Synthesis Of Pharmaceuticals Research Articles

Ketone Scope and Their Limitations in Transition Metal Catalyzed Direct Asymmetric Hydrogenative Aminations

AbstractChiral amines are valuable building blocks in the manufacture of agrochemicals, pharmaceuticals, natural products, fine chemicals, functional materials among others. Compared to asymmetric hydrogenation of imines/enamides and biocatalytic/organocatalytic asymmetric reductive amination, transition metal catalyzed direct asymmetric hydrogenative amination reactions (DAHA) using molecular dihydrogen as the reductant are highly economical, atom and/or step‐efficient and thus attractive for researchers from both industry and academia. In previous reviews, catalysts/methods development, applications in synthesis of pharmaceuticals and [N] source were summarized and discussed. In this review, we summarize and discuss the ketone substrates scope upon utilizing the state‐of‐the‐art transition metal catalysts. The substrate limitations, potential applications and key mechanisms are also critically concluded.

Visible‐Light Mediated C‐3 Amination of Quinoxalin‐ 2(1H)‐ones via Electron Donor‐Acceptor Complexation

AbstractThe formation of carbon‐nitrogen bonds holds paramount importance in the realm of synthetic organic chemistry, finding extensive applications in the synthesis of pharmaceuticals, agrochemicals, and organic materials. Herein, we describe a novel EDA complex mediated, metal‐ and photocatalyst‐free, visible‐light‐initiated direct C‐3 amination of biologically important, quinoxalin‐2(1H)‐one moiety. The key to the success lies in the formation of a photoactivated electron donor‐acceptor complex between quinoxalin‐2(1H)‐one and amine, which undergo subsequent electron transfer reaction to effect the desired transformation. A diverse array of 3‐aminoquinoxalin‐2(1H)‐ones were prepared employing this process and the yields are up to 87%. This work represents a significant advancement toward a more environmentally friendly and efficient approach, characterized by mild reaction conditions and a high atom economy.

In-situ synthesis of SnO/CuSnO3 nanostructures to catalyze azo dye degradation, CO2 reduction, and amines direct alkylation reactions under visible light

The extensive use of photocatalysis to address environmental concerns, energy production, and organic transformations has attracted attention in recent decades. The SnO/CSO photocatalytic materials were fabricated through a single-step hydrothermal method and comprehensively characterized using a muti-technique approach to demonstrate the physicochemical, morphological, and electronic features. According to the photocatalytic experiments, the SnO/CSO could remove >96 % of acid blue 92 (AB92) azo dye under optimum conditions, with rate constant 2.37 × 10−2 min−1. Furthermore, the photocatalyst significantly outperformed commercial TiO2 (P25), in reducing CO2 to CO and CH4 with a production rate of 10.8 and 1.18 μmol g−1 h−1, respectively, under visible light irradiation. The successful direct alkylation of amines to valuable organic compounds within 10 min of the reaction time with a conversion selectivity of >90 % was another capability of the materials, making it a good candidate for pharmaceutical synthesis purposes.

Gas Delivery Relevant to Human Health using Porous Materials.

Gases are essential for various applications relevant to human health, including in medicine, biomedical imaging, and pharmaceutical synthesis. However, gases are significantly more challenging to safely handle than liquids and solids. Herein, we review the use of porous materials, such as metal-organic frameworks (MOFs), zeolites, and silicas, to adsorb medicinally relevant gases and facilitate their handling as solids. Specific topics include the use of MOFs and zeolites to deliver H2S for therapeutic applications, 129Xe for magnetic resonance imaging, O2 for the treatment of cancer and hypoxia, and various gases for use in organic synthesis. This Perspective aims to bring together the organic, inorganic, medicinal, and materials chemistry communities to inspire the design of next-generation porous materials for the storage and delivery of medicinally relevant gases.

Enzyme purification and sustained enzyme activity for pharmaceutical biocatalysis by fusion with phase-separating intrinsically disordered protein.

