Synthesis Of Pharmaceuticals Research Articles

An Alkoxy Modified N‐Heterocyclic Carbene‐Palladacycle: Synthesis, Characterization and Application towards Buchwald‐Hartwig and Suzuki‐Miyaura Coupling Reactions

AbstractA well‐defined N‐heterocyclic carbene‐palladacycles (NHC‐Pdcycle) by introducing alkoxy group was synthesized, and its structure was confirmed using single‐crystal X‐ray diffraction. The complex as catalyst exhibited high catalytic activity in Buchwald‐Hartwig and Suzuki‐Miyaura coupling reactions involving (hetero)aryl chlorides. Remarkably, the protocol with a wide range of substrate compatibility is suitable for the gram‐scale synthesis of Piribedil, a clinical drug for the treatment of Parkinson's disease, highlighting its potential applications in pharmaceutical synthesis.

Reductive Aldol-type Reactions in the Synthesis of Pharmaceuticals.

The efficient chemo-, regio- and stereoselective formation of saturated carbon-carbon fragment is the critical challenge of organic synthesis; therefore, developing new methods for formation of these bonds is paramount. The rising interest for reductive aldol-type reactions is conditioned by its versatile applications, allowing the efficient formation of carbon-carbon bonds. The review aims to highlight the advantages and disadvantage of reductive aldol-type reactions to total synthesis of pharmaceutical substances in order to summarize knowledge and encourage further investigation of the field.

Synthesis of 2-Methylquinoxaline Derivatives from Glycerol and Diamines Catalyzed by Iridium Complexes Bearing an N-Heterocyclic Carbene Ligand

2-Methylquinoxaline derivatives are widely used as intermediates in the synthesis of pharmaceuticals, natural products, and dyes; however, their syntheses usually require excess reagents, making them environmentally burdensome. Meanwhile, glycerol can be sustainably obtained in large quantities as a by-product in the production of biodiesel fuel using waste oil as a raw material. Thus, it is worthwhile to develop a new catalytic system that utilizes glycerol as a C3 source. In this study, an efficient catalytic system was developed to obtain 2-methylquinoxaline derivatives from glycerol and 1,2-phenylenediamines. This system is beneficial because it is environmentally friendly and has excellent atom efficiency.

Sustainable Pd(OAc)2/Hydroquinone Cocatalyst System for Cis‐Selective Dibenzoyloxylation of 1,3‐Cyclohexadiene

AbstractThe 1,4‐diacyloxylation of 1,3‐cyclohexadiene (CHD) affords valuable stereochemically defined scaffolds for natural product and pharmaceutical synthesis. Existing cis‐selective diacyloxylation protocols require superstoichiometric quantities of benzoquinone (BQ) or MnO2, which limit process sustainability and large‐scale application. In this report, reaction development and mechanistic studies are described that overcome these limitations by pairing catalytic BQ with tert‐butyl hydroperoxide as the stoichiometric oxidant. Catalytic quantities of bromide enable a switch from trans to cis diastereoselectivity. A catalyst with a 1:2 Pd:Br ratio supports high cis selectivity while retaining good rate and product yield. Further studies enable replacement of BQ with hydroquinone (HQ) as a source of cocatalyst, avoiding the handling of volatile and toxic BQ in large‐scale applications.

Sustainable Pd(OAc)2 /Hydroquinone Cocatalyst System for Cis-Selective Dibenzoyloxylation of 1,3-Cyclohexadiene.

The 1,4-diacyloxylation of 1,3-cyclohexadiene (CHD) affords valuable stereochemically defined scaffolds for natural product and pharmaceutical synthesis. Existing cis-selective diacyloxylation protocols require superstoichiometric quantities of benzoquinone (BQ) or MnO2 , which limit process sustainability and large-scale application. In this report, reaction development and mechanistic studies are described that overcome these limitations by pairing catalytic BQ with tert-butyl hydroperoxide as the stoichiometric oxidant. Catalytic quantities of bromide enable a switch from trans to cis diastereoselectivity. A catalyst with a 1:2 Pd:Br ratio supports high cis selectivity while retaining good rate and product yield. Further studies enable replacement of BQ with hydroquinone (HQ) as a source of cocatalyst, avoiding the handling of volatile and toxic BQ in large-scale applications.

