Synthesis Of Pharmaceuticals Research Articles

Enantioselective 1,4-Borylamination via Copper-Catalyzed Cascade Hydroborylation and Hydroamination of Arylidenecyclopropanes.

Compounds bearing both boryl and amino groups at distal positions are invaluable synthons for synthesizing pharmaceuticals, drug candidates, and natural products, but their catalytic enantioselective synthesis remains rarely explored. We report the first enantioselective 1,4-borylamination reaction through a copper-catalyzed cascade hydroborylation and hydroamination of arylidenecyclopropanes. This reaction combines four readily available components in a highly chemo-, site-, and enantioselective fashion (>20:1 r.r. and up to 99% ee), yielding a diverse array of synthetically valuable enantioenriched 4-amino alkylboronates. The versatile utility of these products is highlighted by their diverse transformations and wide applications in pharmaceutical synthesis and drug discovery. Preliminary mechanistic studies were conducted to elucidate the operative reaction pathway, intermediates, and origins of its high chemo- and site-selectivity.

Efficient Formylation of Alcohols Using a Core-Shell Magnetic Nanocomposite via Vilsmeier-Haack Complex Formation

Introduction: The protection of the hydroxyl group as formamides is a crucial initial step in pharmaceutical synthesis. Methods: In this study, we investigated the O-formylation of alcohols using dimethylfor-mamide (DMF) in a mixture with a new magnetic nanocomposite Fe3O4@Chitosan/POCl2-x. Results: The results demonstrate that this core-shell heterogeneous nanocomposite facili-tates the formation of alkylformate, yielding products with high efficiency ranging from 79% to 96% within a remarkably short reaction time of 1 to 12 hours at room temperature, depending on the substrate structure. Significantly, the presence of this nanocomposite ex-hibits remarkable selectivity, favoring the formylation of less hindered benzylic and ali-phatic primary alcohols. However, bulkier alcohols and phenols exhibit lower reactivity under these conditions and thiols do not react. The simplicity of the work-up procedure, combined with the magnetic recyclability, makes it reusable and environmentally friendly. Conclusion: This study highlights the efficacy of this novel magnetic nanocomposite in facilitating formylation reactions, emphasizing its potential for application in pharmaceu-tical synthesis and bio compounds. This is due to its attributes of non-toxic nature, stabil-ity, and significant advantages over conventional methodologies.

Advances in Biocatalysis for Sustainable Pharmaceutical Synthesis: Applications, Technological Progress, and Future Directions

Biocatalysis has emerged as a critical tool in pharmaceutical synthesis, offering a range of significant advancements in recent years. This paper provides a comprehensive review of biocatalysis applications in drug synthesis, emphasizing its role in enhancing the efficiency and environmental sustainability of producing complex pharmaceutical molecules. Through detailed case studies, including the biocatalytic synthesis of amoxicillin, paclitaxel, and ribavirin, the paper illustrates the superior reaction efficiency, selectivity, and reduced environmental impact achievable through biocatalysis. The technological advancements discussed include optimizing enzyme activity via genetic engineering, enhancing enzyme stability through covalent modification, and applying enzyme immobilization techniques. Furthermore, the integration of biocatalysis with green chemistry principles is explored, highlighting its potential to reduce harmful byproducts and energy consumption in industrial processes. The paper also delves into the future directions and challenges of scaling biocatalysis for broader industrial application. As an integral part of green chemistry, biocatalysis is poised to play a pivotal role in promoting sustainable development and minimizing environmental impact in the pharmaceutical industry.

Split‐plot experiments with replicated runs in pharmaceutical synthesis

AbstractRestricted randomised designs are essential in the pharmaceutical synthesis due to the operational restrictions and their cost‐effectiveness compared to entirely randomised designs. Specifically, the split‐plot designs are very effective in reducing the cost of an experiment in the presence of hard‐to‐change factors and/or of multi‐stage processes. In classical designs, replicated runs for pure‐error estimation are commonly employed, but they are rarely used in the more complex setting of restricted randomisation. The reason is that, in practice, experiments in industry rarely can follow all the assumptions/conditions that are included in the methodological papers. In this work, we demonstrate how a split‐plot design based on a Bayesian ‐optimality criterion built to ensure more precise pure‐error estimation of the variance components can be easily adapted to fit the additional needs, the speedy implementation and the restrictions that a real case scenario in industry often imposes. We focus on the practical aspect of how to modify the complex design in a way that keeps/improves the desired qualities and on how to assess impact of changes that are more arbitrary.