In recent decades, biocatalysis has emerged as an important alternative to chemical catalysis in pharmaceutical manufacturing. Biocatalysis is attractive because enzymatic cascades can synthesize complex molecules with incredible selectivity, yield, and in an environmentally benign manner. Enzymes for pharmaceutical biocatalysis are typically used in their unpurified state, since it is time-consuming and cost-prohibitive to purify enzymes using conventional chromatographic processes at scale. However, impurities present in crude enzyme preparations can consume substrate, generate unwanted byproducts, as well as make the isolation of desired products more cumbersome. Hence, a facile, nonchromatographic purification method would greatly benefit pharmaceutical biocatalysis. To address this issue, here we have captured enzymes into membraneless compartments by fusing enzymes with an intrinsically disordered protein region, the RGG domain from LAF-1. The RGG domain can undergo liquid-liquid phase separation, forming liquid condensates triggered by changes in temperature or salt concentration. By centrifuging these liquid condensates, we have successfully purified enzyme-RGG fusions, resulting in significantly enhanced purity compared to cell lysate. Furthermore, we performed enzymatic reactions utilizing purified fusion proteins to assay enzyme activity. Results from the enzyme assays indicate that enzyme-RGG fusions purified by the centrifugation method retain enzymatic activity, with greatly reduced background activity compared to crude enzyme preparations. Our work focused on three different enzymes-a kinase, a phosphorylase, and an ATP-dependent ligase. The kinase and phosphorylase are components of the biocatalytic cascade for manufacturing molnupiravir, and we demonstrated facile co-purification of these two enzymes by co-phase separation. To conclude, enzyme capture by RGG tagging promises to overcome difficulties in bioseparations and biocatalysis for pharmaceutical synthesis.

Metal-Organic Frameworks-Based Frustrated Lewis Pairs for Selective Reduction of Nitroolefins to Nitroalkanes.

Nitroalkanes serve as essential intermediates in the synthesis of pharmaceuticals, agrochemicals, and functional materials. To date, nitroalkanes are mainly prepared from homogeneous catalysts such as noble transition metal catalysts with poor recyclability. Herein, we propose a metal-organic framework-frustrated Lewis pair (MOF-FLP) heterogeneous catalyst for selectively reducing nitroolefins to nitroalkanes under moderate reaction conditions. MOF enrichment effect can significantly improve the catalytic efficiency compared to homogeneous FLP catalysts. Benefiting from the strong interaction between FLP and MOF, the MOF-FLP catalyst exhibits outstanding recyclability. This work not only provides a convenient route for nitroalkane synthesis but also showcases the potential of porous heterogeneous FLP catalysts, offering inspiration for future catalytic design strategies.

Red-light-mediated copper-catalyzed photoredox catalysis promotes regioselectivity switch in the difunctionalization of alkenes

Controlling regioselectivity during difunctionalization of alkenes remains a significant challenge, particularly when the installation of both functional groups involves radical processes. In this aspect, methodologies to install trifluoromethane (−CF3) via difunctionalization have been explored, due to the importance of this moiety in the pharmaceutical sectors; however, these existing reports are limited, most of which affording only the corresponding β-trifluoromethylated products. The main reason for this limitation arises from the fact that −CF3 group served as an initiator in those reactions and predominantly preferred to be installed at the terminal (β) position of an alkene. On the contrary, functionalization of the −CF3 group at the internal (α) position of alkenes would provide valuable products, but a meticulous approach is necessary to win this regioselectivity switch. Intrigued by this challenge, we here develop an efficient and regioselective strategy where the −CF3 group is installed at the α-position of an alkene. Molecular complexity is achieved via the simultaneous insertion of a sulfonyl fragment (−SO2R) at the β-position. A precisely regulated sequence of radical generation using red light-mediated photocatalysis facilitates this regioselective switch from the terminal (β) position to the internal (α) position. Furthermore, this approach demonstrates broad substrate scope and industrial potential for the synthesis of pharmaceuticals under mild reaction conditions.

