Development of an efficient and safe process for a grignard reaction via reaction caloremetry

A Grignard reaction of reactantA and phenyl magnesium chloride is used to make a pharmaceutical intermediate at the production scale. The elimination of protecting groups onA was proposed as a means to reduce synthesis costs. This new synthesis route, however, had process efficiency and safety issues associated with it: (1) build-up of unreactedA in the reactor, (2) influence ofA's particle size on the reaction rate, (3) the sensitivity of the reaction rate to the reaction temperature and to the (changing) solvent composition, and (4) the highly exothermic nature of the reaction.The Mettler RC1 Reaction Calorimeter was used to quantify the influence of solvent composition, temperature, and particle size on the reaction rate. Results indicated a dramatic effect of solvent composition and reaction temperature on the reaction rate; for example, over a temperature range of just 30°C, the reaction time decreased from more than a day to just a few minutes. At such high reaction rates, the vessel jacket could not remove the reaction heat sufficiently and the internal temperature rose adiabatically.These results were used to make process design and operation recommendations for safe and efficient plant operation with this modified Grignard reaction system.The authors would like to thank the following for their assistance in this work: E. Daugs for preparing the Grignard reagents, K.L. Gonzales for her help in running the experiments and in the subsequent data work-up; P.M. Russell for his assistance in the design of the slurry addition assembly, and K. Chritz and J. Engel for performing the HPLC analyses of the samples.     

Capillary Electrophoretic Determination of Citalopram in Pharmaceutical Tablets and Serum

Determination of citalopram by capillary electrophoresis is described. Compounds were separated at 28 kV in 75 μm i.d. fused silica capillary tubing (total length 85 cm, effective length 65 cm) with 10 mM borate buffer, pH 8.5, containing 10% (v/v) methanol as running buffer. Citalopram and propylparaben (IS) appeared at 3.5 and 5.5 min, respectively. Repeatable linear results were obtained. The limits of detection and quantification were 5.73 × 10⁻⁶ and 1.72 × 10⁻⁵ M, respectively. When citalopram was determined in a pharmaceutical tablet by capillary electrophoresis and by a UV-spectrophotometric method differences between the results were not significant. The citalopram content of tablets was 100.8 ± 2.95% of the label claim. The amount found in serum was 26.7 ± 0.1% of the free drug, indicating that 73.3% of the drug was bound to protein.     

Synthetic studies of 3-(3-fluorooxindol-3-yl)-l-alanine

Oxidative fluorination of several protected tryptophans 8b-g with Selectfluor™ proceeded smoothly in aqueous media to give a diastereomeric mixture of the corresponding 3-fluorooxindoles 9b-g. Attempted deprotection of the 3-fluorooxindoles 9b-g under various conditions did not afford 3-(3-fluorooxindol-3-yl)-l-alanine (6). Reaction of the suitably protected tryptophan derivative 16 with Selectfluor™ produced the fluorinated product 17. Simultaneous cleavage of all protective groups of 17 under acidic conditions successfully gave the target compound 6 in excellent yield.     

Modelling chromatographic behaviour as a function of pH and solvent composition in RPLC

Summary In this work we establish the basic layout of IONICS, an expert system for optimizing the separation of ionogenic solutes in Reversed-Phase Liquid Chromatography, using the pH and the organic-modifier concentration of the mobile phase as parameters. We also present REMO, a front-end system that automates the retention modelling stage, based on a 9-parameter model. This system uses a scale transformation to suppress several numerical problems previously observed and features a strategy for automatic calculation of an initial approximation to the model optimum. The successful application of this system to a set of seven drugs is described. The final models are accurate and have smaller numerical problems. We also describe the use of a genetic algorithm instead of classical non-linear least-squares for fitting the model to the experimental data. Results indicate that genetic algorithms are a valuable, complementary tool for retention modelling.     

