亚氨基二乙酸及其双乙酯的合成研究

目的主要研究一步法合成亚氨基二乙酸二乙酯以及催化剂的用量、醇酸摩尔比、反应时间等因素对酯化反应的影响.方法通过氯乙酸法和脱氢氧化法分别合成了亚氨基二乙酸,采用十二水合硫酸铁胺催化直接酯化法合成亚氨基二乙酸二乙酯,并通过正交实验优化酯化反应条件.结果十二水合硫酸铁胺催化合成亚氨基二乙酸二乙酯,酯化反应适宜条件是催化剂2 g/1 mol酸,mol酸∶mol醇=1∶8,反应时间是3 h,转化率在85.0%以上.结论十二水合硫酸铁胺催化合成亚氨基二乙酸二乙酯,催化剂活性高,反应温和,操作简单,收率优良.     

Eco-friendly synthesis of maleate ester: A comparison between solid acid and enzyme-catalyzed esterification

In this study, two different eco-friendly methods were investigated for the synthesis of a dicarboxylic acid ester, dimethyl maleate (DMM). One method involves application of molybdate sulfuric acid (MSA) as a solid acid catalyst in the esterification of maleic acid with methanol. The effects of three parameters namely, temperature, time, and catalyst amount on the product synthesis were determined. By using response surface methodology (RSM) based on central composite rotatable design (CCRD), maximum conversion of the maleic acid (87.6%) was obtained at reaction conditions of 120 °C, 0.27 g MSA, and 103 min. In the other method, DMM was synthesized by enzymatic esterification using immobilized Candida antarctica lipase B as the catalyst. Maximum conversion was 72.3%, at the optimal conditions of 62.5 °C, 0.27 g enzyme, and 249 min. The reusability study showed that MSA lost its catalytic activity after five cycles. However, the immobilized enzyme maintained its activity and stability. The results indicated that both employed methods were efficient for the synthesis of DMM. A higher conversion could be obtained using MSA as the catalyst, which could be compensated by better reusability of the enzyme. The enzyme-catalyzed reaction was more energy efficient but it took a longer time to obtain maximum reaction yield.     

对甲苯磺酸催化合成苯甲酸薄荷酯

目的：用对甲苯磺酸做催化剂,苯甲酸和薄荷醇作为原料合成苯甲酸薄荷酯的反应条件进行研究。方法：考察反应时间、醇酸比、催化剂用量因素对合成苯甲酸薄荷酯的影响,得到合成酯的适宜条件。结果：最佳的反应条件：反应时间为8.0h,醇酸摩尔比为1.0：1.4,催化剂用量为反应物料总量的3%。以述条件下,苯甲酸薄荷酯产率可高达80.0%。结论：对甲苯磺酸为合成苯甲酸薄荷酯的良好催化剂,具有较高实际应用价值,酯收率较高,实验的合成工艺简单。     

有机化学实验邻苯二甲酸二丁酯制备的绿色化研究

以对甲苯磺酸（PTS）为催化剂,邻苯二甲酸酐和正丁醇为原料,微量实验合成邻苯二甲酸二丁酯。最佳反应条件为：邻苯二甲酸酐为0．02mol,丁醇、苯酐物质的量比为3：1,催化刑用量为原料邻苯二甲酸酐物质的量的1．5％。反应时间0．45h,回流反应下酯化率可达95．8％。反应时间短．催化剂用量少易分离。能够重复使用,酯化率高,不污染环境,符舍绿色化学原则。     

Solid-state esterification of codeine phosphate by the acid constituent of effervescent tablets

Codeine phosphate in a paracetamol:codeine effervescent tablet was found to react at room temperature and 37 degrees C with the citric acid constituent to form citrate esters of codeine. The esterification was confirmed in a solid-state reaction at elevated temperature. The structures of the three possible monosubstituted esters (1-3) were elucidated from spectroscopic data (nuclear magnetic resonance and mass spectrometry) and by selective hydrolysis of the dimethyl esters to give symmetrical and asymmetrical dimethyl citrates. In the degradation reaction, formation of the symmetrically substituted citrate ester of codeine, 1, was found to predominate. Tartaric acid, which can be used in effervescent tablet formulations, was also found to give an ester with codeine phosphate in a similar nonsolvolytic reaction. A liquid chromatographic method was developed for the separation of the citrate esters of codeine.     

