Electrochemical fluorination of dimethyl glutarate and its characterization

Monofluoro dimethyl glutarate has been successfully synthesized for the first time by electrochemical fluorination. It is done in an undivided polypropylene cell with platinum electrodes. Initially at three different current densities, dimethyl glutarate is subjected to electrofluorination. Maximum yield of monofluoro product is obtained at 15 mA cm⁻². Selecting this current density, electrosynthesis is done at three different charges. Maximum yield of 71.5% of the monofluoro product is obtained with a conversion efficiency of 95.2% when the charge of 6 F/mol is passed. The synthesized product is characterized using Fourier transform infrared (FTIR), gas chromatography/mass spectrometry (GC/MS), and nuclear magnetic resonance (NMR). The product purity and composition are ascertained using GC/MS. The attachment of fluorine to methylene group is indicated using FTIR data. From NMR studies, the environment of fluorine in the neighborhood of carbon and hydrogen has been established. Results are discussed in the paper.     

LC-ESI-MS/MS method for quantification of ambrisentan in plasma and application to rat pharmacokinetic study

A sensitive high‐performance liquid chromatography–positive ion electrospray tandem mass spectrometry method was developed and validated for the quantification of ambrisentan in plasma. The analyte and the internal standard (armodafinil) were extracted from plasma by acetonitrile precipitation and they were separated on a reversed‐phase C₁₈ column with a gradient program. The MS acquisition was performed with multiple reaction monitoring mode using the respective [M + H]⁺ ions, m/z 379–347 for ambrisentan and m/z 274–167 for the IS. The assay exhibited a linear dynamic range of 1–2000 ng/mL for ambrisentan in plasma. Acceptable precision (<10%) and accuracy (100 ± 8%) were obtained for concentrations over the standard curve range. The method was successfully applied to quantify ambrisentan concentrations in a rodent pharmacokinetic study after a single oral administration of ambrisentan at 2.5 mg/kg to rats. Following oral administration the maximum mean concentration in plasma (C_max; 1197 ± 179 ng/mL) was achieved at 1.0 ± 0.9 h (T_max), and the area under the curve (AUC) was 6013 ± 997 ng h/mL. Therefore, development of such a simple and sensitive method in rat plasma should translate into a method for ambrisentan in human plasma for clinical trials. Copyright © 2012 John Wiley & Sons, Ltd.     

Prevention of anode fouling during the electrochemical perfluorination of aromatic carboxylic acid chlorides

The electrochemical perfluorination of benzoyl chloride, p-substituted benzoyl chlorides and cyclo-hexane carboxylic acid chloride in anhydrous hydrogen fluoride (AHF) medium on nickel electrode is reported. Experimental conditions suppressing polymeric film formation on the electrode are optimized. Addition of 1 wt.% dimethyl sulfide based on the volume of AHF in the initial stage of electrochemical fluorination and maintenance of the reactant and intermediate concentrations below a critical level ensured electrochemical fluorination of all the reactants without fouling of the electrode surface. Presence of p-substituents in the benzene ring improved the selectivity of alicyclic perfluoro carboxylic acid. GC/MS and ¹⁹F NMR data for the major perfluorinated products are reported.     

Exploring dried blood spot sampling technique for simultaneous quantification of antiretrovirals: lamivudine, stavudine and nevirapine in a rodent pharmacokinetic study

A high‐performance liquid chromatography/positive ion electrospray tandem mass spectrometry method for the simultaneous quantification of lamivudine, stavudine and nevirapine was developed and validated in dried blood spot (DBS) cards. The analytes were separated using an isocratic mobile phase on a reverse phase column and analyzed by MS/MS in the MRM mode using the respective [M + H]⁺ ions, m/z 230–112 for lamivudine, m/z 225–127 for stavudine, m/z 267–226 for nevirapine, m/z 383–337 for zidovudine (IS). The lower limit of quantification was 1 ng/mL for both lamivudine and stavudine and 10 ng/mL for nevirapine. Acceptable precision and accuracy were obtained for concentrations over the standard curve range. The method was successfully applied to quantify them in a rat pharmacokinetic study in whole blood, plasma and DBS cards after a single oral co‐administration at the dose of 10, 2 and 13 mg/kg for lamivudine, stavudine and nevirapine, respectively, to male Wistar rats. Following oral administration the pharmacokinetic results in all the matrices are in close agreement. Thus accomplishment of this method would facilitate the ease of collection of clinical samples on DBS cards for lamivudine, stavudine and nevirapine during human clinical trials and therapeutic drug monitoring. Copyright © 2012 John Wiley & Sons, Ltd.     