Interaction of Photoactive[Fe（CN）6]4^- with TiO2 Anatase（101） Surface： A Periodic Density Functional Theory Study

The plane-wave pseudopotential function method,based on density-functional theory,has been used to calculate the adsorption,electronic band structures,orbitals and optical absorption spectrum of [Fe(CN)6]4-on TiO2 anatase(101) surface. Our calculations reveal that the surface-modified anatase system has large adsorption energy and a much narrower band gap. [Fe(CN)6]4-adsorption on the (101) surface could lead to a large red shift of the anatase optical absorption threshold,which extends into a visible region significantly. The calculated results are in agreement with the experiment and other theoretical studies reasonably. It is very important for the understanding and further development of photovoltaic materials that are active under visible light.     

The early stages of the sol-gel processing of TEOS

The reactivity of tetraethoxysilane (TEOS) used in many sol-gel syntheses can be increased by prehydrolysis. In contrast to one-step prehydrolysis acidic two-step prehydrolysis causes an increase of the reactivity of the low molecular species provided the total water/TEOS ratios are the same in both cases. By choice of the processing conditions of the hydrolysis—shown on variation of water content, hydrolysis steps and heat treatment—the degree of condensation, the ratio of hydrolyzable (-OC₂H₅) and hydrolyzed groups (-OH) and the structure of the low molecular species (short chains, 3-membered and 4-membered rings) can be influenced systematically. The development of the building units formed in the early reaction stages is ascertained by molybdate method and ²⁹Si NMR measurements.     

Synthesis of TRITON™ X-based phosphate ester surfactants and their self-charring behavior

This paper describes the synthesis and characterization of a series of TRITON™ X-based surfactants with a predominantly alkyl phenol ethoxylate (APE) backbone and a phosphate ester chain end. Four phosphate-terminated TRITON™ X (or APE) derivatives (OPE2-OPO(OH)₂, OPE5-OPO(OH)₂, OPE10-OPO(OH)₂, and NPE10-OPO(OH)₂) were prepared from commercially available octyl phenol ethoxylate (OPE) of different oxyethylene units (n = 2, 5 and 10), nonyl phenol ethoxylate (NPE) of 10 oxyethylene units and phosphorous pentoxide via a simple condensation reaction. Depending on their composition and chain length of oxyethylene units used in the reaction, the surfactants show different self-charring behaviors. The phosphate-terminated TRITON™ X of the lowest number of oxyethylene units (i.e. OPE2-OPO(OH)₂) gives the largest amount of char (up to 23 wt%) at 600 °C under air condition. The carboxylic acid-terminated TRITON™ X derivatives (i.e. OPE-COOH) were also tested for comparison.     

Changes in Rat Retinal Ganglion Neuronotrophic Factor and Its mRNA During Postnatal Development

The monoclonal antibody specific to the retinal ganglion neuronotrophic factor (RGNTF) was used to localize and quantify the presence and amount of RGNTF during the postnatal development of the visual system in the rat.The results showed that in the 0-1-day age group, neurons at the superficial layers and deep part of superior colliculus, and as well as retinal ganglion cells were strongly stained with their RGNTF contents quantified to be 88%, 100% and 100%, respectively. In the 5-6-day age group, RGNTF contents were significantly reduced to merely 50%, 30% and 80%, respectively.The RGNTF contents reduced further to 0% as age increased to 2 years old. A ~(32)P-DNA probe specific to the first 7 amino acid sequence of RGNTF at its N-terminal end was synthesized and used for in situ hybridization studies. The results revealed that strong hybridized signals (i.e. mRNA of RGNTF) were localized in the same neurons in the superficial layers and deep part of the superior colliculus only in the 0-1-day age grou     

分光光度法快速测定玉米叶片中的叶绿素

以玉米叶片为材料,利用双波长双光束紫外可见分光光度计,用最大决定系数增量回归算法,研究了叶片叶绿素a、b及SPAD值同时、快速测量方法.结果表明,用3个波长点建立的模型可以达到良好的预测效果,预测叶绿素a、b及SPAD值的相关系数分别为0.9919、0.9816和0.9757;标准差分别为1.52、0.43和1.96;预测相对标准差分别为4.64%、5.50%和4.88%.同时研究了仪器波长误差和带宽变化对测定结果的影响, 发现波长偏移超过0.2 nm,误差快速增大,且波长向长波方向偏移时对测量的影响要大于向短波方向偏移的影响;仪器带宽变大,预测误差也就越大.