Modular Synthesis of Conjugated Aromatic Boronate Esters by Radical Xanthate Addition

AbstractConjugated aromatic boronate esters serve as crucial intermediates in the synthesis of pharmaceuticals and polymer materials. Traditional methods for their synthesis typically involve organoboration of aromatic ring compounds, where pre-constructions of aromatic rings are required. Here, we present a general strategy for the synthesis of diverse conjugated aromatic boronate esters based on the radical addition of xanthates. Through this method, we synthesized various boronate ester xanthates that could be utilized as a platform to furnish conjugated aromatic building blocks, including thiophenes, pyrroles, tetralones, naphthols, and naphthylamines. This cost-effective strategy holds promise as a viable method for the industrial-scale production of (hetero)aromatic boronate esters.

Palladium‐Catalyzed Carbonylation of Aryl Sulfonium Salts with CO2 as a CO Surrogate

AbstractPalladium‐catalyzed carbonylation of aryl sulfonium salts with CO2 as a CO surrogate has been successfully developed via a one‐pot two‐step procedure. Thus, by merging thianthrenation and the carbonylation, site‐selective aromatic C−H carbonylation of a plethora of readily available arenes can be realized with CO2, providing access to a variety of structurally diverse and useful benzamides, esters and carboxylic acids. Simple operation, broad substrate scope, good functional group tolerance and mild reaction conditions are the attractive features of the method. Late‐stage functionalization of complex bioactive molecules as well as the precise synthesis of pharmaceuticals 1‐BCP and butoxycaine demonstrated the potential application of the established protocol.

Identifying Substructures That Facilitate Compounds to Penetrate the Blood-Brain Barrier via Passive Transport Using Machine Learning Explainer Models.

The local interpretable model-agnostic explanation (LIME) method was used to interpret two machine learning models of compounds penetrating the blood-brain barrier. The classification models, Random Forest, ExtraTrees, and Deep Residual Network, were trained and validated using the blood-brain barrier penetration dataset, which shows the penetrability of compounds in the blood-brain barrier. LIME was able to create explanations for such penetrability, highlighting the most important substructures of molecules that affect drug penetration in the barrier. The simple and intuitive outputs prove the applicability of this explainable model to interpreting the permeability of compounds across the blood-brain barrier in terms of molecular features. LIME explanations were filtered with a weight equal to or greater than 0.1 to obtain only the most relevant explanations. The results showed several structures that are important for blood-brain barrier penetration. In general, it was found that some compounds with nitrogenous substructures are more likely to permeate the blood-brain barrier. The application of these structural explanations may help the pharmaceutical industry and potential drug synthesis research groups to synthesize active molecules more rationally.

Transforming Pharmaceutical Synthesis with Sein-E-B Nanocomposite Photocatalyst through 1,4-NAD(P)H Cofactor Regeneration and C-N Bond Activation.

The need for sunlight chemical renewal and contemporary organic transformation has fostered the advancement of environmentally friendly photocatalytic techniques. For the first time, we report on the novel crafting of a bright future with selenium-infused Eosin-B (Sein-E-B) nanocomposite photocatalysts in this work. The Sein-E-B nanocomposite materials were created using a hydrothermal process for solar chemical regeneration and organic transformation under visible light. The synthesized samples were subjected to UV-DRS-visible spectroscopy, FT-IR, SEM, EDX, EIS and XRD analysis. The energy band gap of the Sein-E-B nanocomposite photocatalyst was measured using UV-DRS, and the result was around 2.06 eV. to investigate the generated Sein-E-B catalytic activity as a nanocomposite for 1,4-NADH/NADPH re-formation and C-N bond activation. This novel photocatalyst offers a promising alternative for the regeneration of solar chemicals and C-N bond creation between pyrrole and aryl halides.

Liraglutide innovations: a comprehensive review of patents (2014-2024).

