electron-acceptor (cyano) groups on the absorption maxima of some diketo-pyrrolo-pyrroles in DMSO solution was investigated both experimentally and theoretically. The syntheses of push–pull substituted 3-(4-piperidinophenyl)-6-(4-cyanophenyl)-2,5-dihydropyrrolo[3,4-c]pyrrol-1,4-dione are reported for the first time; 3,6-diphenyl-2,5-dihydropyrrolo[3,4-c]pyrrol-1,4-diones substituted with either one or two piperidino or cyano groups in the para-positions of the phenyl rings were also synthesized. Whilst both types of substituent produce a bathochromic and hyperchromic shifts with respect to the parent unsubstituted compound, the influence of the piperidino group is strongest. Symmetrically substituted derivatives show well-resolved vibronic structures, while the spectra of polar, unsymmetrical compounds were poorly resolved because of strong dipole–dipole interaction with the polar solvent. The fluorescence of all compounds was intense and a significant increase in the Stokes shift of polar derivatives was another consequence of dipole–dipole interactions with the solvent in the excited state.     

一种新型含砜基青成色剂的合成

采用对羟基苯硫酚和溴丁酸甲酯为原料合成含砜基型青成色剂N-{[3-羟基-4-(3,4-二氯苯甲酰氨基)-6-氯]苯基}-2-([4-十二烷氧基苯基)砜基]-丁酰胺,总收率43%,发色后吸收曲线与标样相同,感光性能接近标样。     

Amino Alcohol Acrylonitriles as Activators of the Aryl Hydrocarbon Receptor Pathway: An Unexpected MTT Phenotypic Screening Outcome

Lead (Z)-N-(4-(2-cyano-2-(3,4-dichlorophenyl)vinyl)phenyl)acetamide, 1 showed MCF-7 GI₅₀=30 nM and 400-fold selective c.f. MCF10A (normal breast tissue). Acetamide moiety modification ( 13 a - g ) to introduce additional hydrophobicity was favoured with MCF-7 breast cancer cell activity enhanced at 1.3 nM. Other analogues were potent against the HT29 colon cancer cell line at 23 nM. Textbook SAR data was observed in the MCF-7 cell line, in an MTT assay, via the ortho ( 17 a ), meta ( 17 b ) and para ( 13 f ). The amino alcohol -OH moiety was pivotal, but no stereochemical preference noted. But, these data did not fit our homology modelling expectations. Aberrant MTT ((3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) screening results and metabolic interference confirmed by sulforhodamine B (SRB) screening. Interfering analogues resulted in 120 and 80-fold CYP1A1 and CYP1A2 amplification, with no upregulation of SULT1A1. This is consistent with activation of the AhR pathway. Piperidine per-deuteration reduced metabolic inactivation. 3-OH / 4-OH piperidine analogues showed differential MTT and SRB activity supporting MTT assay metabolic inactivation. Data supports piperidine 3-OH, but not the 4-OH, as a CYP substrate. This family of β-amino alcohol substituted 3,4-dichlorophenylacetonitriles show broad activity modulated via the AhR pathway. By SRB analysis the most potent analogue was 23 b , (Z)-3-(4-(3-(4-phenylpiperidin-1-yl)-2-hydroxypropoxy)phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile.