Project description:One unknown impurity (Imp-II) during the analysis of laboratory batches of isoproterenol hydrochloride was detected in the level ranging from 0.04% to 0.12% by high performance liquid chromatography with UV detection. The unknown impurity structure was proposed as 4-[2-(propan-2-ylamino)ethyl]benzene-1,2-diol (Imp-II) using the liquid chromatography--mass spectrophotometry (LC--MS) analysis. Imp-II was isolated by semi-preparative liquid chromatography from the impurity-enriched reaction crude sample. Its proposed structure was confirmed by nuclear magnetic spectroscopy such as 1H, 13C, DEPT (1D NMR), HSQC (2D NMR) and infrared spectroscopy (IR), and retention time and purity with HPLC followed by the chemical synthesis. Due to less removable nature of Imp-II during the purification, the synthetic process was optimized proficiently to control the formation of Imp-II below to the limit<0.12% in the course of reaction. The new chemical route was developed for the preparation of this impurity in required quantity with purity to use as reference standard. The most probable mechanism for the formation of Imp-II was discussed in details.
Project description:Benidipine hydrochloride, used as an antihypertensive agent and long-acting calcium antagonist, is synthesized for commercial use as a drug substance in highly pure form. During the synthetic process development studies of benidipine, process related impurities were detected. These impurities were identified, synthesized and characterized and mechanisms of their formation were discussed in detail. After all standardization procedures, they were used as reference standards for analytical studies. In addition, a separate HPLC method was developed and validated for detection of residual 1-benzylpiperidin-3-ol (Ben-2), which is used during benidipine synthesis and controlled as a potential process related impurity. As complementary of this work, stress-testing studies of benidipine were carried out under specified conditions and a stability-indicating UPLC assay method was developed, validated and used during stability studies of benidipine.
Project description:This study looked at the doxorubicin hydrochloride (DOX) anticancer drug's adsorption characteristics on a silver-based metal-organic framework (Ag-MOF). X-ray diffraction (XRD), scanning electron microscopy (SEM), and X-ray photoelectron spectroscopy (XPS) were used for the characterization of Ag-MOF. The pore volume and surface area of Ag-MOF were determined through Brunauer-Emmett-Teller (BET) testing at 77 K to be 0.509 cm3/g and 676.059 m2/g, respectively. Adsorption at pH 6 was established to be the best for DOX compared to alkaline solution. Ag-MOF has a good capacity for eliminating DOX (1.85 mmol/g), according to adsorption experiments. From the adsorption results, we can find that Langmuir is the most fitted adsorption isotherm model and the pseudo-second order model best fitted the adsorption kinetics. The energy of activation for adsorption, which was determined to be 15.23 kJ/mol, also supported a chemisorption process. The mechanism of adsorption was evaluated, and details of all possible interactions between DOX and Ag-MOF were illustrated. On the other hand, while examining the impact of temperature, we identified the thermodynamic constraints as ΔG°, ΔH°, and ΔS° and confirmed that the reaction was an endothermic one and spontaneous. Even after numerous reuse cycles, the efficiency remained constant. The synthetic adsorbent was remarkably recyclable at a rate of more than 91.6%. By using the MTT assay, the cytotoxicity of the tested Ag-MOF and DOX@Ag-MOF against human breast cancer cells (MCF-7) was evaluated in vitro. The in vitro antimicrobial activity of Ag-MOF and DOX@Ag-MOF was also tested.
Project description:NKY-312 is a highly active insecticide candidate with a simple structure. In order to carry out field trials and toxicity tests, its scale preparation is urgently needed, but the final step of the original synthetic route is a low-yielding sulfonylation reaction that generates a high proportion of a bissulfonylated by-product, its foliar contact activities against bean aphid (80% at 100 mg/kg) is significantly lower than that of NKY-312 (100% at 5 mg/kg), and uses pyridine as the solvent. In this work, we developed a highly selective (4-dimethylaminopyridine)-catalyzed monosulfonylation reaction that avoids the use of pyridine as a solvent and shows a much higher yield (98% yield with 98% HPLC purity) than the original reaction (68%). Then, we carried out the field trials and toxicity tests. In field experiments, the activities of NKY-312 against rice planthopper and wheat aphid were equal to pymetrozine and imidacloprid respectively.