Type-2 diabetes mellitus (T2DM) is a complicated long-term disorder associated with metabolism that is identified by insulin resistance, imbalance in glucose regulation and reduced secretion of insulin. GLP-1(Glucagon-like peptide-1) is an incretin mimetic that has excellent effects on the regulation of blood glucose levels and also the management of disorders associated with vital organs. GLP-1 agonist is an effective class of drug for the treatment of type-2 diabetes mellitus and associated complications. Liraglutide is one of the potent drugs of this class having similar effects as biological GLP-1. This review includes clinical trials and patents related to the pharmaceutical formulation, synthesis and biological action of liraglutide.

An In Vitro Hybrid Biocatalytic System Enabled by a Combination of Surface-Displayed, Purified, and Cell-Free Expressed Enzymes.

Enzymatic cascades have become a green and sustainable approach for the synthesis of valuable chemicals and pharmaceuticals. Using sequential enzymes to construct a multienzyme complex is an effective way to enhance the overall performance of biosynthetic routes. Here we report the design of an efficient in vitro hybrid biocatalytic system by assembling three enzymes that can convert styrene to (S)-1-phenyl-1,2-ethanediol. Specifically, we prepared the three enzymes in different ways, which were cell surface-displayed, purified, and cell-free expressed. To assemble them, we fused two orthogonal peptide-protein pairs (i.e., SpyTag/SpyCatcher and SnoopTag/SnoopCatcher) to the three enzymes, allowing their spatial organization by covalent assembly. By doing this, we constructed a multienzyme complex, which could enhance the production of (S)-1-phenyl-1,2-ethanediol by 3 times compared to the free-floating enzyme system without assembly. After optimization of the reaction system, the final product yield reached 234.6 μM with a substrate conversion rate of 46.9% (based on 0.5 mM styrene). Taken together, our strategy integrates the merits of advanced biochemical engineering techniques, including cellular surface display, spatial enzyme organization, and cell-free expression, which offers a new solution for chemical biosynthesis by enzymatic cascade biotransformation. We, therefore, anticipate that our approach will hold great potential for designing and constructing highly efficient systems to synthesize chemicals of agricultural, industrial, and pharmaceutical significance.

Rational screening of ionic liquids as phase transfer catalysts for aromatic O- and S-glycosidations examplified by acetobromo-alpha-D-galactose with phenolic compound

The heterogeneous liquid–liquid O-glycosidation is a crucial step in pharmaceutical synthesis. Herein, a theoretical methodology based on COSMO-RS, quantum chemical calculations combined with Transformer-CNN model was used to screen ionic liquids (ILs) as phase transfer catalysts (PTCs) to intensify O-glycosidation between 4-nitrophenol and 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide. The anions of ILs were screened by the evaluation of ILs hydrophilicity via infinite dilution selectivity of ILs and the molecular descriptor HB_acc3 of the anion using COSMO-RS, a predictive model for thermodynamic properties. Additionally, the binding energy between the phenoxide anion and IL cation was used to assess reaction extent in the aqueous phase through quantum chemical calculation. The cations of ILs were evaluated by the infinite dilution selectivity of the combination between phenoxide anion and IL cations, and physical properties including viscosity and melting point were also predicted using an advanced Transformer-CNN model. The screened IL 1-octyl-3-methylimidazolium acetate and 1-hexyl-3-methylimidazolium acetate were demonstrated its superior catalytic activity for the aromatic O-glycosidation of not only 4-nitrophenol, but also various phenols and thiophenols. Moreover, the presence of PTCs enhances the likelihood of the reactant migrating into another phase. This behavior is validated by COSMO-RS calculated liquid–liquid equilibrium (LLE) and interaction energy analysis. The method provides great potential for screening and designing ILs as phase transfer catalysts for heterogeneous liquid–liquid reactions.