The effect of substituents and operating conditions on the electrochemical fluorination of alkyl phenylacetates in Et3N·4HF medium

Selective electrochemical fluorination of alkyl phenylacetates (Ph-CH₂-COOR, where R is methyl, ethyl, n-propyl, n-butyl, i-propyl and sec-butyl) under galvanostatic conditions were reported in Et₃N·4HF medium. Preparative electrolysis experiments were carried out both in pre-electrolysed dry Et₃N·4HF and the same electrolyte medium without pre-electrolysis. Very little hydrolysed fluorinated products were obtained in pre-electrolysed medium where as significant quantities of hydrolysed products leading to fluorinated phenylacetic acid were obtained from Et₃N·4HF without pre-electrolysis. Under optimum experimental conditions up to 87% selectivity of monofluoro ester could be achieved. Difluoro alkyl phenylacetate, monofluoro and difluoro phenylacetic acids were the other predominant side products obtained. The hydrolysis appears to be initiated by tautomeric transformation of proton after the initial electro oxidative formation of the cation radical. ¹⁹F as well as ¹H NMR spectroscopy have been employed to identify the minor constituents formed during the electro oxidative process.     

Diffusion tensor imaging in horizontal gaze palsywith progressive scoliosis

Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare disorder characterized by absence of conjugate horizontal eye movements, preservation of vertical gaze and convergence, progressive scoliosis developing in childhood and adolescence. It is caused by mutations in the ROBO3 gene which are critical for the crossing of long ascending medial lemniscal and descending corticospinal tracts in the medulla. Diffusion tensor imaging on a 14-year-old boy with HGPPS revealed ipsilateral ascending and descending connectivity in the brainstem without any crossing over of the major tracts although normal interhemispheric connections in the corpus callosum was demonstrable. Absent decussation of smaller sized superior cerebellar peduncles but with normal crossing over of the middle cerebellar peduncle was also observed. Tractography is a valuable investigative modality to assess neuronal connections in the brain and is a useful adjunct to the structural magnetic resonance imaging in confirming the diagnosis of HGPPS.     

Green synthesis and characterization of Ag and Ag/Fe3O4 nanocomposites for antimicrobial effect and rhodamine- B dye degradation

We used a simple two-stage tactic to design and synthesize a magnetically separable catalyst (MSC) Ag/Fe₃O₄ by combining independently synthesized Fe₃O₄ and Jatropha curcas root functionalized Ag nanoparticles (NPs) at room temperature. The phase composition of Ag/Fe₃O₄ NCs was revealed by morphological and structural assessment. The derived Ag/Fe₃O₄ nanocomposites demonstrated outstanding antimicrobial activity against Gram-negative Pseudomonas aeruginosa comparing to Gram-positive Bacillus subtilis which was determined by the agar well diffusion method. This is due to positively charged surface of metal oxide NPs that may bind to cell membrane. Interestingly, Ag–Fe₃O₄ NCs demonstrated good photocatalytic activity for organic dye degradation. According to a kinetic study, Ag/Fe₃O₄ MSC removed 99% of Rhodamine B at a rate constant of 1.89 min^?1. The photoelectron could perhaps ultimately collide only with dissolved solids in the substrate to form superoxides, which can damage the dye. Notably, the MSCs reusability was tested using magnetic detachment without sacrificing photocatalytic efficiency. This finding represents a significant breakthrough in the domain of wastewater treatment and biomedicine.     

Detection of α2u‐globulin and its bound putative pheromones in the preputial gland of the Indian commensal rat (Rattus rattus) using mass spectrometry

The role of pheromones and pheromone‐binding proteins in the laboratory rat has been extensively investigated. However, we have previously reported that the preputial gland of the Indian commensal rat produces a variety of pheromonal molecules and preputial glands would seem to be the predominant source for pheromonal communication. The presence of pheromone‐binding proteins has not yet been identified in the preputial gland of the Indian commensal rat; therefore, the experiments were designed to unravel the α_2u‐globulin (α2u) and its bound volatiles in the commensal rat. Total preputial glandular proteins were first fractionated by sodium dodecyl sulfate/polyacrylamide gel electrophoresis (SDS‐PAGE) and subsequently analyzed by mass spectrometry. Further, we purified α2u and screened for the presence of bound pheromonal molecules with the aid of gas chromatography/mass spectrometry (GC/MS). A novel α2u was identified with a high score and this protein has not been previously described as present in the preputial gland of Indian commensal rats. This novel α2u was then characterized by tandem mass spectrometry (MS/MS). Peptides with m/z values of 969, 1192, 1303 and 1876 were further fragmented with the aid of MS/MS and generated de novo sequences which provided additional evidence for the presence of α2u in the preputial gland. Finally, we identified the presence of farnesol 1 and 2 bound to α2u. The present investigation confirms the presence of α2u (18.54 kDa) in the preputial gland of the Indian commensal rat and identifies farnesol 1 and 2 as probably involved in chemo‐communication by the Indian commensal rat. Copyright © 2010 John Wiley & Sons, Ltd.