2，3-二氢-1-氨基-2-羟基-4-硝基茚的合成研究

最近几年，国外开发了不少以茚为母体的系列药物和兽药。如：以系列抗HIV药物L-689，502；L-685，927；L-735，524等、系列平滑肌迟缓药SARs及系列抗精神分裂药物。此外，作为农药应用，有日本开发的除草剂一茚草酮及美国杜邦公司于1992年开发，并于2001年登记上市的氨基甲酸酯类杀虫剂——茚虫威等。     

4-氯-2-氧代-1,2-二氢喹啉-3-甲醛的合成工艺研究

目的：对4-氯-2-氧代-1,2-二氢喹啉-3-甲醛的合成工艺进行研究。方法以苯胺为原料通过酯的氨解、环合、胺亚甲基化、水解反应得到目标化合物。结果合成了目标化合物,并利用MS和1H-NMR确证了结构,此路线所得产品收率为62.1%。结论此路线操作简单,成本低廉,设计合理,收率高,适合该化合物的工业化生产。     

1-[3-（3-苄基-4-乙氧基苄基）-4-氯苯基]-1,6-二脱氧-β-D-吡喃葡萄糖的合成工艺研究

目的：设计并合成1-[3-（3-苄基-4-乙氧基苄基）-4-氯苯基]-1,6-二脱氧-β-D-吡喃葡萄糖。方法以5-溴-2-氯-4＆#39;-乙氧基二苯甲烷为原料,通过Friedel-Crafts酰基化、还原、亲核加成、还原乙酰化、脱乙酰化反应的得到目标化合物。结果根据理化性质和波谱数据鉴定了目标化合物的结构,总收率为32%,质量分数为98.48%。结论1-[3-（3-苄基-4-乙氧基苄基）-4-氯苯基]-1,6-二脱氧-β-D-吡喃葡萄糖的合成为tianagliflozin中杂质的研究提供了方便。     

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??OBJECTIVE To prepare inclusion complex of SBE₇-??-CD with trimethoprim(TMP) and optimize the preparation process, to evaluate the products by structural characterization and molecular simulation. METHODS The TMP/SBE₇-??-CD inclusion complex was prepared by the ultrasound-freeze-dry method and the preparation process was optimized by Box-Behnken Design-response surface method(BBD-RSM). Inclusion complex was characterized by FT-IR, DSC, XRPD and ¹H-NMR. Molecular docking method was used to simulate 3-dimensional conformations of the inclusion complex and the binding energy was calculated. The dissolution and stability were tested. RESULTS The optimum conditions of TMP/SBE₇-??-CD inclusion complex were: temperature(52 ??), time(45 min), and the ratio of SBE₇-??-CD and TMP(mol/mol, 1.7??1). All characterizations(FT-IR, DSC, XRPD and ¹H-NMR) indicated the formation of TMP/SBE₇-??-CD inclusion complex. The best 3-dimensional docking conformation was consistent with the characterizations, and the binding energy was -9.015 kcal??mol^-1. The TMP dissolution rate of the inclusion complex increased significantly, the hygroscopicity is strong. CONCLUSION The preparation process of TMP/SBE₇-??-CD inclusion complex optimized by BBD-RSM is reasonable and feasible. The characterizations of inclusion complex are reliable. The molecular simulation is corresponded to the characterized results and provided reliable theoretical basis for inclusion experiments.     

铁皮石斛1-羟基-2-甲基-2-(E)-丁烯基-4-焦磷酸还原酶基因的克隆与表达分析

目的从铁皮石斛Dendrobium officinale中克隆1-羟基-2-甲基-2-(E)-丁烯基-4-焦磷酸还原酶[1-hydroxy-2-methyl-2-(E)-butenyl-4-diphosphatereductase,HDR]基因,并分析其在铁皮石斛不同组织中的表达差异以及不同信号分子诱导下的表达模式。方法采用RT-PCR和RACE等方法获得铁皮石斛HDR基因(Do HDR)全长,利用DNAMAN和MEGA6.0对其他物种的HDR基因编码的氨基酸序列进行同源性分析和进化关系分析,使用实时荧光定量分析HDR基因的表达模式。结果成功获得Do HDR基因,Gen Bank登录号为KC344827,全长1 658 bp,编码460个氨基酸,与其他科属植物的同源性达到80%以上。Do HDR基因在铁皮石斛叶片中表达量最高,从高到低依次是根、茎、原球茎;且受到脱落酸(abscisic acid,ABA)、水杨酸(salicylic acid,SA)信号分子的诱导。结论从铁皮石斛中获得Do HDR基因,为进一步阐明铁皮石斛萜类化合物合成途径中该基因的重要作用奠定了理论基础。     