Thermodynamic and quantum chemical investigation of MIBK as a liquid phase extraction solvent for separating pyridine compounds from water

Pyridine compounds play a crucial role in the synthesis of fine chemicals and pharmaceuticals; however, the generation of a large amount of wastewater may pose a threat to the ecological environment and human health. Considering environmental factors and economic benefits, it is essential to explore efficient methods for separating pyridine compounds from water. In this study, pyridine compounds were separated from water by liquid–liquid extraction using MIBK as solvent. Liquid-liquid equilibrium (LLE) data for the ternary system water + pyridine compounds(pyridine, 2-methylpyridine, 3-methylpyridine, 2,6-dimethylpyridine, and 2,4,6-trimethylpyridine) + MIBK were measured at 303.2 K and 101.3 kPa. Subsequently, the distribution coefficient (D) and separation factor (S) were calculated based on the obtained data, serving as indicators to evaluate the performance of the extractant. The LLE data were then correlated with NRTL and UNIQUAC models to obtain binary interaction parameters. The accuracy of the regressed binary interaction parameters was assessed through Gibbs energy topology analysis. To explore the intrinsic mechanism of extraction between MIBK and pyridine or alkylpyridines, the σ-profile was used to investigate the interaction form between MIBK and pyridine or alkylpyridines. Based on this, quantum chemical calculations and wave function analysis were used to reveal the molecular-level separation mechanism. The interaction behavior of the MIBK and pyridine or alkylpyridines systems was systematically investigated. The results indicate that van der Waals forces are the main intermolecular interactions, and it is through these strong forces that MIBK can efficiently separate pyridine and alkylpyridines from water.

Real-Time Monitoring of Multistep Batch and Flow Synthesis Processes of a Key Intermediate of Lifitegrast by a Combined Spectrometer System with Both Near-Infrared and Raman Spectroscopies Coupled to Partial Least-Squares.

Process analytical technology (PAT) has been successfully applied in numerous chemical synthesis cases and is an important tool in pharmaceutical process research and development. PAT brings new methods and opportunities for the real-time monitoring of chemical processes. In multistep synthesis, real-time monitoring of the complex reaction mixtures is a significant challenge but provides an opportunity to enhance reaction understanding and control. In this study, a combined multichannel spectrometer system with both near-infrared and Raman spectroscopy was built, and calibration models were developed to quantify the desired products, intermediates, and impurities in real-time at multiple points along the synthetic pathway. The capabilities of the system have been demonstrated by operating dynamic experiments in both batch and continuous-flow processes. It represents a significant step forward in data-driven, multistep pharmaceutical ingredient synthesis.

Stemphylium lycopersici immobilized in polyurethane (PU) treated in pressurized fluid CO2 as biocatalyst for ω-transamination reactions

Lyophilized whole cells and the crude enzymatic extract from the fungus Stemphylium lycopersici were successfully immobilized in situ in rigid polyurethane foam, as an alternative biocatalyst for the kinetic resolution of rac-1-phenylethylamine, an interesting building block in the synthesis of pharmaceuticals. The enzymatic activity of immobilized whole cells and the crude enzymatic extract was 2.52 and 5.05 U/g, respectively. The immobilization yield in polyurethane of both forms was at least above 100%, and the process did not change the affinity of the biocatalyst for the substrate. The optima reaction conditions for the kinetic resolution of rac-1-phenylethylamine into acetophenone were: 32.5 °C, 120 rpm by 24 h containing 10 mL (20% m/v) of phosphate buffer (pH 7.5) and 20% biocatalyst mass, resulting in conversions of 45% and 34% using the immobilized lyophilized fungus and crude enzymatic extract, respectively. Stemphylium lycopersici was also subjected to high pressure using CO2. The best conditions provided conversions of 49 (99% ee) and 26.21 (without ee) using the immobilized lyophilized fungus and the immobilized lyophilized crude enzyme extract, respectively, with 20 cycles of reuse and recovery greater than 50% (fungus). Interestingly, the compounds were satisfactorily converted to the corresponding ketones with up to 90% ee for the R-enantiomer. The capacity for conversion of the immobilized lyophilized fungus to different amines: rac-1,2,3,4-tetrahydro-1-naphthylamine, rac-1-phenylpropylamine, and rac-phenylbutylamine was also evaluated. ω-transaminase activity changed significantly depending on the experimental conditions applied, allowing the selection of proper operating conditions for advantageous application of this biocatalyst in transamination reactions.

