Synthesis Of Pharmaceuticals Research Articles

Photoinduced Generation of Active Intermediates from Unmodified 1,3‐Dicarbonyl Compounds for Organic Transformations

AbstractPhotocatalysis utilizes light as the initial driving force for chemical reactions, enabling reactions with high energy barriers in traditionally thermal chemistry to proceed under mild conditions. 1,3‐Dicarbonyl compounds occur as important active molecules in nature and are intermediates in pharmaceutical syntheses. In recent years, there have been numerous studies of these compounds, and it is common practice to pre‐modify them before the reaction, which is, however, unfavorable for the atom economy of the process. This paper provides a comprehensive review of the latest advancements in the site‐specific activation of unmodified 1,3‐dicarbonyl compounds by photoinduction. The focus is on elucidating the mechanisms of these reactions to provide insights and directions for future research in designing novel reactions.

Site-specific mutation of ω-transaminase and the biocatalytic preparation of (S)-1-(2-fluorophenyl) ethylamine

(S)-1-(2-fluorophenyl) ethylamine plays a crucial role as a chiral building block in pharmaceutical synthesis. ω-transaminases are widely recognized as environmentally friendly and efficient catalysts for the preparation of chiral amines. In this study, we isolated a novel ω-transaminase, PfTA, from Pseudogulbenkiania ferrooxidans through gene mining in the NCBI database. By employing semi-rational design, we obtained a Y168R/R416Q variant with enhanced enzyme activity. This variant exhibited the ability to catalyze the synthesis of (S)-1-(2-fluorophenyl) ethylamine from 2-fluorophenone, achieving a yield of 83.58% and an enantioselectivity exceeding 99% after a 10 h reaction. Compared to the wild type, the specific enzyme activity of the Y168R/R416Q variant reached 47.04 U/mg, which represents an increase of 11.65 times. Additionally, the catalytic efficiency, as measured by kcat/Km, was increased by 20.9 times. Molecular docking and structural simulation analysis revealed that the primary factor contributing to the improved catalytic efficiency is the expansion of the enzyme's active pocket and the alleviation of steric hindrance.

Gold-catalyzed synthesis of small-sized carbo- and heterocyclic compounds: A review

Abstract Research on gold catalysis has flourished over the last 20 years, and gold catalysts are now acknowledged as the “best choice” for a range of organic transformations. Gold complexes have emerged as promising candidates for this use in recent years because of their high reactivity, which enables them to induce a broad range of transformations under mild conditions. Extensive demonstrations have showcased the extraordinary efficiency of synthesizing complex organic compounds from the basic starting components. In addition to its traditional applications in catalysis, gold catalysis has expanded to include the total synthesis of natural compounds, which is a complex and demanding undertaking. The class of molecules known as carbo- and heterocycles, which is arguably the most important, has a significant impact on the synthesis of agrochemicals and pharmaceuticals among the numerous additional products made possible by the novel procedures pioneered. The main topic of this review is how to use Au salts in homogeneous catalysis to create cyclization processes for small heterocyclic and carbocyclic systems. This study gives an overview of most of the books and articles written after 2013 that discuss making three- and four-membered carbo- and heterocyclic rings with gold as a catalyst. We have made every effort to include all outstanding reports on this subject; nonetheless, we apologize for any omissions.

Modulating the Catalytic Properties of Polyoxovanadates with Transition-Metal-Complex Units for Selective Oxidation of Sulfides.

Selective oxidation of sulfides to sulfoxides is of great significance in the synthesis of pharmaceuticals, desulfurization of fuels, and detoxification of sulfur mustard chemical warfare agents. Designing selective catalysts to achieve the efficient transformation of sulfides to sulfoxides is thus highly desired. Herein, we report three transition metal-complex-functionalized polyoxovanadates, [Zn2(BPB)2][V4O12]·0.5BPB·H2O (1), [Ni(BPB)(H2O)][V2O6]·2H2O (2), and [Co(HBPB)2][V4O12] (3) (BPB = 1,4-bis(pyrid-4-yl)benzene)), and explore their applications for selective oxidation of sulfides using H2O2 as an oxidant. All three compounds were catalytically effective for the oxidation of methyl phenyl sulfide to methyl phenyl sulfoxide, with 1 being best-performing with complete conversion and a selectivity of 96.7%. In the selective oxidation of a series of aromatic and aliphatic sulfides to corresponding sulfoxides, 1 also showed satisfactory performance; in particular, the chemical warfare agent stimulant 2-chloroethyl ethyl sulfide can be completely and selectively oxidized to the nontoxic 2-chloroethyl ethyl sulfoxide within 20 min at room temperature. Catalyst 1 can be recycled and reused at least six times with uncompromised performance. The perfect performance of 1 is attributed to the synergistic effect of coordinatively unsaturated V and Zn sites in bimetallic oxide, as revealed by comparative structural and catalytic studies.