Project description:A simple and economical process for producing amantadine hydrochloride (1) on a 250 g scale, an antiviral and anti-Parkinson drug, has been developed. Several methods for the preparation of 1 through intermediate N-(1-adamantyl)-acetamide (4) in four or three steps were reported. These procedures started with adamantine (2) or 1-bromoadamantane (3), acetonitrile, and sulfuric acid by using the Ritter-type reaction to obtain N-(1-adamantyl)-acetamide, which was deacetylated to afford 1-amino-adamantane (5) and then the salt formed with anhydrous HCl gives 1 with the overall yield of 1 being 50-58%. In this article, a two-step procedure for the synthesis of 1 from 1-bromadamantane (3) and formamide via N-(1-adamantyl)-formamide (6) in two steps with an overall yield of 88% was reported. In this procedure, the preparation of 6 from 3 is a key step with a yield of 94%, followed by the hydrolysis of 6 with an aq. solution of HCl to give 1 in high yield (93%). The procedure was also carried out under optimal conditions established to reduce the use of toxic reagents or solvents and was carried out in one pot to make it more environmentally friendly. The procedure can be considered as more suitable for the large-scale production of 1. The structures of product 1 and intermediate 6 were confirmed by IR, MS, 1H NMR, 13C NMR.
Project description:Flow synthesis is becoming increasingly relevant as a sustainable and safe alternative to traditional batch processes, as reaction conditions that are not usually achievable in batch chemistry can be exploited (for example, higher temperatures and pressures). Telescoped continuous reactions have the potential to reduce waste by decreasing the number of separate unit operations (e.g., crystallization, filtration, washing, and drying), increase safety due to limiting operator interaction with potentially harmful materials that can be reacted in subsequent steps, minimize supply chain disruption, and reduce the need to store large inventories of intermediates as they can be synthesized on demand. Optimization of these flow processes leads to further efficiency when exploring new reactions, as with a higher yield comes higher purity, reduced waste, and a greener synthesis. This project explored a two-step process consisting of a three-phase heterogeneously catalyzed hydrogenation followed by a homogeneous amidation reaction. The steps were optimized individually and as a multistep telescoped process for yield using remote automated control via a Bayesian optimization algorithm and HPLC analysis to assess the performance of a reaction for a given set of experimental conditions. 2-MeTHF was selected as a green solvent throughout the process, and the heterogeneous step provided good atom economy due to the use of pure hydrogen gas as a reagent. This research highlights the benefits of using multistage automated optimization in the development of pharmaceutical syntheses. The combination of telescoping and optimization with automation allows for swift investigation of synthetic processes in a minimum number of experiments, leading to a reduction in the number of experiments performed and a large reduction in process mass intensity values.
Project description:In this study electrospun nanofibers of partially sulfonated polyether ether ketone have been produced as a preliminary step for a possible development of composite proton exchange membranes for fuel cells. Response surface methodology has been employed for the modelling and optimization of the electrospinning process, using a Box-Behnken design. The investigation, based on a second order polynomial model, has been focused on the analysis of the effect of both process (voltage, tip-to-collector distance, flow rate) and material (sulfonation degree) variables on the mean fiber diameter. The final model has been verified by a series of statistical tests on the residuals and validated by a comparison procedure of samples at different sulfonation degrees, realized according to optimized conditions, for the production of homogeneous thin nanofibers.
Project description:In this study, the central composite design of response surface methodology was applied to optimize the ultrasonic synthesis of multiwalled carbon nanotube-titanium dioxide (MWNT-TiO2) composites. Twenty composites were prepared by adjusting three parameters (MWNT concentration in water, sonication to disperse/exfoliate MWNTs in water, and sonication to attach TiO2 onto MWNTs) at five levels. On the basis of the experimental design, semiempirical expressions were developed, analyzed, statistically assessed, and subsequently applied to predict the impact of the studied parameters on composite synthesis. The composite synthesis process was optimized to capture the experimental conditions favoring the highest productivity (i.e., MWNT-TiO2 formation or percent TiO2 attachment) utilizing minimal resources. The synthesis process optimization results showed that, to make a MWNT-TiO2 composite in 10 mL of water, 23.2 mg (∼99% of 23.4 mg) of TiO2 can be attached to 2.6 mg of MWNTs. This process requires only 727 J sonication energy, of which 592 J is invested to exfoliate MWNTs (Sonication 1) and 135 J to attach TiO2 (Sonication 2) to MWNTs. Finally, the optimally synthesized composite was extensively characterized using SEM, surface area and porosity analysis, TGA, and ζ-potential analysis/DLS. Also, this composite was tested for stability under variable pH and solvent polarity. The approach developed in this study could be used to optimize the synthesis process of other similar composites.
Project description:A novel route to asymmetric synthesis of cinacalcet hydrochloride by the application of (R)-tert-butanesulfinamide and regioselective N-alkylation of the naphthyl ethyl sulfinamide intermediate is described.