Single-Atom Catalysis: From Simple Reactions to the Synthesis of Complex Molecules.

To date, the scope of single-atom catalysts (SAC) in liquid-phase transformations is rather limited owing to stability issues and the inability to activate complex substances. This calls for a better design of the catalyst support that can provide a dynamic coordination environment needed for catalytic action, and yet retain robustness against leaching or aggregation. In addition, the chemical orthogonality of SAC is useful for designing tandem or multicomponent reactions, in which side reactions common to metal nanoparticles are suppressed. In this review, the intrinsic mechanism will be highlighted that controls reaction efficiency and selectivity in SAC-catalyzed pathways, as well as the structural dynamism of SAC under complex liquid-phase conditions. These mechanistic insights are helpful for the development of next-generation SAC systems for the synthesis of high-value pharmaceuticals through late-stage functionalization, sequential and multicomponent strategies.

Molecular Transformation Based on an Innovative Catalytic System.

Novel innovative catalytic systems such as hydrogen-bond donors and thiourea hybrid catalysts have been developed for the asymmetric synthesis of biologically important pharmaceuticals and natural products. Benzothiadiazines possess a stronger hydrogen-bond donor ability compared to thioureas and exhibit remarkable catalytic performance for the activation of α,β-unsaturated amides. Hybrid thioureas (bearing an arylboronic acid and an ammonium salt) efficiently promote the hetero-Michael addition to α,β-unsaturated carboxylic acids and the O-alkylation of keto enols with 5-chlorofuran-2(5H)-one. These hybrid catalysts enable the first total synthesis of non-racemic avenaol, a noncanonical strigolactone, as well as the asymmetric synthesis of several pharmaceuticals. In addition, this study discovers unique chemical phenomena (i.e., the dual role of benzoic acid as a boron ligand and a proton shuttle, the chirality switch of products by solvent used, and the dynamic kinetic resolution of a racemic electrophile in an SN2-type reaction).

Recent advance in selective hydrogenation reaction catalyzed by biomass-derived non-noble metal nanocomposites

The green and sustainable synthesis of fine chemicals and pharmaceuticals urgently demands a new generation of efficient and robust catalysts in diverse organic transformations. Owing to their unique features of ready availability, natural abundance and renewability, environmental friendliness, and low-cost, the development of catalytically active materials derived from biomass has attracted extensive attention in the field of organic synthesis over the past few years. In this review, we summarize major progress in design and preparation of efficient and robust non-noble metal catalysts derived from various biomass feedstocks for green and sustainable selective hydrogenation transformations, with a particular focus on catalytic hydrogenation of nitro compounds, unsaturated CC bonds, quinoline compounds, CO bonds and so on. Finally, the challenges remaining in this research area are discussed and feasible future research directions are proposed.

Organocatalytic Enantioselective Construction of Chiral Azepine Skeleton Bearing Multiple‐Stereogenic Elements

AbstractEnantioselective construction of molecules bearing multiple stereogenic elements is increasingly related to the synthesis of enantiopure natural products, pharmaceuticals, and functional materials. However, atom‐economical and enantioselective approaches to install multiple stereogenic elements in a small molecular template by limited chemical transformation remain challenging. We describe an organocatalytic enantioselective method for the preparation of polychiral molecules bearing four types of stereogenic elements in fused azepines via vinylidene ortho‐quinone methide (VQM)‐mediated intramolecular electrophilic aromatic substitution. This method was proved robust with a wide range of substrate scope (46–92 % yield), with excellent diastereoselectivity (>20:1 dr) and enantioselectivity achieved (up to 97 % ee). Optical properties and Ru3+‐induced fluorescence responses of these compounds suggest their potential applications in optoelectronic materials and heavy metal ion detection.