Kinetic study of peptide synthesis in the presence of imidazole

The interaction of N-protected amino acid active esters with imidazole has been found to be a reversible reaction. The rate constant values for a direct reaction of tert.-butyloxycarbonylglycine p-nitrophenyl ester with imidazole and for a reverse reaction of tert.-butyloxycarbonylglycine imidazolide with p-nitrophenol are reported. The effect of imidazole on the kinetics of active ester and imidazolide reactions with l -threonine methyl ester were studied. The influence of imidazole on the kinetics of O-acylation of N-benzyloxycarbonyl-l -serine amide was also investigated. The data obtained enable the optimum strategy to be chosen in the synthesis of peptides containing hydroxy-amino acid and histidine residues.     

头霉素关键中间体7-MAC的合成方法改进

目的改进头霉素关键中间体7α-甲氧基-7β-氨基-3-[（1-甲基-1H-四氮唑-5-基）硫甲基]头孢-3-烯4-羧酸二苯甲酯（7-MAC）的合成方法。方法以7-氨基-3-乙酰氧甲基头孢烯酸（7-ACA）为原料,经亲核取代反应合成3-（1-甲基-1胁四氮唑-5-基）硫甲基-7-氨基头孢烯酸（2）,2经取代．消除反应、酯化反应制得7-甲硫亚胺-3-[（1-甲基-1H-四氮唑-5-基）硫甲基]头孢-3-烯4-羧酸二苯甲酯（5）,在中间体5的7α位引入甲氧基制得目标化合物7-MAC。结果与结论目标化合物的结构经质谱、核磁共振氢谱确证,总收率为60％以上,纯度为99．1％,透光率高于75％。该方法反应条件温和,得到的产品质量好,有利于工业化生产。     

苄青霉素亚砜对-甲氧基苄酯的合成研究

以苄青霉素钾盐为原料，用低浓度CH3CO3H作氧化剂．所得苄青霉素亚砜以固体形式直接从溶液中结晶析出，再以对-甲氧基苄氯酯化，制得头孢类药物的母核7-苯乙酰胺基-3-氯甲基头孢烷酸对甲氧苄酯（GCLE）的关键中间体苄青霉素亚砜对-甲氧基苄酯，实验总收率82．6％。本工艺只使用一种有机溶剂，缩短了皮应时间，降低了成本，适合规模生产。     

一种改进的匹多莫德制备方法

以L-半胱氨酸和L-焦谷氨酸为起始原料,经两步合成匹多莫德.在传统的合成方法的基础上进行了一定的改进,在第二步的酯化反应中直接用盐酸乙醇作为酯化溶剂,所得L-噻唑烷基-4-羧酸乙酯盐酸盐不经提纯在乙酸乙酯溶液中直接用碳酸钾中和.整个工艺操作简单,对设备无苛刻要求,收率及产品纯度高,适合工业化生产.     

Effect of tertiary amines and amine salts on racemization in peptide synthesis

An effect of different tertiary amines, anions and cations on yield, product purity and reaction rate in DCC-mediated Ac-Phe-Leu-OMe synthesis was studied. Degree of racemization and side-product yields down to 0.05% were readily determined by HPLC. The increasing effect of tertiary amino salts on degree of racemization was determined more precisely than previously and, more interestingly, their suppression of N-acylurea formation was discovered. Unexpectedly, we found that the suppressing effect of the racemization of l-hydroxybenztriazole was completely blocked by tribenzylamine. Furthermore, kinetic investigation showed that degree of racemization was not directly linked with 5(4H)-oxazolone formation and aminolysis. The much greater racemization observed than calculated from the rate of formation and aminolysis of 5(4H)-oxazolone led us to the conclusion that an activated form of Ac-Phe other than 5(4H)-oxazolone could be co-responsible for racemization in the investigated reaction. An efficient method for preparation of N-(acetyl-DL-phenylalanyl)-dicyclohexylurea is described.     

