水饱和离子液体中脂肪酶催化萘普生甲酯对映选择性水解

 对比研究了水饱和异辛烷和水饱和离子液体1-正丁基-3甲基咪唑六氟磷酸盐([bmim]PF6)中脂肪酶催化萘普生甲酯不对称水解反应. 结果表明,由于离子液体[bmim]PF6同时具有极性和疏水性,因而成为萘普生甲酯不对称水解反应的理想介质. 与水饱和异辛烷相比,水饱和离子液体不仅明显降低了水解反应的平衡常数(K),增大了对映体比率(E),从而有效提高了水解反应的平衡转化率(ceq)和产物的对映体过量值(eep),而且由于离子液体对另一产物甲醇的溶解度高,还明显地提高了脂肪酶的操作稳定性.     

Enantioselective Synthesis of Naproxen

The optically active naproxen was synthesized in good chemical yield and high optical purity starting from a chiral α-ketoalcohol which was prepared from enzymatic resolution of the corresponding racemic acetate using lipase as a catalyst.     

A Large-Scale Procedure for the Preparation of 3-Bromothiophene from 2-Bromothiophene and Sodamide in Liquid Ammonia

3-Bromothiophene can be prepared on a scale of several moles by treatment of 2-bromothiophene with an excess of sodamide in liquid ammonia and subsequent quenching of the reaction mixture with solid ammonium chloride.     

水饱和离子液体中萘普生的酶法拆分

 考察了五种水饱和离子液体反应介质中固定化脂肪酶催化外消旋萘普生甲酯的水解. 结果表明,这些具有不同阴阳离子组合的咪唑基离子液体作为反应介质都能促进水解反应的有效进行,但在水饱和1-正丁基-3-甲基咪唑六氟磷酸盐(［bmim］PF6)中,反应进行得更快,转化率更高. 这些离子液体对脂肪酶均有一定的溶解作用并使溶解的脂肪酶失活. 脂肪酶在离子液体中的溶解度与其剩余活性之间有一定的相关性. 为了解决脂肪酶在离子液体中的溶解问题,使用非极性、高比表面积的无定形多孔硅胶YWG-C6H5对脂肪酶进行了固定化. 在水饱和［bmim］PF6中使用固定化脂肪酶催化反应,反应72 h的转化率为28.3%, 产物的对映体过量值为98.2%, 继续进行反应,转化率将增加,但产物的对映体过量值明显下降. 利用离子液体有别于传统有机溶剂的特性,对离子液体的循环使用、产物的回收和水的补充方法进行了研究. 在反复批式反应中,固定化脂肪酶连续使用五次,活性仅略微下降.     

脂肪酶催化一步酯化协同拆分合成S-萘普生淀粉酯前药

利用CRL脂肪酶选择性催化外消旋萘普生甲酯与玉米淀粉进行转酯化反应合成光学纯S-萘普生淀粉酯前药,同时达到拆分外消旋萘普生的目的。考察了有机溶剂、脂肪酶用量、底物浓度比、反应温度对酯化协同拆分反应的影响,结果表明在异辛烷中脂肪酶CRL可以催化S-萘普生甲酯与淀粉发生转酯化反应同时完成外消旋萘普生的拆分,并且在脂肪酶用量为10%、底物浓度比为1:3、异辛烷用量为15mL、反应温度为60℃的条件下反应6d,外消旋萘普生甲酯的转化率为27.2%,产物对应体过量值eep高达99.4%可以作为萘普生的前药进行应用。     

Extractionless HPLC Method for the Determination of Naproxen in Human Plasma and Urine

Abstract

A simple and rapid (extractionless) high-performance liquid chromatographic method with ultraviolet detection, at 278 nm, is described for the determination of naproxen in human plasma and urine. Niflumic acid is used as internal standard. The chromatographic system consists of a reversed-phase C18-Spherisorb column with acetonitrile/0.1 M sodium acetate (35:65 v/v, pH 6.14) as the mobile phase. The retention time is 3.0 min for naproxen and 3.8 min for niflumic acid. The total run time is 5 min and the typical assay time is 10 min. The method is sufficiently sensitive for biopharmaceutical studies, after the oral administration of a single sustained release dose.     