Characterization of a novel 3-quinuclidinone reductase possessing remarkable thermostability

The 3-quinuclidinone reductase plays an irreplaceable role in the biopreparation of (R)-3-quinuclidinol, an intermediate vital for synthesis of various pharmaceuticals. Thermal robustness is a critical factor for enzymatic synthesis in industrial applications. This study characterized a new 3-quinuclidinone reductase, named SaQR, with significant thermal stability. The SaQR was overexpressed in a GST-fused state, and substrate and cofactor screening were conducted. Additionally, three-dimensional structure prediction using AlphaFold and analysis were performed, along with relevant thermostability tests, and the evaluation of factors influencing enzyme activity. The findings highlight the remarkable thermostability of SaQR, retaining over 90% of its activity after 72 h at 50°C, with an optimal operational temperature of 85°C. SaQR showed typical structural traits of the SDR superfamily, with its cofactor-determining residue being aspartic acid, conferring nicotinamide adenine dinucleotide (NAD(H)) preference. Moreover, K+ and Na+, at a concentration of 400 mM, could significantly enhance the activity, while Mg2+ and Mn2+ only display inhibitory effects within the tested concentration range. The findings of molecular dynamics simulations suggest that high temperatures may disrupt the binding of enzyme to substrate by increasing the flexibility of residues 205–215. In conclusion, this study reports a novel 3-quinuclidinone reductase with remarkable thermostability.

Unlocking enhanced selectivity of Pd/Al2O3 in semihydrogenation of alkynes by in situ ligand‐reduction strategy

AbstractThe partial hydrogenation of alkynes into alkenes constitutes a pivotal chemical transformation in the synthesis of fine chemicals, pharmaceuticals, and polymers. Nevertheless, the extant industrial catalyst falls short of achieving a felicitous equilibrium between its catalytic potency and selectivity. Herein, triphenylphosphine (PPh3) modified Pd/Al2O3 catalysts are fabricated through a “one‐pot” process, which achieve highly selective hydrogenation of alkynes at room temperature. PPh3 plays a dual role—as a reducing agent and a ligand. Kinetic and characterization studies reveal PPh3 alters H2 activation from homolytic to heterolytic cleavage, which facilitate the formation of alkene. Moreover, PPh3 can also optimize the reaction microenvironment, achieving the reduced self‐poisoning of alkyne and promoted desorption of alkene. In the realm of alkyne hydrogenation, our philosophy encompasses a global optimization of active sites, ligand systems, and reaction microenvironmental. This method steers the course of catalyst development for other reactions beyond the field of alkyne hydrogenation.

Exploitation of Selected Fungal Endophytes of Andrographis paniculata (Burm. f.) Wall. ex Nees for the Production and Optimisation of Tannase and Screening for their Associated Hydrolysing Enzymes; Amylase, Protease, Lipase, and Laccase

Endophytes represent a diverse domain of microorganisms with immense biotechnological potentialities. Metabolites from endophytes, especially fungi, are useful in industrial as well as pharmaceutical aspects. Here, endophytic fungal isolates of Andrographis paniculata collected from the Tapobon, Junglemahal region of West Bengal, India, have been studied for their hydrolyzing enzyme production abilities. Out of eighty-one isolates, twenty-one were positive for amylase, protease, lipase, laccase, and tannase action. Microscopic features of positive isolates revealed that the enzyme producers were Aspergillus sp., Fusarium sp., Alternaria sp., Trichoderma sp., Exerohilum sp., Nigrospora sp., Curvularia sp., Cladosporium sp., Cochliobolus sp., Tricothecium sp., Penicillium sp., Verticillium sp., and Cephalosporium sp. The amylolytic activity was remarkable in the case of endophytic Aspergillus sp. and Fusarium sp. Also, Aspergillus sp. and Alternaria sp. had proteolytic activity. Aspergillus sp., Mycelia sterilia-2, and Trichoderma sp. were potent lipase producers. Along with Exerohilum sp. endophytic Aspergillus sp. had positive laccase activity. The tannic acid degrading activity was highest for Aspergillus sp. APL11 followed by Helicosporium sp. and Fusarium sp. Tannase producing ability of Aspergillus sp. was optimized and an incubation time- 96h, incubation temperature- 29°C, initial medium pH- 6.5, carbon source- glucose, and nitrogen source- NaNO3 exhibited a two-fold scale-up of (2.83±0.05 u mL-1) in tannase action. These enzymes offer eco-friendly and efficient solutions across a wide range of industrial processes including food production, textile processing, and pharmaceutical synthesis. Fungal endophytes of medicinal plants act as an alternative source for hydrolysing enzymes.