Cholesterol ester hydrolase mediated conjugation of haloethanols with fatty acids

The formation of fatty acid conjugates of haloethanols was studied under in vitro conditions by using purified bovine pancreatic cholesterol ester hydrolase (EC 3.1.1.13). The enzymatic formation of 2-chloroethyl and 2-bromoethyl esters of oleic, linoleic, linolenic, and arachidonic acids was confirmed by proton nuclear magnetic resonance spectroscopy and chemical ionization mass spectrometry. 2-Bromoethanol was a better substrate than 2-chloroethanol for fatty acid esterification using cholesterol ester hydrolase. Among the chloroethanols, 2-chloroethanol was a better substrate than 2,2-dichloroethanol and 2,2,2-trichloroethanol. The saturated fatty acids (palmitic and stearic) showed a small amount of ester formation when cholesterol ester hydrolase was used. The kinetics of haloethanol and oleic acid incorporation into haloethyl oleate catalyzed by cholesterol ester hydrolase were determined. In vitro experiments were also conducted to study the conjugation of haloethanols with fatty acids using rat liver microsomes. The saturated fatty acid (palmitic) was more reactive compared to unsaturated fatty acid (oleic) when haloethanols were used. The results using rat liver microsomes were in contrast to those obtained when cholesterol ester hydrolase was used. The synthesis, purification, and characterization of 2-chloroethyl and 2-bromoethyl esters of oleic, linoleic, linolenic, and arachidonic acids are also described.     

Binding of DNA to albumin and transferrin modified by treatment with water-soluble carbodiimides

N-Acylurea derivatives of albumin and transferrin prepared with the water-soluble carbodiimides N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide and N-ethyl-N'-(3-trimethylpropylammonium)carbodiimide iodide have been found to bind different types of DNA. The two proteins were reacted with varying amounts of carbodiimide in water at pH 5.5 for 36-60 hr at 20 degrees, and then purified. In the case of iron-loaded transferrin, reactions with carbodiimides were in phosphate-buffered saline (pH 7.5) to prevent loss of iron from the protein. [3H]N-Ethyl-N'-(3-trimethylpropylammonium)carbodiimide iodide was used for the determination of covalently attached N-acylurea groups in the modified proteins, and gel electrophoresis for changes in charge and possible aggregation through cross-linking. Binding of DNA to N-acylurea proteins was studied by means of gel electrophoresis and nitrocellulose filter binding. N-Acylurea albumin and N-acylurea transferrin at low concentrations retarded the migration of lambda-Pstl restriction fragments, pBR322 plasmid and M13 mp8 single-stranded DNA on agarose gels, while at higher concentrations of modified protein the N-acylurea protein-DNA complexes were unable to enter the gel. Nitrocellulose filter assays showed that binding pBR322 DNA and calf thymus DNA to N-acylurea proteins is rapid and dependent on protein concentration and the ionic strength of the medium. N-Acylurea albumins prepared with each each of the two carbodiimides gave comparable plots for DNA bound versus protein concentration. On the other hand, binding of DNA by N-acylurea transferrins differed according to the carbodiimide used in the synthesis. N-Acylurea CDI-tkransferrin (prepared with tertiary carbodiimide) was less effective than either of the two N-acylurea albumins in binding DNA. In contrast with these results, N-acylurea Me+-CDI-transferrin (prepared with quaternary carbodiimide) was far more effective in binding DNA and in this respect was similar to the N-acylurea albumins. On the basis of experiments in which N-acylurea protein-DNA complexes were treated with heparin, two types of binding could be distinguished. These were a weak binding occurring in the initial stages of interaction and a tight binding which developed on further incubation of the complexes. These studies show that binding of DNA by N-acylurea proteins is a reversible process dependent on ionic strength; interaction appears to be electrostatic in nature, although other forms of binding might be involved.(ABSTRACT TRUNCATED AT 400 WORDS)     

丹酚酸A衍生物的合成方法研究

目的：探讨六甲基丹酚酸A、苄酯的合成方法。方法：以3-甲基邻苯二酚为原料，将酚羟基醚化保护，通过氯甲基化，Sommelet反应，Knoevenagel缩合，Wittig反应，还原，酯化等多步反应，同时使用硼氢化钾代替锌汞齐还原羰基，通过乙酰化反应对丹参素及其衍生物进行结构修饰。结果：得到酚羟基醚化保护的衍生物-六甲基丹酚酸A苄酯，经^1H—NMR证实其结构。结论：为人工全合成丹酚酸A提供了必要的基础。     

3-己基异香豆素的合成研究

目的研究3-己基异香豆素的合成方法。方法以邻碘苯甲酸为原料,经酯化、Sonogashira交叉偶联以及亲电环化反应三步合成3-己基异香豆素。结果重点考察了催化剂、配体和碱等因素对Sonogashira交叉偶联反应的影响,以及催化剂、溶剂和温度等因素对亲电环化反应的影响,在最佳的反应条件下,反应总产率为79.5%,中间产物和目标产物的结构经NMR和MS得以确证。结论该法操作简单,收率较高,产物立体选择性好。     