A neural network model for free-falling condensation heat transfer in the presence of non-condensable gases

Condensation heat transfer has been widely studied for various applications such as power generation, water desalination, data centers, chemical and pharmaceutical syntheses, heating and air conditioning systems, and especially, the passive containment cooling system (PCCS) in nuclear power plants. The PCCS is designed to reduce the risk resulting from a loss of AC power or compounding human error. In a hypothetical accident situation, one of the main safety systems, the PCCS, condenses water vapor with gravity-driven force to remove the heat from the containment vessel. Although the condensation heat transfer in the presence of non-condensable gases for predicting the heat transfer performance of the PCCS has been successfully investigated, there is still no generalized model or correlation available. In this work, we focused on the development of universal models for predicting the heat transfer coefficients of free-fall condensation heat transfer on the external surfaces of vertical tubes in the presence of non-condensable gases. For this, we created a consolidated database covering a broad range of geometric values and operating conditions, including tube hydraulic diameter Dh = 10–41.2 mm, tube length L = 0.3–3.5 m, total pressure Ptot = 0.15–2.0 MPa, wall subcooling temperature ΔTsub = 5–71 K, average condensation heat transfer coefficients of 90 ≤ ͞h ≤ 19,400 W/m2K, and Reynolds numbers of the film of 8 ≤ Refilm ≤ 7160. We analyzed the influence of varying the geometric and operational parameter values by using this database. Conventional machine learning techniques such as nonlinear regression and multilayer perceptron (MLP) neural network methods were adopted to predict the condensation heat transfer rate based on the consolidated database. Moreover, the prediction accuracies of the condensation heat transfer rates of the proposed prediction models and 12 relevant correlations were compared by using the consolidated database. The proposed nonlinear regression model exhibited good prediction accuracy with a mean absolute error (MAE) of 12.7 % for average ͞h, which is much lower than those achieved by previously proposed relevant correlations. In addition, the MLP neural network model showed excellent prediction accuracy with an MAE of 4.2 % for the consolidated database.

Efficient enantioresolution of aromatic α-hydroxy acids with Cinchona alkaloid-based zwitterionic stationary phases and volatile polar-ionic eluents

Single enantiomers of mandelic acid (1), 3-phenyllactic acid (2), and 3-(4-hydroxyphenyl)lactic acid (3) are the subject of many fields of investigation, spanning from the pharmaceutical synthesis to that of biocompatible and biodegradable polymers, while passing from the interest towards their antimicrobial activity to their role as biomarkers of particular pathological conditions or occupational exposures to specific xenobiotics. All above mentioned issues justify the need for accurate analytical methods enabling the correct determination of the individual enantiomers. So far, all the developed liquid chromatography (LC) methods were not or hardly compatible with mass spectrometry (MS) detection. In this paper, a commercially available Cinchona-alkaloid derivative zwitterionic chiral stationary phase [that is, the CHIRALPAK® ZWIX(−)] was successfully used to optimize the enantioresolution of compounds 1–3 under polar-ionic (PI) conditions with a mobile phase consisting of an acetonitrile/methanol 95/5 (v/v) mixture with 80 mM formic acid. With the optimized conditions, enantioseparation and enantioresolution values up to 1.46 and 4.41, respectively, were obtained. In order to assess the applicability of the optimized enantioselective chromatography conditions in real-life scenarios and on MS-based systems, a proof-of-concept application was efficiently carried out by analysing dry urine spot samples spiked with 1 by means of a LC-MS system. The (S)<(R) enantiomer elution order (EEO) was established for compounds 1 and 2 by analysing a pure enantiomeric standard of known configuration. This was not possible for 3 because not commercially available. For this compound, the same EEO was identified applying a procedure based on ab initio time-dependent density-functional theory simulations coupled to electronic circular dichroism analyses. Moreover, a molecular dynamics simulation unveiled the role of the phenolic OH in compound 3 in the retention mechanism.