ProPhos: A Ligand for Promoting Nickel-Catalyzed Suzuki-Miyaura Coupling Inspired by Mechanistic Insights into Transmetalation.

Nickel-catalyzed Suzuki-Miyaura coupling (Ni-SMC) offers the potential to reduce the cost of pharmaceutical process synthesis. However, its application has been restricted by challenges such as slow reaction rates, high catalyst loading, and a limited scope of heterocycles. Despite recent investigations, the mechanism of transmetalation in Ni-SMC, often viewed as the turnover-limiting step, remains insufficiently understood. We elucidate the "Ni-oxo" transmetalation pathway, applying PPh2Me as the ligand, and identify the formation of a nickel-oxo intermediate as the turnover-limiting step. Building on this insight, we develop a scaffolding ligand, ProPhos, featuring a pendant hydroxyl group connected to the phosphine via a linker. The design preorganizes both the nucleophile and the nickel catalyst, thereby facilitating transmetalation. This catalyst exhibits fast kinetics and robust activity across a wide range of heteroarenes, with a catalyst loading of 0.5-3 mol %. For arene substrates, the catalyst loading can be further reduced to 0.1 mol %.

BIBLIOGRAPHIC REVIEW OF THE APPLICATION OF CINNAMALDEHYDE AS A DRUG IN DENTISTRY

Cinnamon (Cinnamomum sp) has been used as a spice for millennia, offering nutritional, aromatic, and pharmaceutical properties. The essential oil from cinnamon bark predominantly contains cinnamaldehyde, which exhibits applications as an antioxidant, anti-inflammatory, antimicrobial, and wound-healing agent. These characteristics have drawn the interest of the pharmaceutical industry, seeking to identify alternative uses of this compound for the treatment of oral diseases. In light of this, the present study aims to conduct a literature review, justifying the potential presented by cinnamon essential oil, specifically cinnamaldehyde, for the synthesis of new pharmaceuticals intended for dental use.

Development of Synthetic Route for 3‐Amino‐5‐halo‐2‐iodobenzoates: Versatile Starting Materials in Pharmaceuticals Synthesis

AbstractA novel synthetic route to 3‐amino‐5‐halo‐2‐iodobenzoates, which are used as versatile starting materials in the synthesis of pharmaceuticals, was developed using commercially available 2‐aminobenzoates bearing a suitable halogen atom at the C5 position as the starting material. Synthesis was initiated with the introduction of a nitro group at the C3 position of the appropriate 2‐aminobenzoates, forming 2‐amino‐3‐nitrobenzoates with a C5‐halogen atom. The subsequent conversion of the C2‐amino group to an iodide yielded 5‐halo‐2‐iodo‐3‐nitrobenzoates, which were further converted into the desired 3‐amino‐5‐halo‐2‐iodobenzoates by reducing the C3‐nitro group to an amino group. It is worth noting that this transformation can be conducted on a 50 mmol scale, and the desired benzoate compounds were obtained in good yield, demonstrating the practical applicability of this protocol.

Nickel-Catalyzed Reductive Cross-Coupling of Propargylic Acetates with Chloro(vinyl)silanes: Access to Silylallenes.

Because of their various reactivities, propargyl acetates are refined chemical intermediates that are extensively applied in pharmaceutical synthesis. Currently, reactions between propargyl acetates and chlorosilanes may be the most effective method for synthesizing silylallenes. Nevertheless, owing to the adaptability and selectivity of substrates, transition metal catalysis is difficult to achieve. Herein, nickel-catalyzed reductive cross-coupling reactions between propargyl acetates and substituted vinyl chlorosilanes for the synthesis of tetrasubstituted silylallenes are described. Therein, metallic zinc is a crucial reductant that effectively enables two electrophilic reagents to selectively construct C(sp2)-Si bonds. Additionally, a Ni-catalyzed reductive mechanism involving a radical process is proposed on the basis of deuteration-labeled experiments.