新型肝靶向载体[(2-乳糖酰胺基)乙胺基]甲酸胆固醇酯的合成与鉴定

目的将肝靶向基团半乳糖基引入到胆固醇结构中,制备[(2-乳糖酰胺基)乙胺基]甲酸胆固醇酯(CH-ED-LA)。方法以乳糖酸、乙二胺和胆固醇氯甲酯为原料,设计了内酯法和活性酯法2条合成路线,通过一系列酯化反应和酰化反应合成CH-ED-LA,采用IR、MS和NMR对其进行表征。结果采用工艺简单、收率较高的内酯法合成CH-ED-LA。结论CH-ED-LA是乙二胺与乳糖酸和胆固醇氯甲酯通过酰胺键连接的半乳糖化胆固醇衍生物。     

固体酸催化合成3-苯甲酰基丙烯酸乙酯的工艺

目的 提高3-苯甲酰基丙烯酸乙酯的产品纯度和总收率.方法 以SO2-4/Si2O2-TiO2复合固体超强酸作为酯化反应催化剂,以苯和顺酐为起始原料,经傅-克、酯化反应制得目标产物,并采用精馏脱水酯化工艺,不断排除酯化过程中的水.结果 酯化毕,用烷基苯转型,产品纯度>98%,总收率≥75%.结论 合成的3-苯甲酰基丙烯酸乙酯,以SO2-4/Si2O2-TiO2复合固体超强酸作为酯化反应的催化剂,可提高产品的纯度和总收率.     

关于血吸虫病药物的研究 Ⅰ.硫代水楊酸类化合物的合成

利用硫代水杨酸和它的甲基、丁基、苄基醚、以及双硫代水杨酸为原料,与β-二乙氨基氯乙烷及β-(1-六氢吡啶基)-氯乙烷在异丙醇中起Horenstein与Pahlicke反应,制成六个碱性酯类化合物的盐酸盐.曾由中国科学院药物研究所对这六个化合物进行治疗日本血吸虫病动物疗效试验,初步认为对小白鼠无治疗效果.     

Identification of reaction products between drug substances and excipients by HPLC–SPE–NMR: Ester and amide formation between citric acid and 5-aminosalicylic acid

The reaction between the high-dose drug substance 5-aminosalicylic acid (5-ASA) and the excipient citric acid during storage of an experimental enema preparation has been studied and three isobaric reaction products, i.e., an ester and an amide with non-symmetrically substituted citric acid moieties and a symmetrical amide, were identified by combined use of HPLC–SPE–NMR and HPLC–MS. After storage for 1 week at 70 °C, approximately 5% of the 5-ASA present in the formulation was transformed into these impurities. Storage of the enema for 32 months at room temperature led to loss of approximately 10% of the original amount of 5-ASA, with the ester as the main reaction product.     

阿德福韦酯的合成

用亚磷酸二乙酯和多聚甲醛经缩合、酯化得到对甲苯磺酸二乙氧基磷酰基甲酯(6)。另用腺嘌呤和碳酸亚乙酯反应得到9-(2-羟乙基)腺嘌呤,与6在NaH作用下缩合后,经水解、酰化等反应制得抗病毒药阿德福韦酯,总收率18%。     

Kinetics and mechanisms of vinpocetine degradation in aqueous solutions

Under stressed conditions, vinpocetine (1; ethyl apovincamin-22-oate) equilibrates with vincaminic acid ethyl ester (2) and 14-epivincaminic acid ethyl ester (3), and hydrolyzes to apovincaminic acid (4). Sequentially, 2 is equilibrated with 14-epivincaminic acid ethyl ester (3) and hydrolyzes to vincaminic acid (5), which equilibrates with 4 and 14-epivincaminic acid (6). At acidic pH, the major route of degradation is 1 in equilibrium 2----5. However, at neutral pH, the major route of degradation is 1----4 in equilibrium 5. The kinetics for the degradation of 1 in the pH 1-3 region is represented by a consecutive reaction with a reversible step (second-order), but the degradation of 1 in the pH 3.5-6.0 region follows pseudo first-order kinetics. Significant buffer catalysis is observed with acetate and phosphate buffers. Reactions are dependent on the ionic strength, pH, and temperature. No oxygen effect on the degradation of vinpocetine is found.