Phosphorus coordinated Rh single-atom sites on nanodiamond as highly regioselective catalyst for hydroformylation of olefins

Single-atom Rh catalysts present superior activity relative to homogeneous catalyst in olefins hydroformylation, yet with limited success in regioselectivity control. In the present work, we develop a phosphorus coordinated Rh1 single-atom catalyst with nanodiamond as support. Benefiting from this unique structure, the catalyst exhibits excellent activity and regioselectivity in hydroformylation of arylethylenes with wide substrate generality, i.e., with high conversion (>99%) and high regioselectivity (>90%), which is comparable with the homogeneous counterparts. The coordination interaction between Rh1 and surface phosphorus species is clarified by 31P solid-state NMR and X-ray absorption spectroscopy (XAS). Rh single atoms are firmly anchored over nanodiamond through Rh-P bonds, guaranteeing good stability in the hydroformation of styrene even after six runs. Finally, by using this catalyst, two kinds of pharmaceutical molecules, Ibuprofen and Fendiline, are synthesized efficiently with high yields, demonstrating a new prospect of single-atom catalyst in pharmaceutical synthesis.

Visible Light Mediated Synthesis of Oxindoles

AbstractFunctionalized oxindoles are privileged heterocyclic scaffolds and common core structural motifs that are broadly present in numerous natural products and serve as key intermediates in the synthesis of biological products, agrochemicals, and pharmaceuticals. Oxindoles exhibit a broad pharmacological and physiological activities, and diverse range of applications in medicinal chemistry and biomedical research. Owing to these fascinating biological and physiological activities of oxindoles, several methodologies have been developed for the construction of oxindoles. In the past decade, the visible light mediated methodologies have attracted substantial attention and emerged as a promising approach for the construction of oxindoles. In this review, the visible light mediated synthesis of oxindoles have been described.magnified image

Metabolic Engineering of Escherichia coli for High-Yield Production of (R)-1,3-Butanediol.

1,3-Butanediol (1,3-BDO) is an important C4 platform chemical widely used as a solvent in cosmetics and a key intermediate for the synthesis of fragrances, pheromones, and pharmaceuticals. The development of sustainable bioprocesses to produce enantiopure 1,3-BDO from renewable bioresources by fermentation is a promising alternative to conventional chemical routes and has aroused great interest in recent years. Although two metabolic pathways have been previously established for the biosynthesis of (R)-1,3-PDO, the reported titer and yield are too low for cost-competitive production. In this study, we report the combination of different metabolic engineering strategies to improve the production of (R)-1,3-BDO by Escherichia coli, including (1) screening of key pathway enzymes; (2) increasing NADPH supply by cofactor engineering; (3) optimization of fermentation conditions to divert more flux into 1,3-BDO pathway; (4) reduction of byproducts formation by pathway engineering. With these efforts, the best engineered E. coli strain can efficiently produce (R)-1,3-BDO with a yield of 0.6 mol/mol glucose, corresponding to 60% of the theoretical yield. Besides, we also showed the feasibility of aerobically producing 1,3-BDO via a new pathway using 3-hydroxybutyrate as an intermediate.

Sulfamic Acid as Versatile Green Catalyst Used For Synthetic Organic Chemistry: A Comprehensive Update

AbstractIn recent times, synthetic organic reactions have gained significant attention as they are becoming a versatile tool in the synthesis of pharmaceuticals, agrochemicals and their intermediates. Sulfamic acid (SA) is an acid catalyst that demonstrated high efficiency in various organic transformations that will be highlighted in this review. These include efforts to develop green approaches using SA catalyst for the C−C bond formation reactions and functional group transformations, as well as the synthesis of various O− and N‐heterocyclic compounds and other miscellaneous reactions including multicomponent reactions. The easy recovery (for subsequent reuse) of the catalyst by filtration without the need for solvents is an important advantage of SA catalyst. In this review, SA promoted greener methodologies that were developed and the applicability of these methodologies are addressed.

Effect of the Solvent and Substituent on Tautomeric Preferences of Amine-Adenine Tautomers.