Design,characterization and enhanced bioavailability of hydroxypropylcellulose-naproxen conjugates

Polysaccharides are beneficially used as drug carriers via prodrug formation and offer a mechanism for better effectiveness and delivery of the drug. The unique geometry of hydroxypropylcellulose (HPC), a polysaccharide, allows the attachment of drug molecules with a higher degree of substitution because the hydroxyls groups are projected outside the HPC chains. Therefore HPC-Naproxen conjugates, i.e., macromolecular prodrugs, were synthesized using a powerful acylation reagent carbonyldiimadazole (CDI) in N,N' dimethylacetamide (DMAc) solvent. The reactions were carried out at 80 °C under stirring for 24 h and inert environment. This reaction strategy appeared efficient to obtain a high degree of drug substitution (DS = 0.88–1.40) on the polymer parent chain as calculated by UV–visible spectrophotometry after hydrolysis of the samples. The method provides high efficacy as product yields were high (77–81%). Macromolecular prodrugs (MPDs) with different DS of naproxen designed were found soluble in organic solvents.     

The effects of conformation and intermolecular hydrogen bonding on the structural and vibrational spectral data of naproxen molecule

The structural and vibrational properties of naproxen, an inhibitor of cyclooxygenase (COX) enzyme, were investigated by molecular modeling and experimental IR and Raman spectroscopic techniques. Possible conformers of the molecule were searched via a molecular dynamics simulation carried out with MM2 force field. The total energies, equilibrium geometries, force fields, IR and Raman spectral data of the found stable conformers were determined by means of geometry optimization and harmonic frequency calculations carried out using the B3LYP method and Pople-style basis sets of different size. The stability order obtained for the lowest-energy conformers was confirmed by high-accuracy thermochemistry calculations performed with G3MP2B3 composite method. Some electronic structure parameters of naproxen and the anharmonicity characters of its vibrational modes were determined by means of natural population analysis (NPA) and anharmonic frequency calculations at B3LYP/6-31++G(d,p) and B3LYP/6-311++G(d,p) levels of theory. A part of these calculations carried out for free naproxen molecule were repeated also for its energetically most favored dimer forms. Two different scaling procedures ((1) “SQM-FF methodology” and (2) “Dual scale factors”) were independently applied to the obtained harmonic vibrational spectral data to fit them to the corresponding experimental data. In the light of the obtained calculation results, which confirm the remarkable effects of conformation and intermolecular hydrogen bonding on the structural and vibrational spectral data, in particular, on those associated with the functional groups in the propanoic acid chain, a reliable assignment of the fundamental bands observed in the experimental IR and Raman spectra of the molecule was achieved.     

Sensitive sequential injection determination of naproxen based on interaction with beta-cyclodextrin

A sensitive sequential injection analysis (SIA) methodology for the fluorimetric determination of naproxen is proposed. The developed automatic analytical procedure is based on the complexation of naproxen with β-cyclodextrin (β-CD) yielding an enhanced fluorimetric signal (λ_ex = 280 nm, λ_em = 356 nm).Linear calibration plots were obtained for naproxen concentrations up to 1 × 10⁻⁵ mol l⁻¹. The developed methodology exhibited a good precision, with a R.S.D. < 2.1% (n = 15). The detection limit of the determination was 1.9 × 10⁻⁷ mol l⁻¹ with a sampling rate of about 70 h⁻¹. The automatic method was applied to the determination of naproxen in pharmaceutical formulations. The obtained results were compared with those furnished by the reference procedure and the relative deviations were lower than 3.6%. No interference was found from the excipients usually used in solid pharmaceutical formulations.     

不对称催化氢化制备（S）—（＋）—萘普生：Ⅱ.不对称氢化反应条件

不对称催化氢化制备（Ｓ）－（＋）－萘普生１）Ⅱ．不对称氢化反应条件赵培庆宫照阳（中国科学院兰州化学物理研究所羰基合成与选择氧化国家重点实验室兰州７３００００）关键词萘普生不对称催化氢化反应条件分类号Ｏ６４３．３２不对称催化是分子催化研究中的前沿领域之...     

