Multigram Synthesis Research Articles

Anodic Desulfurization of Heterocyclic Thiones - A Synthesis to Imidazoles and Analogues.

An electrochemical desulfurization of 2-mercapto-imidazoles to the corresponding imidazole is established. This novel anodic transformation is bromide-mediated and easy to conduct in the simplest electrochemical setup, consisting of an undivided cell, carbon electrodes, and constant current electrolysis. The method proved successful in 14 diverse examples of imidazoles and triazoles with up to a 97% yield. The scalability was proven in the multigram synthesis of a technically relevant N-heterocyclic carbene (NHC) ligand precursor.

Multigram synthesis of 2-vinylpyridine using bio-renewable 2-methyl tetrahydrofuran solvent

The present work reports the synthesis of 2-vinylpyridine in multigram synthetic approach as it has tremendous application in pharmaceutical science as well as in material science and industries. This present method emphasizes the usage of commercially available inexpensive raw materials and bio renewable solvents. Nontoxic TCCA was used as green chlorinating reagent and its corresponding bi-product obtained in the course of the reaction is biodegradable in nature. This entire three step procedure does not require any chromatographic techniques and the product is obtained in 95% yield with > 98% purity.

Asymmetric Synthesis of 3,3′-Pyrrolidonyl Spirooxindole-5’-Carboxylic Ester from L-Tryptophan

A highly efficient, multi-gram scale asymmetric synthesis of 3,3'-pyrrolidonyl spirooxindole-5'-carboxylic ester, which could be a potential precursor for the synthesis of cyanogramide, is accomplished from commercially available L-1-methyl-tryptophan in two pots. Fluoride-promoted desilylative spiro-cyclization of (semi) in situ generated isocyanate derived from (L)-1-methyl tryptophan is the key reaction. Further, a variety of arene-substituted 3,3′-pyrrolidonyl spirooxindole-5’-carboxylxic acid ester were synthesized by late stage functionalization of easily accessible 3,3'-pyrrolidonyl spirooxindole-5'-carboxylic ester.

Room Temperature Ni‐Catalyzed Ullmann Reaction of (Hetero)aryl/Vinyl Chlorides Enabled by Silylchloride‐Activated Mn Powders

AbstractA room temperature Ni‐catalyzed Mn‐mediated homocoupling of (hetero)aryl and vinyl chlorides using Mn powders pre‐activated by trimethylsilylchloride (TMSCl) in DMA is reported. Large steric effects were observed while electronic influences from aryl chlorides proved to be rather small. High regioselectivity could be achieved between ortho‐Cl and para‐Cl/Br of aryl halides benefiting from the large steric effects. A double‐face role of TMSCl, i. e. activation of Mn powders but deactivation of nickel catalyst, was observed although TMSCl‐activated Mn powders appeared to be the privileged metallic reductant. Applications of the protocol have been demonstrated in a multigram synthesis of Daclatasvir.

A Telescopic, Scalable and Industrially Feasible Method for the Synthesis of Antidepressant Drug, Moclobemide

AbstractAn improved, scalable, industrially feasible telescopic process for multigram synthesis of highly commercialized antidepressant drug, moclobemide has been developed. Unlike the conventional approaches, this process enjoys the privilege of being an economical, operationally simple, effectively scalable, and quantitative method for the synthesis of amide‐containing drug moclobemide, showcasing easy isolation and purification without the aid of column chromatography. An environmentally benign reagent combination of TBN and NHS very effectively converts the acyl source, 4‐chlorobenzaldehyde into its N‐hydroxysuccinimide ester intermediate, which simply affords the drug molecule after nucleophilic substitution with the amine source. The synthetic process has successfully been scaled‐up upto ~145 g scale with 75 % overall yield and >95 % first crop HPLC purity.

Solvent-free multigram synthesis using camphor derivatives as versatile building blocks in drug discovery

Este artigo descreve a síntese de novos blocos de construção em escala multigramas, N-alil-1,7,7-trimetilbiciclo[2.2.1]heptan-2-imina e (E)-1,7,7-trimetil-N-(prop-2-in-1-il)biciclo[2.2.1]heptan-2-imina, utilizando-se de uma metodologia sem solvente e com nitroiminas derivadas da Cânfora como material de partida. Estes novos blocos de construção tiveram sua atividade contra a doença de leishmania testada in vitro em testes preliminares. Estes novos blocos de construção também podem ser intermediários úteis para a preparação de diveras substâncias com atividade biológica de interesse na descoberta de novos fármacos através de transformações químicas, uma vez que a Cânfora possui uma estrutura provilegiada com diversas aplicações em química medicinal.

First Comprehensive Study of Energetic (Methoxy-NNO-azoxy)furazans: Novel Synthetic Route, Characterization, and Property Analysis