Transition‐Metal‐Catalyzed α,β‐Dehydrogenation of Carbonyl Compounds

Abstractα,β‐Unsaturated compounds are one of the most important functional compounds. Due to their unique property and versatile utility, they usually occur as the key intermediates for the synthesis of pharmaceuticals and biological materials. Thus, their synthesis has attracted more attentions than before. The early approaches to α,β‐unsaturated compounds are mainly about transition‐metal‐free methods, such as halogenation‐dehydrohalogenation methods and strong oxidants methods (organosulfur, organoselenium, benzoquinone). Subsequently, palladium and the other transition‐metals catalyzed dehydrogenation of carbonyl compounds appeared respectively. In this review, transition‐metal‐catalyzed α,β‐dehydrogenation is discussed, which is categorized by functional groups.

Recovery of Isoamyl Alcohol by Graphene Oxide Immobilized Membrane and Air-Sparged Membrane Distillation.

Isoamyl alcohol is an important biomass fermentation product that can be used as a gasoline surrogate, jet fuel precursor, and platform molecule for the synthesis of fine chemicals and pharmaceuticals. This study reports on the use of graphene oxide immobilized membra (GOIMs) for the recovery of isoamyl alcohol from an aqueous matrix. The separation was performed using air-sparged membrane distillation (ASMD). In contrast to a conventional PTFE membrane, which exhibited minimal separation, preferential adsorption on graphene oxide within GOIMs resulted in highly selective isoamyl alcohol separation. The separation factor reached 6.7, along with a flux as high as 1.12 kg/m2 h. Notably, the overall mass transfer coefficients indicated improvements with a GOIM. Optimization via response surfaces showed curvature effects for the separation factor due to the interaction effects. An empirical model was generated based on regression equations to predict the flux and separation factor. This study demonstrates the potential of GOIMs and ASMD for the efficient recovery of higher alcohols from aqueous solutions, highlighting the practical applications of these techniques for the production of biofuels and bioproducts.

Advancement in chiral heterocycles for the antidiabetic activity.

For the synthesis and development of pharmaceuticals, chirality is an important structural component. Chiral heterocyclic compounds have annoyed the interest of synthetic chemists who are working to create useful and efficient techniques for these molecules. As indicated by the expanding number of chiral drugs created in the last two decades, the link between chirality and pharmacological activity has become more important in the pharmaceutical and biopharmaceutical industries. Approximately 65% of currently used drugs are chiral, and many of them are promoted as racemates in many circumstances. There are a growing number of new chiral heterocyclic compounds with important biological properties and intriguing uses in medical chemistry and drug discovery. In this study, we review current breakthroughs in chiral heterocycles and their different physiological activities that have been published in the last year (from 2010 to early 2023). This study focuses on the current trends in the use of chiral heterocycles in drug design and the creation of several powerful and competent candidates for diabetic illnesses.

Sustainable Aerobic Allylic C-H Bond Oxidation with Heterogeneous Iron Catalyst.

Emerging techniques are revolutionizing the realm of chemical synthesis by introducing new avenues for C-H bond functionalization, which have been exploited for the synthesis of pharmaceuticals, natural compounds, and functional materials. Allylic C-H bond oxidation of alkenes serves as possibly the most employed C-H bond functionalization reaction. However, sustainable and selective approaches remain scarce, and the majority of the existing conditions still hinge on hazardous oxidants or costly metal catalysts. In this context, we introduce a heterogeneous iron catalyst that addresses the above-mentioned concerns by showcasing the aerobic oxidation of steroids, terpenes, and simple olefins to the corresponding enone products. This novel method provides a powerful tool for the arsenal of allylic C-H bond oxidation while minimizing the environmental concerns.

Evaluating Multienzyme Cascade Routes for Pharmaceutically Relevant Molecules

AbstractThe constant demand for sustainable approaches to pharmaceutical synthesis has thrived the enzyme catalysis (biocatalysis) field. The most sought‐after features like high specificity, environmentally benign, and biodegradable nature have rendered enzymatic processes predominantly eco‐friendly. Owing to these merits, biocatalysis is now being developed extensively to exploit their applications in designing alternate and sustainable synthetic routes for manufacturing pharmaceuticals, in line with green chemistry principles. Further, combining multiple enzymes in one‐pot is a highly efficient methodology as it eliminates intermediate isolation, shifts equilibrium in the forward direction, and proceeds in ambient aqueous conditions. This review highlights the importance of recently developed multienzyme cascade synthesis of pharmaceutically important bioactive molecules by relating them with their well‐known chemical route.