Thermodynamic quantities relative to solution processes of Naproxen in aqueous media at pH 1.2 and 7.4

Based on van’t Hoff and Gibbs equations, the thermodynamic functions Gibbs free energy, enthalpy, and entropy of solution, mixing and solvation of naproxen (NAP) in water at pH 1.2 and 7.4, were evaluated from solubility values determined at several temperatures. The solubility at pH 7.4 and 25.0°C was almost 150 times higher with respect to pH 1.2. The enthalpies of solution were positive and greater for pH 1.2, while the entropies of solution were both negative, thereby implying a greater molecular organization at pH 7.4. The results were discussed in terms of solute–solvent interactions.     

Interaction of Naproxen with transition metals: synthesis,characterization, anti-inflammatory activity and kinetic studies

Coordination complexes of transition metals (Co, Ni, Cu, Fe, Cr, Ru, Ir, Mn, and Zn) with 6-methoxy-α-methyl-2-naphthalene acetic acid (Naproxen) and triphenylphosphine have been synthesized and characterized by conductance, elemental analysis, UV-Vis, AAS, and FT-IR spectroscopy. The elemental analyses data reveal the presence of 1:1 (metal : ligand) stoichiometry and the IR data suggest that naproxen functions as a bidentate ligand in coordination with transition metals. The anti-inflammatory assays of these complexes have significant effect.     

Room-temperature luminescence optosensings based on immobilized active principles actives: Application to nafronyl and naproxen determination in pharmaceutical preparations and biological fluids

This paper presents two easy and selective methods for determining the active principles nafronyl (NFL) and naproxen (NAP), using a flow-through fluorescence optosensor based on the on-line immobilization on a nonionic-exchanger (Silica Gel, Davisil™ and Amberlite XAD 7, respectively) solid support. The determination was performed in 5×10⁻³ M HAc/NaAc buffer solution at pH 5 for NFL and 15×10⁻³ M glycine/HCl buffer solution at pH 2.5 for NAP at a working temperature of 20 °C. The fluorescence intensities were measured at λ_ex/em=294/336 nm and λ_ex/em=332/354 nm for NFL and NAP, respectively. The response time for these optosensors were practically instant, obtaining a linear concentration range between 0 and 700.0 ng ml⁻¹ with a detection limit of 20.8 ng ml⁻¹, an analytical sensitivity of 10.1 ng ml⁻¹ and a standard deviation of 1.27% at a 500 ng ml⁻¹ concentration level for NFL and a linear concentration range between 0 and 200.0 ng ml⁻¹ with the detection limit of 13.3 ng ml⁻¹, an analytical sensitivity of 6.0 ng ml⁻¹ and a standard deviation of 3.52% at a 100 ng ml⁻¹ concentration level for NAP. The proposed methods were satisfactorily applied to real samples (three commercial formulations and urine samples). The effects of the possible interferences were evaluated in all cases.     

萘普生分子印迹拆分及亲和吸附平衡常数的测定

分子印迹 (Molecular imprinting)是一种新的、很有发展潜力的分离技术 [1～ 3 ] .该技术已成功地用于氨基酸、糖类及其衍生物和药物的手性分离 .萘普生是一种重要的非甾体消炎、解热和镇痛药 ,为了减少给药量和对人体产生的毒副作用 ,必须对其进行手性拆分 . Mosbach等 [4 ] 曾以 4-乙烯基吡啶为功能单体 ,利用分子印迹对外消旋萘普生进行了手性拆分 ,但 4-乙烯基吡啶使用前需经过减压蒸馏 ,使用不便 . Haginaka等 [5～ 7] 也采用 4-乙烯基吡啶为功能单体 ,以 (S) -萘普生为模板制得了均一粒径的分子印迹介质 .尽管分子印迹分离技术发展…     

Voltammetric Analysis of Naproxen in Graphite Electrodes and Its Determination in Pharmaceutical Samples

The present work discuses new findings in the electrochemistry of naproxen over graphite electrodes. This new approach, allows the proposal of a simple and competitive low‐cost method to carry out naproxen’s voltammetric quantification. Naproxen’s indirect quantification through an adsorption anodic wave was performed at a graphite bar electrode using differential pulse voltammetry. An anodic current maximum was recorded at a potential of ?0.3 V referred to a saturated Ag/AgCl reference electrode. The calibration plot having a correlation coefficient of 0.990, sensibility of 4.19±0.62 µA cm³ µg^?1, with detection and quantification limits of 0.68 and 3.3 µg cm^?3, respectively.     