Continuous Inertial Alignment and Isolation of Spherical Microparticles and Nonspherical Flagellate Microalgae

Flagellate microalgae play an increasingly significant role in environmental management and biotechnology for valuable bioproducts, excellent photosynthetic capability, and autonomic movement. However, multiple flagellate microalgae practically live together in the ocean and lake areas, and they are susceptible to contamination as a result of improper operations. Enthused by these aspects, we develop a reliable inertial microfluidic method to overcome the influence of flagella movement and non-spherical shape on the alignment and isolation of target flagellate microalgae. Firstly, a computational model incorporating fluid-structure interaction was established to investigate influence of releasing position and shape parameters on the displacement and rotation of non-spherical microalgal cells and numerically studied the processes of shape- and size-based particle separation. Secondly, the movement of different-size particles under diverse flow rates in the channel was explored, and the capability of this method was validated by aligning and separating 10 μm and 20 μm polystyrene particles. Thirdly, this method was applied to align H. pluvialis and isolate Dunaliella salina from the mixed microalgal samples to explore the influence of flow rate on the alignment and isolation of flagellate microalgae. Fourthly, this method was engineered to select 20 μm polystyrene particles from three types of particles and isolate H. pluvialis from the mixture of multiple microalgae species. Finally, we leveraged this approach to realize separation of H. pluvialis and Synedra ulna to explore the performance of this method in shape-based cell separation, and we isolated Euglena from microalgal cell wastes, including dead cells, bacteria, and particles. This method has promising prospects to be a reliable tool to isolate target flagellate microalgae to address problematic issues in environmental monitoring, pharmaceutical synthesis, and chronic wound treatment for the advantage of good adaptability and reliability.

High efficient synthesis of benzyl lactate through waste PLA alcoholysis by protic ionic salt

Benzyl lactate (BL) is a critical reagent in pharmaceutical and chemical synthesis due to its versatility. Traditional synthesis of BL was constrained by the high cost and low yield, thereby hindering the feasibility of large-scale production. Here, we reported a novel synthesis strategy for BL by utilizing the alcoholysis of waste polylactic acid (PLA) by benzyl alcohol with the protic ionic salt, HTBD-OAc, as the catalyst. The gram-scale experiments achieved a 94.9 % yield, and the robustness of this reaction was evidenced by the yield maintaining 92.5 % across six recycling experiments. More impressively, kilogram-scale synthesis facilitated a complete conversion of PLA to BL, achieving an unprecedented yield of 98.7 % at 180 °C within two hours. The exceptional catalytic efficiency of this reaction is attributed to the synergistic functions between the HTBD+ cation and OAc− anion in the catalyst HTBD-OAc. This study heralds a significant stride towards the sustainable and scalable production of high-purity benzyl lactate, paving the way for extended industrial applicability for this essential compound.

A Comprehensive Review on Imperative Role of Ionic Liquids in Pharmaceutical Sciences.

Ionic liquids (ILs) are poorly-coordinated ionic salts that can exist as a liquid at room temperatures (or <100 °C). ILs are also referred to as "designer solvents" because so many of them have been created to solve particular synthetic issues. ILs are regarded as "green solvents" because they have several distinctive qualities, including better ionic conduction, recyclability, improved solvation ability, low volatility, and thermal stability. These have been at the forefront of the most innovative fields of science and technology during the past few years. ILs may be employed in new drug formulation development and drug design in the field of pharmacy for various functions such as improvement of solubility, targeted drug delivery, stabilizer, permeability enhancer, or improvement of bioavailability in the development of pharmaceutical or vaccine dosage formulations. Ionic liquids have become a key component in various areas such as synthetic and catalytic chemistry, extraction, analytics, biotechnology, etc., due to their superior abilities along with highly modifiable potential. This study concentrates on the usage of ILs in various pharmaceutical applications enlisting their numerous purposes from the delivery of drugs to pharmaceutical synthesis. To better comprehend cuttingedge technologies in IL-based drug delivery systems, highly focused mechanistic studies regarding the synthesis/preparation of ILs and their biocompatibility along with the ecotoxicological and biological effects need to be studied. The use of IL techniques can address key issues regarding pharmaceutical preparations such as lower solubility and bioavailability which plays a key role in the lack of effectiveness of significant commercially available drugs.