Synthetic methodologies to access bioactive bis-coumarin scaffold: a recent progress

Abstract Heterocyclics particularly those containing oxygen and nitrogen atoms are unique precursors for the synthesis of various agrochemicals and pharmaceuticals. Bis-coumarins are well-known oxygen-containing heterocycles of great significance. The development of methods to prepare bis-coumarins is of great interest in synthetic organic chemistry because of their versatile importance in medicinal chemistry and chemical biology. Bis-coumarins are well known for their antibiotic, antimicrobial, anti-HIV, and antitumor activity. Due to the vast application of bis-coumarins, the synthesis of these heterocycles has attracted huge interest from researchers. In this review, we have summarized the diverse synthetic routes of bis-coumarin synthesis making use of different catalysts and solvents under versatile reaction conditions.

Copper Dispersed Covalent Organic Framework for Azide-Alkyne Cycloaddition and Fast Synthesis of Rufinamide in Water.

A crystalline porous bipyridine-based Bpy-COF with a high BET surface area (1864m2g-1) and uniform mesopore (4.0nm) is successfully synthesized from 1,3,5-tris-(4'-formyl-biphenyl-4-yl)triazine and 5,5'-diamino-2,2'-bipyridine via a solvothermal method. After Cu(I)-loading, the resultant Cu(I)-Bpy-COF remained the ordered porous structure with evenly distributed Cu(I) ions at a single-atom level. Using Cu(I)-Bpy-COF as a heterogeneous catalyst, high conversions for cycloaddition reactions are achieved within a short time (40min) at 25°C in water medium. Moreover, Cu(I)-Bpy-COF proves to be applicable for aromatic and aliphatic azides and alkynes bearing various substituents such as ester, hydroxyl, amido, pyridyl, thienyl, bulky triphenylamine, fluorine, and trifluoromethyl groups. The high conversions remain almost constant after five cycles. Additionally, the antiepileptic drug (rufinamide) is successfully prepared by a simple one-step reaction using Cu(I)-Bpy-COF, proving its practical feasibility for pharmaceutical synthesis.

Broad Spectrum Enantioselective Amide Bond Synthetase from Streptoalloteichus hindustanus.

The synthesis of amide bonds is one of the most frequently performed reactions in pharmaceutical synthesis, but the requirement for stoichiometric quantities of coupling agents and activated substrates in established methods has prompted interest in biocatalytic alternatives. Amide Bond Synthetases (ABSs) actively catalyze both the ATP-dependent adenylation of carboxylic acid substrates and their subsequent amidation using an amine nucleophile, both within the active site of the enzyme, enabling the use of only a small excess of the amine partner. We have assessed the ability of an ABS from Streptoalloteichus hindustanus (ShABS) to couple a range of carboxylic acid substrates and amines to form amine products. ShABS displayed superior activity to a previously studied ABS, McbA, and a remarkable complementary substrate specificity that included the enantioselective formation of a library of amides from racemic acid and amine coupling partners. The X-ray crystallographic structure of ShABS has permitted mutational mapping of the carboxylic acid and amine binding sites, revealing key roles for L207 and F246 in determining the enantioselectivity of the enzyme with respect to chiral acid and amine substrates. ShABS was applied to the synthesis of pharmaceutical amides, including ilepcimide, lazabemide, trimethobenzamide, and cinepazide, the last with 99% conversion and 95% isolated yield. These findings provide a blueprint for enabling a contemporary pharmaceutical synthesis of one of the most significant classes of small molecule drugs using biocatalysis.

Removal of Aromatic Amino-derivatives from Aqueous Solutions Using Polymeric Supports Functionalized with Aminophosphonated/aminoacid-phosphonated Groups

Aromatic amines are the significant compounds used as intermediates in the organic synthesis, for obtaining such as azo dyes, antioxidants, fuel additives, corrosion inhibitors, pesticides, antiseptic agents, poultry medicine, and pharmaceutical synthesis. However, the presence of aromatic amines in water, even at very low concentrations, is extremely harmful to aquatic life and human health. Pollution of natural waters by aromatic amines is a serious environmental concern. The aim of this work was to obtain new adsorbents for use in the removal of aromatic amines from aqueous solutions. Styrene-15%divinylbenzene copolymers grafted with aminophosphonate groups (code: AP-S15%DVB) and amino acid-phosphonate groups (code: AM-S15%DVB) were used for the removal of pollutants such as: aniline, 2-methyl-aniline and 4-methyl-aniline. The adsorption capacity and the adsorption kinetic using the pseudo-first order and pseudo-second order equations were examined. From a kinetic point of view, it was established that the adsorption of the studied amino derivatives on the used adsorbents took place according to the pseudo-second order model. It was found that the adsorption rate constant increased with the increase of temperature, so the speed of the adsorption process increased. The obtained results confirm that the polymer adsorbents studied can be successfully used for the removal of aromatic amino derivatives from aqueous solutions for the purpose of wastewater treatment.