New Facile One-Pot Synthesis of Isobutyl Thiocarbamate in Recycling Solvent Mixture

The specific objectives of the presented study were related to the optimization of the production process of N-alkyl-, N,N-dialkyl-, and N-cycloalkyl-O-isobutyl thiocarbamate; trial industrial production of N-ethyl-O-isobutyl thiocarbamate; and the evaluation of flotation efficiency of N-ethyl-O-isobutyl thiocarbamate using a real ore sample. The optimization of thiocarbamate syntheses were performed by varying the molar ratio of isobutyl alcohol, carbon disulfide, potassium hydroxide, reaction time, and reaction temperature. In the first step, one-pot reaction took place to produce alkyl xanthate and was followed with chlorination to give alkyl chloroformate (O-alkyl carbonochloridothioate); finally, thiocarbamates were obtained by the reaction with corresponding amines. N-alkyl-O-ethyl thiocarbamate was synthesized as a comparative flotation agent. The structure of the synthesized compounds was confirmed by IR, 1H and 13C NMR, and MS instrumental methods, and the purity was determined by gas chromatographic method and elemental analysis. The optimized methods gave high-purity products in a significant yield that was also confirmed by semi-industrial production of N-ethyl-O-isobutyl thiocarbamate. The optimized thiocarbamate synthesis, without isolation of intermediates, is of great importance from the aspect of green technologies. Flotation efficiency test results, using real copper and zinc ores, showed the highest activity of N-ethyl-O-isobutyl thiocarbamate. The optimal one-pot thiocarbamate synthesis provides a simple procedure with a high conversion degree, and, thus, offers valuable technology applicable at the industrial scale.

Development and Validation of Head-space Gas Chromatographic Method in Tandem with Flame ionized detection for the determination of Residual solvents in Simeprevir API Synthesis

Residual solvent testing is an integral part of reference material certification. A gas chromatography/flame ionization detector/headspace method has been developed and validated to detect and quantitate commonly used residual solvents in our production processes: Methanol, Tetrahydrofuran, Toluene, Dichloromethane and Dichloroethane in Simeprevir API. A simple and selective HS-GC method is described for the determination & quantification of Residual Solvents in Simeprevir API. Chromatographic separation was achieved on USP G43 equivalent capillary column Thermo Scientific™ Trace GOLD™ TG-624 SilMS, 30m × 0.32mm × 1.8µm column (P/N 26059-3390) using nitrogen as carrier gas by using different temperature gradient of FID Detectors. Linearity was observed in the range 40-120% of standard concentrations for Methanol, Tetrahydrofuran, Toluene, Dichloromethane and Dichloroethane (r2>0.999) for the amount of solvent estimated by the proposed methods was in good agreement. The proposed methods were validated. The accuracy of the methods was assessed by recovery studies at three different levels. Recovery experiments indicated the absence of interference from commonly encountered diluent and API. The method was found to be precise as indicated by the repeatability analysis, showing %RSD less than 10 for Methanol, Tetrahydrofuran, Toluene, Dichloromethane and Dichloroethane. All statistical data proves validity of the methods and can be used for routine analysis of pharmaceutical active ingredients for estimation of Residual Solvents of Methanol, Tetrahydrofuran, Toluene, Dichloromethane and Dichloroethane in Simeprevir. Baseline separation of all five solvents and Simeprevir API is achieved within 20.5 minutes of analysis time. Method validation comprised the following parameters: limit of detection (LOD), limit of quantitation (LOQ), linearity and range, accuracy, precision (repeatability and intermediate precision), system suitability, specificity, and robustness. Linearity and LOQ (ppm) are listed for each solvent in manuscript. The present method was proven to be robust and accurate for quantitative analysis of residual solvent in neat materials.