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??Endogenous neurotoxin 1-methyl-6,7-dihydroxy-1,2,3,4 -tetrahydroisoquinoline (salsolinol,Sals), an endogenous dopamine metabolite, were shown to be toxic to dopaminergic neurons in vitro as well as in vivo, and was known to be involved in the pathogenesis of Parkinson??s disease (PD). Sals is a more realistic model for selective toxicity to nigral dopaminergic neurons, and mimic the natural course of PD that develops slowly, allowing the brain to adapt to progressive damage. Sals lead to neurotoxicity in dopaminergic cells through induction of oxidative stress and apoptotic dopaminergic cell death,which made it as an important tool drugs to study the pathogenesis of PD.     

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??OBJECTIVE To prepare small interfering RNA(siRNA) lipid complexes (TPOS-L/siRNA) modified by D-α-tocopheryl poly (2-ethyl-2-oxazoline) succinate (TPOS).METHODS The conventional siRNA lipid complexes (CLs/siRNA) and PEGylated CLs/siRNA (PEG-L/siRNA) were used as controls. CLs/siRNA was prepared by mixing blank CLs and siRNA directly of equal volume according to the electrostatic interaction of positive and negative charges. The encapsulation efficiency, morphology, stability, in vitro release and cell uptake of TPOS-L/siRNA were investigated.RESULTS The CLs/siRNA had obvious lipid bilayer structure, the encapsulation efficiency (EE) was (86.68±1.41)%, and the particle size of CLs/siRNA was less than 200 nm. The modification with TPOS or PEG-DSPE had no significant effect on the EE and particle size of CLs/siRNA, which could endow the lipid complexes with good stability. In addtion, TPOS-L/siRNA had good pH-sensitive property, and could respond to slightly acidic environment, which significantly enhanced the cell uptake.CONCLUSION TPOS can construct good siRNA carrier and increase the stability and pH sensitivity of the nanocarrier.     

中间体2-(2-羟乙基)-3-氨基-4-羧基吡唑的合成研究

 目的目的2-(2-羟乙基)-3-氨基-4-羧基吡唑是制备硫酸头孢噻利的重要中间体。方法经三步反应合成2-(2-羟乙基)-3-氨基-4-羧基吡唑:以氰乙酸乙酯为起始原料,与原甲酸三乙酯反应得2-氰基-3-乙氧基丙烯酸乙酯,与羟乙肼环合后再水解而得。结果在此条件下,收率可达60.8%。结论本实验方法与其他合成方法比较,具有收率高,操作容易,实用性强等特点,具有一定推广价值。     

高效液相色谱法测定2-(2,6-二氯苯基氨基)苯乙酸-4-(4-苯基-1,2,5-噁二唑-2-氧化物-3-)甲氧基苯甲酯原料药的研究

 目的采用反相高效液相色谱法建立2-(2,6-二氯苯基氨基)苯乙酸-4-(4-苯基-1,2,5-二唑-2-氧化物-3-)甲氧基苯甲酯(ZLR-8)原料药质量控制的方法。方法色谱柱为Lichrospher ODS柱(4.6 mm×250 mm),流动相为甲醇-乙腈-水(55∶20∶10),检测波长为226 nm,流速为1.0 mL·min^-1。结果中间体及各降解产物对样品测定不产生干扰,ZLR-8的浓度为11.18～223.6mg·L^-1时与峰面积呈良好线性关系(r=0.999 8,n=5),重复性良好(RSD%=0.47,n=6),检测限为54μg·L^-1。结论该方法可以用于ZLR-8原料药的含量测定和有关物质检查。     

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??OBJECTIVE To prepare the inclusion complex of Lignum dalbergia odorifera oil with hydroxyl-??-cyclodextrin(HP-??-CD), and to optimize the preparation process of it. METHODS The inclusion complex was prepared by the stirring-freeze-dry method. The preparation process was optimized by central composite design-response surface method (CCD-RSM),with the colligation score which was calculated by the yield of inclusion, the utilization rate of volatile oil and the content of trans-nerolidol as index. The inclusion complex was verified by phase-solubility method, DSC,UV and microscopical identification. RESULTS The optimum inclusion technology was: inclusion solvent 5% ethanol, stirring rate 500 r??min^-1, HP-??-CD to volatile oil 33??1, inclusion temperature 42 ??,inclusion time 2.5 h. The formation of inclusion complex can change the solubility, optical and thermodynamic properties of volatile oil. CONCLUSION The preparation process of inclusion complex of Lignum dalbergia odorifera oil with HP-??-CD optimized by CCD-RSM is reasonable and feasible, and provide a reliable experiment basis for its application.     