Solubility and Kinetic Release Studies of Naproxen and Ibuprofen in Soluble Epichlorohydrin-β-cyclodextrin Polymer

Naproxen (NAP) and ibuprofen (IBU) are poor water soluble anti-inflammatory drugs. A water-soluble epichlorohydrin-β-cyclodextrin polymer (β-CDEPI) was synthesized in a highly basic aqueous solution and at a molar ratio β-CD/EPI of 1:12. Drug solubility and kinetic release of NAP and IBU from the inclusion complexes they form with β-CDEPI as host was studied. Water solubility for both drugs in the presence of this polymer increased (NAP 0.28 mmol and IBU 0.40 mmol per gram of β-CDEPI). The apparent inclusion constants for both drugs in β-CDEPI were calculated from the solubility-phase diagrams with K_incl values of 4300 ± 100 L.mol^? 1 for NAP and 5100 ± 300 L.mol^? 1 for IBU. Kinetic release of Ibuprofen gave a pure Fick trend (t^1/2) behavior. However, for Naproxen a zero order was obtained (t). These results indicate that the nature and bulkiness of the drugs are ruling these kinetic behaviors in the environment of a highly branched polymer.     

对萘普生和萘普生甲酯的毛细管电泳手性分离

以磺化β－ＣＤ作为手性分离添加剂,分别对萘普生和萘普生甲酯进行了手性分离研究,当磺化β－ＣＤ的浓度为３．５％（Ｗ／Ｖ）时,萘普生和萘普生甲酯的手性分离度都可大于２,但萘普生与萘普生甲酯不能达到同时拆分。如果同时以磺化β－ＣＤ和ＨＰ－β－ＣＤ作为作为手性分离添加剂,则可对萘普生甲酯达到同时拆分,当磺化β－ＣＤ和ＨＰ－β－ＣＤ的浓度分别为３．５％和１．５％（Ｗ／Ｖ）时,对萘磺生和萘普生甲酯两种消旋体的     

萘普生及其衍生物的手性固定相法直接拆分机理

用不同的酰氯化合物与萘普生反应,制备了一系列萘普生衍生物。在正相色谱条件下,对萘普生及其衍生物系列在(R,R)-Whelk-O 1手性固定相(chiral stationary phase,CSP)上进行了对映体拆分研究。实验考察了流动相组成、分离温度等因素对手性分离的影响,并根据相应热力学参数对萘普生及其衍生物在该手性固定相上的手性识别机理进行了初步探讨。研究结果表明:萘普生及其衍生物在Whelk-O 1 CSP上的对映体分离有着与一般正相色谱明显不同的特征,其分离因子α值与流动相组成关系曲线出现了峰值,且分离因子极大值所对应的流动相组成分别为极性较大的20%(V/V,下同)异丙醇/正己烷混合溶剂体系和40%异丙醇/正己烷混合溶剂体系。     

Photochemistry of a naphthalene-thymine dyad in the presence of acetone

Irradiation of dyad 1 in aqueous acetone leads to the introduction of an acetonyl substituent at the naphthalene 5-position, to give photoproduct 2. The proposed reaction mechanism involves electron transfer from the naphthalene excited singlet state to the ketone. Neither thymine dimers, nor acetone photoadducts involving the thymine ring were detected. These photoproducts would arise from the thymine triplet excited state, which in dyad 1 must be efficiently depopulated via a fast intramolecular energy transfer to the naphthalene chromophore, due to the lower energy of its excited triplet state.     

脂肪酶的固定化及其在有机酶促反应中稳定性研究

利用吸附法,将圆柱状假丝酵母脂肪酶固定于４种疏水性不同的载体上,固定化酶的活性及稳定性随载休疏水性的增大而增大。用ＹＧＷ－Ｃ６Ｈ５作为载体,在有机溶剂－水双液相体系中催化萘普生甲酯的不对称水解,反应１２０ｈ转化率为２４．７２％,产品的对映体过量值为９４．８２％。