Comparative assessment of physics-based in silico methods to calculate relative solubilities.

Relative solubilities, i.e. whether a given molecule is more soluble in one solvent compared to others, is a critical parameter for pharmaceutical and agricultural formulation development and chemical synthesis, material science, and environmental chemistry. In silico predictions of this crucial variable can help reducing experiments, waste of solvents and synthesis optimization. In this study, we evaluate the performance of different physics-based methods for predicting relative solubilities. Our assessment involves quantum mechanics-based COSMO-RS and molecular dynamics-based free energy methods using OPLS4, the open-source OpenFF Sage, and GAFF force fields, spanning over 200 solvent-solute combinations. Our investigation highlights the important role of compound multimerization, an effect which must be accounted for to obtain accurate relative solubility predictions. The performance landscape of these methods is varied, with significant differences in precision depending on both the method used and the solute considered, thereby offering an improved understanding of the predictive power of physics-based methods in chemical research.

Exploring the Impact of Environmental Conditions and Bioreactors on Microalgae Growth and Applications

Microalgae and their bioproducts have diverse applications, including wastewater remediation, CO2 fixation, and the synthesis of nutraceuticals, pharmaceuticals, and biofuels. However, the production of these organisms heavily relies upon environmental conditions, which can significantly impact growth. Furthermore, microalgae cultivation itself can be a source of economic and environmental concerns. Thus, microalgae growth systems have become a critical consideration for both research and industry, to bolster microalgae cultivation and address its accompanying issues. Both open and closed systems, such as raceway ponds and photobioreactors, respectively, are commonly used during the growth process but have their own advantages and drawbacks. However, for microalgae growth, photobioreactors may address most concerns as the system’s design lowers the risk of contamination and provides the ability to control the delivery of desired growth factors. To determine the appropriate system for targeted microalgae cultivation, it is crucial to determine factors such as the scale of cultivation and growth and productivity targets. Additionally, efficient usage of these growth systems and carefully selected incubation factors can aid in addressing some of the economic and environmental issues associated with microalgae production. This review will summarize the current applications of bioreactors in both research and industrial capacities and summarize growth and incubation factors for microalgae.

Green Chemistry in Pharmaceutical Synthesis: Sustainable Strategies for Drug Production

The world is shifting from traditional synthetic or chemical technologies towards greener methods due to increasing concerns about maintaining a clean and sustainable environment. The development of eco-friendly products through processes that support environmental sustainability is referred to as a "green approach." In the pharmaceutical industry, there is growing attention to green synthesis of chemicals and materials, both in research and applied science, because green chemistry eliminates harmful processes and materials while promoting innovation in drug and therapeutic agent development. Green chemistry encompasses chemical reactions that minimize environmental impact and reduce toxicity. This field is rapidly evolving within pharmaceutical synthesis, focusing on the creation of sustainable medicines. This review explores the principles and practical applications of this innovative strategy within the pharmaceutical sector. By using environmentally friendly chemical processes, green chemistry reduces hazardous materials and pollution. Its aim is to mitigate the environmental footprint of drug production without compromising the quality and effectiveness of medicines. The approach also emphasizes the use of renewable and sustainable resources, such as shifting from petrochemical-based to bio-based feedstocks, allowing pharmaceutical companies to reduce their greenhouse gas emissions