Adenine is one of the basic molecules of life; it is also an important building block in the synthesis of new pharmaceuticals, electrochemical (bio)sensors, or self-assembling molecular materials. Therefore, it is important to know the effects of the solvent and substituent on the electronic structure of adenine tautomers and their stability. The four most stable adenine amino tautomers (9H, 7H, 3H, and 1H), modified by substitution (C2– or C8−) of electron-withdrawing NO2 and electron-donating NH2 groups, are studied theoretically in the gas phase and in solvents of different polarities (1 ≤ ε < 109). Solvents have been modeled using the polarizable continuum model. Comparison of the stability of substituted adenine tautomers in various solvents shows that substitution can change tautomeric preferences with respect to the unsubstituted adenine. Moreover, C8 substitution results in slight energy differences between tautomers in polar solvents (<1 kcal/mol), which suggests that in aqueous solution, C8–X-substituted adenine systems may consist of a considerable amount of two tautomers—9H and 7H for X = NH2 and 3H and 9H for X = NO2. Furthermore, solvation enhances the effect of the nitro group; however, the enhancement strongly depends on the proximity effects. This enhancement for the NO2 group with two repulsive N···ON contacts can be threefold higher than that for the NO2 with one attractive NH···ON contact. The proximity effects are even more significant for the NH2 group, as the solvation may increase or decrease its electron-donating ability, depending on the type of proximity.

Dynamic response surface methodology using Lasso regression for organic pharmaceutical synthesis

Dynamic response surface methodology using Lasso regression for organic pharmaceutical synthesis

Oxidative Cleavage of Alkenes by O2 with a Non-Heme Manganese Catalyst.

The oxidative cleavage of C=C double bonds with molecular oxygen to produce carbonyl compounds is an important transformation in chemical and pharmaceutical synthesis. In nature, enzymes containing the first-row transition metals, particularly heme and non-heme iron-dependent enzymes, readily activate O2 and oxidatively cleave C=C bonds with exquisite precision under ambient conditions. The reaction remains challenging for synthetic chemists, however. There are only a small number of known synthetic metal catalysts that allow for the oxidative cleavage of alkenes at an atmospheric pressure of O2, with very few known to catalyze the cleavage of nonactivated alkenes. In this work, we describe a light-driven, Mn-catalyzed protocol for the selective oxidation of alkenes to carbonyls under 1 atm of O2. For the first time, aromatic as well as various nonactivated aliphatic alkenes could be oxidized to afford ketones and aldehydes under clean, mild conditions with a first row, biorelevant metal catalyst. Moreover, the protocol shows a very good functional group tolerance. Mechanistic investigation suggests that Mn–oxo species, including an asymmetric, mixed-valent bis(μ-oxo)-Mn(III,IV) complex, are involved in the oxidation, and the solvent methanol participates in O2 activation that leads to the formation of the oxo species.

Synthesis of Difluorinated Halohydrins by the Chemoselective Addition of Difluoroenolates to α-Haloketones.

α-Haloketones are valuable intermediates in the synthesis of pharmaceuticals and natural products because they display two electrophiles. Although chemoselective additions to each of these functional groups are known, the use of fluorinated nucleophiles has not been characterized, except for the dimerization of fluorohalomethyl ketones. Our studies demonstrate the use of difluoroenolates to create difluorinated bromohydrins and chlorohydrins from α-haloketones without any cyclization or rearrangement due to the mild conditions.

Essential hazard and process safety assessment of para-toluene sulfonic acid through calorimetry and advanced thermokinetics

Para-toluene sulfonic acid is a typical intermediary for the synthesis of pharmaceuticals, pesticides, and dyes and is a catalyst for organic synthesis. The consumption of para-toluene sulfonic acid used in organic synthesis has increased substantially. The toluene sulfonation process is the central path for synthesizing para-toluene sulfonic acid in China. However, the process has risks and has resulted in numerous disasters. This study utilized a reaction calorimeter 1 to reproduce the commercial toluene sulfonation process in a laboratory. The para-toluene sulfonic acid product was examined with an accelerating rate calorimeter and through differential scanning calorimetry. Both differential and integral isoconversional methods were used to determine the thermal stability of and appropriate thermokinetic models for para-toluene sulfonic acid. The safety parameters of para-toluene sulfonic acid were estimated. The research findings can be used for optimization of the toluene sulfonation process and for safe handling of para-toluene sulfonic acid.