Recent Progress in the Synthesis of α‐Hydroxy Carbonyl Compounds with ThDP‐dependent Carboligases

AbstractThiamine diphosphate (ThDP) dependent carboligases catalyze the formation of carbon‐carbon bonds. These enzymes are prominent biocatalysts for the production of valuable α‐hydroxy carbonyl compounds, which serve as key building blocks in the synthesis of various pharmaceuticals and fine chemicals. Carboligases act in selective manner to afford regio‐ and stereochemically defined products from simple starting materials. This review explores the catalytic prowess of carboligases for synthetic purposes and is aimed at providing a selection tool of enzymes for particular sets of substrates or desired products. The comprehensive overview encompasses structural insights, relationships of the currently known sequence space and practical applications with a focus on recent literature, showcasing carboligases as potent tools for sustainable and efficient synthesis.

Metallosalen modified carbon nitride a versatile and reusable catalyst for environmentally friendly aldehyde oxidation

The development of environmentally friendly catalysts for organic transformations is of great importance in the field of green chemistry. Aldehyde oxidation reactions play a crucial role in various industrial processes, including the synthesis of pharmaceuticals, agrochemicals, and fine chemicals. This paper presents the synthesis and evaluation of a new metallosalen carbon nitride catalyst named Co(salen)@g-C3N4. The catalyst was prepared by doping salicylaldehyde onto carbon nitride, and subsequently, incorporating cobalt through Schiff base chemistry. The Co(salen)@g-C3N4 catalyst was characterized using various spectroscopic techniques including Scanning Electron Microscopy (SEM), X-ray Diffraction (XRD), Infrared Spectroscopy (IR), and Thermogravimetric Analysis (TGA). Furthermore, after modification with salicylaldehyde, the carbon nitride component of the catalyst exhibited remarkable yields (74–98%) in oxidizing various aldehyde derivatives (20 examples) to benzoic acid. This oxidation reaction was carried out under mild conditions and resulted in short reaction times (120–300 min). Importantly, the catalyst demonstrated recyclability, as it could be reused for five consecutive runs without any loss of activity. The reusable nature of the catalyst, coupled with its excellent yields in oxidation reactions, makes it a promising and sustainable option for future applications.

Process intensification in flow chemistry using micro and millidevices: Numerical simulations of the syntheses of three different intermediate API compounds for diabetes mellitus drug production

Microreactor Technology (MRT) appears as an interesting alternative for process intensification, including the development of continuous synthesis of fine chemicals and Active Pharmaceutical Ingredients (API). The inherent proposal of MRT is to reduce the scale-up time by simply increasing the number of microreactors in parallel, the numbering-up concept using optimal designed micro or millidevices. Among the API, rosiglitazone and lobeglitazone are derivatives of thiazolidine-2,4-dione (TZD), which is used as a building block, for molecules with biological activity, sensitive to insulin and, thus, with its administration the body makes better use of the insulin it produces, being an important structural element in medicinal chemistry, especially for type 2 diabetes mellitus, one of the biggest concerns in the health area worldwide, affecting nowadays more than 180 million people. The numerical assessment of MRT for various API synthesis related to type 2 diabetes mellitus drugs indicates its comparable or superior performance compared to traditional batch process. Specifically, proposed micromixer designs facilitate successful scale-up to milliscale while maintaining microscale performance, with significantly lower pressure drops than commercial Asia microreactors. The proposed flow distributors offer good performance in ensuring uniform distribution across outlets due to their conical shape design and laminar flow regime, with low pressure drops. The flow distributor with eights outlet is preferred for higher flow rates due to its superior performance, minimizing the pressure drops. Efficient flow rate and molar concentration control at each reactor unit can be ensured by using one distributor for each reactant's feed stream. This approach guarantees accurate concentration, flow rate control and ideal residence time, ultimately facilitating higher total throughput for scale-up. The potential use of micromixer actuators lies in its ability to maintain or enhance performance while transitioning from micro to milli-scale, offering promising alternatives for process intensification and scale-up in pharmaceutical synthesis, particularly for medications targeting type 2 diabetes mellitus.