THE GREEN APPROACH FOR THE SYNTHESIS OF SOME HYDROQUINOLINE DERIVATIVES COMPOUND VIA HANTZSCH REACTION

Since that hydroquinoline and acridine compounds serve as the fundamental building blocks for the synthesis of many different pharmaceuticals, they are among the most significant classes of chemical compounds that attract the interest of numerous researchers and pharmacologists. Therefore, in this research, The Hantzch reaction was used to prepare these types hydroquinoline and acridine derivatives of compounds, through the reaction of a number substituted benzaldehyde with demidone and α-β diketone substitutes by refluxed with sodium acetate in the presence of iodine and a 1-sulfo-4-(3-(Ferricoxide-Silicondioxide nanopowdertrioxisilyl)propyl) piperazinum-1,4-diphosphate as a catalyst to form 7,7- dimethyl -4,6,7,8-tetrahydroquinoline derivatives which is represented by compounds (1-12) or in the same way by react benzaldehyde substitutes react with demidone and 4-isopropyl cyclohexanone 1-one to form acridin derivatives represented by compounds (13 -17). All product compound are characterized using 1H-NMR spectra and the results confirmed the structures.

Impact of C-H Cross-Coupling Reactions in the One-Step Retrosynthesis of Drug Molecules.

Pharmaceutical synthesis requires a diversity of chemical reactions. The discovery of new reactions enable novel retrosynthetic disconnections, potentially expediting access to complex molecules. This Synopsis demonstrates the use of enumerative combinatorics to find impactful underdeveloped reactions for drug synthesis. By mapping pharmaceutical target molecules onto available building blocks using just one retrosynthetic disconnection even if the requisite reaction is not yet known, we highlight the importance of site-selective C-H cross-coupling methods. This cheminformatics-driven retrosynthetic analysis identifies novel reaction methods of value to the synthesis toolbox.

Machine learning-assisted amidase-catalytic enantioselectivity prediction and rational design of variants for improving enantioselectivity

Biocatalysis is an attractive approach for the synthesis of chiral pharmaceuticals and fine chemicals, but assessing and/or improving the enantioselectivity of biocatalyst towards target substrates is often time and resource intensive. Although machine learning has been used to reveal the underlying relationship between protein sequences and biocatalytic enantioselectivity, the establishment of substrate fitness space is usually disregarded by chemists and is still a challenge. Using 240 datasets collected in our previous works, we adopt chemistry and geometry descriptors and build random forest classification models for predicting the enantioselectivity of amidase towards new substrates. We further propose a heuristic strategy based on these models, by which the rational protein engineering can be efficiently performed to synthesize chiral compounds with higher ee values, and the optimized variant results in a 53-fold higher E-value comparing to the wild-type amidase. This data-driven methodology is expected to broaden the application of machine learning in biocatalysis research.

Lipase Enzymes for Sustainable Synthesis of Pharmaceuticals and Chiral Organic Building Blocks

AbstractBiocatalysis is a green and sustainable process for synthesizing chiral organic building blocks and active pharmaceutical ingredients (API). United Nations' Sustainable Development Goals 2030 advocates using green, sustainable, recyclable chemicals by industries to reduce environmental pollution. Pharmaceutical companies are adopting biocatalysis technologies for manufacturing chiral active pharmaceutical ingredients. The lipase‐catalyzed kinetic and dynamic‐kinetic resolution method is a pharmaceutically accepted process for manufacturing chiral API. This review describes the reported methods for synthesizing chiral API/KSM (Key Starting Material) molecules using lipase enzymes over the last ten years.

Automated Optimization of a Multistep, Multiphase Continuous Flow Process for Pharmaceutical Synthesis.

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.

Electrolytic Conversion of Nitro Compounds into Amines in a Membrane Reactor.

Aromatic and aliphatic amines are key intermediates in the synthesis of pharmaceuticals, dyes, and agrochemicals. These amines are often sourced from nitro compounds. The hydrogenation of nitro compounds into amines requires harsh reaction conditions (e.g., high pressures and high temperatures) or additives that are usually toxic. Here we demonstrate the electrochemically-driven hydrogenation of nitro compounds into amines in the hydrogenation compartment of a membrane reactor. The hydrogen is sourced from water in an adjacent electrolysis compartment separated by a hydrogen-permeable palladium membrane. Modifications of the palladium membrane with catalyst coatings enabled a wide range of commercially relevant nitro compounds to be hydrogenated into amines, without any additives, at ambient pressure and room temperature. This membrane reactor also enables nitro hydrogenation at high reagent concentrations with high functional group tolerance.