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??OBJECTIVE To isolate and purify 2??,3??,24-trihydroxy-12-alkene-28-ursolic acid from the roots of Actinidia eriantha Benth, establish its determination method, and compare the contents in different extracted parts and samples from different sources. METHODS An HPLC-PDA method was established for the content determination. The contents of 2??,3??,24-trihydroxy-12-alkene-28-ursolic acid in the roots of Actinidia eriantha Benth from five different sources and different extracted parts were determined by standard curve method. RESULTS The content of 2??,3??,24-trihydroxy-12-alkene-28-ursolic acid was higher in the samples from Shouning county of Fuzhou city and Yunhe county of Lishui city while lower in those from Yongjia county of Wenzhou city and Lishui city. And in different extracted parts, the content was the highest in dichloromethane part, lower in ethanol part, and the lowest in methanol part. CONCLUSION The method is stable and accurate with good reproducibility and can be used for the determination of 2??,3??,24-trihydroxy-12-alkene-28-ursolic acid in the roots of Actinidia eriantha Benth. The content of 2??,3??,24-trihydroxy-12-alkene-28-ursolic acid is different in Actinidia eriantha Benth samples from different sources, which is the highest in dichloromethane part.     

4-（2＇,3＇;-二氯苯基）-1,4-二氢-2,6-二甲基-3-吡啶甲酸甲酯的合成

目的：设计并合成4-（2＇,3＇-二氯苯基）-1,4-二氢-2,6-二甲基-3-吡啶甲酸甲酯。方法以2,3-二氯苯甲醛为起始原料经缩合、环合、水解反应制备得到目标化合物。结果合成了目标化合物,并利用MS和1H-NMR确证了结构;HPLC归一化法测得质量分数为98.3%。结论4-（2＇,3＇-二氯苯基）-1,4-二氢-2,6-二甲基-3-吡啶甲酸甲酯的合成为丁酸氯维地平中杂质的研究提供了方便。     

西洋参根中4-羟基-3-甲氧基-苯甲醛的分离鉴定

 目的对西洋参(Panax quinquefolius L.)进行化学成分研究。方法利用D101大孔树脂吸附-低压硅胶干柱色谱对西洋参醇提液进行分离,根据化合物的理化性质和光谱数据鉴定其结构。结果从西洋参(Panax quinquefolius L.)根中分离得到一个化合物,经核磁、质谱、紫外和红外光谱法鉴定为4-羟基-3-甲氧基苯甲醛。结论首次从西洋参根中分离得到4-羟基-3-甲氧基苯甲醛,其为镇静抗惊厥药物。     

(2S,3R)-1-二甲氨基-3-(3-甲氧基苯基)-2-甲基戊-3-醇的合成工艺研究

目的 对(2S,3R)- 1-二甲氨基-3-(3-甲氧基苯基)-2-甲基戊-3-醇合成工艺进行研究.方法 以3-戊酮为起始原料,经Mannich反应、手性拆分、Grignard反应等步骤合成(2S,3R)-1-二甲氨基-3-(3-甲氧基苯基)-2-甲基戊-3-醇,并对化学拆分进行工艺优化.结果 合成(2S,3R)-1-二甲氨基-3-(3-甲氧基苯基)-2-甲基戊-3-醇,总收率为30.6％.结论 工艺改进后提高了目标产物的收率,同时也减少了原料的浪费.     

白及中2,7-二羟基-4-甲氧基-9,10-二氢菲含量的高效液相色谱法测定

目的 建立白及中2,7 -二羟基-4-甲氧基-9,10-二氢菲高效液相含量测定方法.方法 采用Hypersil ODS(4.6mm x 250 mm,5μm)色谱柱,以40％乙腈/水(V/V)为流动相,流速1.0 ml/min,检测波长为280 nm,柱温30℃.结果 2,7-二羟基-4-甲氧基-9,10-二氢菲在0.027 -0.437 μg呈良好的线性关系,r=0.999 5,平均回收率98.64％.结论 该方法简便、快速、准确、灵敏度高,可用于白及的质量控制.     