Phase behavior and biological activity of lyotropic liquid crystal systems doped with 1,2,3-triazole derivative

Heterocyclic compounds are important for the synthesis of pharmaceuticals, especially substituted triazoles, which have high biological activity. The development of approaches to the creation of delivery systems for bioactive heterocyclic compounds is of particular importance for improving the biopharmaceutical aspects of therapy. In this work, we report synthesis and characterization of a new 1,2,3-triazole: ethyl 2-((1-decyl-1H-1,2,3-triazol-4-yl)methyl)-3-oxobutanoate (TR). The efficient incorporation into lyotropic mesophases as a drug delivery platform demonstrated. Polarized optical microscopy studies confirmed formation of a lyotropic mesophase in the binary P123/TR system as well as in tertiary systems with added water, ethanol, and DMSO. This allows to dope 5 % of triazole into lyomesophases. IR and UV spectroscopy studies detected intermolecular interactions occurring in the P123/TR system. Release of TR from binary and tertiary lyomesophases was studied. Impacts of composition and temperature on the release time were analyzed. Evaluation of cytotoxicity to M-Hela and HuTu-80 cancer lines and Chang Liver living cells revealed antitumor properties of the studied substituted 1,2,3-triazole. The lowest IC50 of TR is 57 μg·mL−1 toward HuTu-80. This is at the level of the reference drug Fluconazol. For the P123/DMSO/TR LLC system in concentration range of 31.3–124 µg·ml−1, the viability percentage of liver cells is comparable to those of cancer cells. These results demonstrate the potential opportunity for application LLC P123/DMSO used as a TR delivery for and enhance its antitumor effect.

I2-promoted direct C–H arylselenylation of pyrrolo[1,2-a]quinoxalines

An I2-promoted C–H arylselenylation of pyrrolo[1,2-a]quinoxalines with diaryl diselenides is developed, providing an efficient route to a series of 1 (or 3)-arylselenylated and/or 1,3-diaryl diselenylated pyrrolo[1,2-a]quinoxalines. The methodology is characterised by a wide range of substrates, good functional group tolerance and gram-level synthesis. Further transformations of the products to form structurally diverse pyrrolo[1,2-a]quinoxalines were successfully achieved. Similarly, I2-promoted C–H sulfenylation of pyrrolo[1,2-a]quinoxaline with 1,2-diphenyldisulfane were investigated. We believe that these novel pyrrolo[1,2-a]quinoxaline compounds will have promising applications in pharmaceutical synthesis.

A Concise Review on Microwave Assisted Synthetic Approches of Sulfonamides

AbstractSulfonamides have been played a critical role in the history of medicinal chemistry development for decades. In particular, sulfonamides display a broad spectrum in pharmaceutical drugs synthesis. This review presents a short discussion of the microwave‐assisted synthetic approaches, enhancement of sulfonamides moieties and their pharmacological applications are being discussed. During the past few decades, microwave‐assisted technology in organic synthesis has been highlighted to introducing ‐SO2NH functional group in the multi synthetic routes for the development of bioactive molecule and also assisted in the estimation of their credible mechanistic routes for the reactions.

Nitrogen accountancy in space agriculture.

Food production and pharmaceutical synthesis are posited as essential biotechnologies for facilitating human exploration beyond Earth. These technologies not only offer critical green space and food agency to astronauts but also promise to minimize mass and volume requirements through scalable, modular agriculture within closed-loop systems, offering an advantage over traditional bring-along strategies. Despite these benefits, the prevalent model for evaluating such systems exhibits significant limitations. It lacks comprehensive inventory and mass balance analyses for crop cultivation and life support, and fails to consider the complexities introduced by cultivating multiple crop varieties, which is crucial for enhancing food diversity and nutritional value. Here we expand space agriculture modeling to account for nitrogen dependence across an array of crops and demonstrate our model with experimental fitting of parameters. By adding nitrogen limitations, an extended model can account for potential interruptions in feedstock supply. Furthermore, sensitivity analysis was used to distill key consequential parameters that may be the focus of future experimental efforts.