3-乙酰基-11-羰基-β-乳香酸在大鼠体内的代谢途径研究

目的 研究3-乙酰基-11-羰基-β-乳香酸(AKBA)在大鼠体内的代谢途径.方法 大鼠ig AKBA 60 mg/kg后,收集胆汁、尿液及粪便,应用高效液相色谱-四级杆-离子阱质谱(HPLC-QTRAP-MS)技术分析AKBA在大鼠体内的代谢途径.结果 共检测到除原形药物外的15个代谢产物,提示AKBA在大鼠体内的主要代谢途径为去乙酰化、单羟基化、脱氢化及葡萄糖醛酸结合物.结论 AKBA在大鼠体内经历了广泛的Ⅰ相、Ⅱ相代谢,产生的代谢产物主要通过粪便及胆汁排泄;利用QTRAP技术的自动切换扫描(IDA)软件及增强型产物离子(EPI)扫描功能,能够快速得到高质量的MS2谱图,为AKBA代谢产物的鉴定提供了有效的检测手段.     

1-羟基茚-2-甲酸的合成△

目的：Knoevenagel反应合成1-羟基茚-2-甲酸。方法：以邻苯二甲醛和丙二酸为原料，以三乙胺或哌啶为催化剂，进行合成反应。结果：合成反应产物经1H—NMR和13C-NMR波谱测定，确定其化学结构为1-羟基茚-2-甲酸。结论：以邻苯二甲醛和丙二酸为原料，以三乙胺或哌啶为催化剂，反应产物是1-羟基茚-2-甲酸。     

气相色谱法对药物中间体5-氯-2-异丙基-4-戊烯酸苯乙胺盐的质量分析

目的:采用气相色谱法建立5-氯-2-异丙基-4-戊烯酸苯乙胺盐(以下简称SintonB)异构体和手性测定方法。方法:用岛津GC2010型气相色谱,以空气、氢气、氮气、氦气(手性测定)为载气。结果:在50～90mg/mL范围内峰面积与浓度呈良好的线性关系,精密度(RSD=0.16%)良好。该方法重现性、稳定性良好。结论:本方法简便,迅速,准确,专属性强。     

(1E,4E)-1,5˫(2,3-������������)��-1,4-��ϩ-3-ͪ������ĺϳɼ������⿹θ�����Ե��о�

??OBJECTIVE To explore the efficient and economical synthesis method of asymmetric monocarbonyl curcumin analogues(AMCACs), design and sgnthesize a series of B19(1E,4E)-1,5-bis(2,3-dimethoxyphenyl)penta-1,4-dien-3-one analogs to investigate their anti-gastric cancer activities in vitro.METHODS A series of asymmetric B19 analogues containing 2,3-dimethoxyphenyl were designed via the combination principle of medicinal chemistry, and obtained a method for synthesizing intermediate (E)-2-(2,3- dimethoxybenzylidene)cyclopentanone by one step catalyzed by L-proline. The targeted compounds were screened by MTT assay, and colony cloning experiments were used to further verify its anti-gastric cancer activity in vitro.RESULTS Ten novel target compounds were synthesized, and the structures were confirmed by LC-MS and ¹H-NMR spectral analysis. Among them, compound 6e had the highest inhibitory activity on the growth of gastric cancer cells SGC-7901 and BGC-823, whose IC₅₀ were 9.80 and 13.50 μmol·L^-1, respectively.CONCLUSION L-proline could be used as a catalyst to synthesize asymmetric monocarbonyl curcumin analogues efficiently and economically. Compound 6e could effectively inhibit the growth of gastric cancer cells in vitro, and its toxicity and inhibition mechanism of tumor cell growth need to be further studied.     

4-（6-脱氧-β-D-吡喃葡萄糖基）-1-甲氧基-2-【（反式-4-正丙基环己基）甲基】苯的合成及其晶型研究．

目的寻找一条合成目标化合物4-（6-脱氧-β-D-吡喃葡萄糖基）-1-甲氧基-2-【（反式-4-正丙基环己基）甲基】苯的简易路线,并研究其晶型。方法利用苯基溴化物片段和6-脱氧葡萄糖酸内酯片段作为起始原料合成目标化合物;采用有机混合溶剂和含水混合溶剂结晶的方式制备目标化合物的晶型,采用粉末X射线衍射分析和热重-差热分析技术对其进行表征,并对其进行了初步稳定性研究。结果目标化合物的总收率为74％,通过上述制备方法获得了同一种晶型,该晶型对光、热和湿均是稳定的。结论设计了一条合成目标化合物的简易路线,该路线操作简便、路线短、收率高,并制备了一种具有良好稳定性的目标化合物的晶型。