This paper provides the first in-depth study of energetic methoxy-NNO-azoxy compounds. 3-Amino-4-(methoxy-NNO-azoxy)furazan (7) is a useful precursor to a number of high-enthalpy substituted (methoxy-NNO-azoxy)furazans enriched with explosophoric functionalities (azofurazan 8, nitrofurazan 9, azoxyfurazan 10 and methylene dinitramine 11). It was shown for the first time that the interaction of nitroso compounds with salts of O-substituted N-nitrohydroxylamines leads to the formation of corresponding azoxy-oxy [N(O)=N–O] compounds, as exemplified by the reaction of 3-amino-4-nitrosofurazan (15) with the ammonium salt of O-methyl-N-nitrohydroxylamine (16) to give 3-amino-4-(methoxy-NNO-azoxy)furazan (7). This novel approach turned out to be the most suitable for the multigram synthesis of aminofurazan 7. The resulting (methoxy-NNO-azoxy)furazans 7–11 have good thermal stability (onset decomposition temperatures 148–238 °C), high experimental enthalpies of formation (1435–2750 kJ∙kg–1) and acceptable densities (1.57–1.75 g∙cm–3). In terms of detonation performance, all synthesized compounds (detonation velocities D = 7.9–8.5 km·s–1, detonation pressures PC–J = 26–32 GPa) lie between 1,3,5-trinitro-1,3,5-triazinane (RDX) (D = 8.9 km·s–1, PC–J = 36 GPa) and N-methyl-N-(2,4,6-trinitrophenyl)nitramide (Tetryl) (D = 7.6 km·s–1, PC–J = 26 GPa). The sensitivity study was performed and the results were compared to those for prevalent energetic materials. We have shown the extent to which introduction of the methoxy-NNO-azoxy group into a molecule can be used to tune the crucial properties of energetic materials (enthalpy of formation and thermal stability).

Elastomers based on polynorbornene with polar polysiloxane brushes for soft transducer applications

Elastomers based on cross‐linked bottlebrush polymers combine an extreme softness at low strains with a strain‐stiffening effect, which makes them attractive as active components in dielectric elastomer actuators (DEA). Their main disadvantage concerns the small relative permittivity, which lies in the range of 3.5, requiring relatively high driving voltage in actuators. We synthesized a bottlebrush polymeric elastomer with polar brushes, which exhibit an enhanced dielectric permittivity of 4.4. Anionic ring‐opening polymerization of a polar cyclosiloxane afforded telechelic polar brushes, while ring‐opening polymerization of a norbornene macromonomer gave a bottlebrush polymer which was cross‐linked to elastomers by a thiol‐ene reaction. Elastomers with a small elastic modulus below 100 kPa, strain at break exceeding 100%, attractive elasticity, and small mechanical loss factors (tanδ) were achieved. Temperature‐dependent impedance measurements revealed a transition temperature of ‐95 °C and an interfacial polarization. The multigram scale synthesis demonstrates the potential for scaling up, which opens the door to broader applications of these materials beyond actuators, such as capacitive sensors, batteries, and electroluminescent devices. Notably, these devices operate at extremely low voltages where the dielectric breakdown does not limit their functionality, but still, the softness and the increased dielectric permittivity are a plus.

2‐ and 3‐Fluorocyclobutane Building Blocks for Organic and Medicinal Chemistry

Multigram synthesis of 3‐fluorinated cyclobutane building blocks has been disclosed. The proposed synthetic schemes were based on the nucleophilic fluorination and eventually led to 3‐fluorocyclocutanecarboxylic acid as a key target compound and intermediate. Further functional group transformations provided monofluorinated cyclobutane‐derived alcohols, amines, bromides, thiols, sulfonyl chlorides, etc. Furthermore, the synthesis of diastereopure cis‐ and trans‐isomeric 2‐ and 3‐fluorocyclobutane­carboxylic acids and amines was also performed. In both cases, diastereomer separation was used to obtain pure stereoisomers. The effect of the fluorine position and relative spatial orientation on the physicochemical properties of the corresponding monoflurinated derivatives was studied by measurements of pKa and logP values.

Synthesis of Quillaic Acid through Sustainable C-H Bond Activations.

To meet the demand for quillaic acid, a multigram synthesis of quillaic acid was accomplished in 14 steps, starting from oleanolic acid, leading to an overall yield of 3.4%. Key features include C-H activation at C-16 and C-23. Through Pd-catalyzed C-H acetoxylation, the oxidation at C-23 was observed as the major product, as opposed to at C-24. A copper-mediated C-H hydroxylation using O2 successfully afforded the single isomer, 16β-ol triterpenoid, followed by configuration inversion to the desired 16α-ol compound. In summary, with steps optimized and conducted on a multigram scale, quillaic acid could be feasibly acquired through C-H activation with inexpensive copper catalysts, promoting a more sustainable approach.

A novel approach toward the multigram synthesis of a novel Bcl2-specific inhibitor, and evaluation of its biological activity

The antiapoptotic protein BCL2 is overexpressed in several cancers. It contributes to prolonged cell survival and chemoresistance, making it an excellent target for targeted cancer therapy. Over the years, several BCL2 inhibitors have been investigated extensively for their anticancer potential; however, most of them were abolished before clinical use due to their pan activity. There is only one FDA-approved BCL2-specific inhibitor, Venetoclax, currently used in clinics. Previously, we reported the characterization and development of a novel BCL2 inhibitor, Disarib, which is selective against BCL2 and predominantly binds to the BH1 domain of BCL2. Importantly, the efficacy of Disarib was equally good or better than Venetoclax in various in vitro and in vivo assays. In the present study, we report the development of a scalable and practical method for the large-scale synthesis of Disarib to support the ongoing pre-clinical studies. The parameters of each step were optimized through prior knowledge, helping in improving the yield and purity to 98.8 %. Further, we compared the efficiency of a large-scale synthesized Disarib in a GLP-certified laboratory with that of an in-house synthesized Disarib. The results showed that the biological activity, including Disarib-induced cytotoxicity and cell cycle progression, were comparable. Besides, the tumor regression efficacy and pharmacokinetics analysis of Disarib have shown comparable results when Disarib synthesized in both routes were tested. Thus, a robust and scalable synthetic pathway of Disarib has developed to address small-scale synthesis's limitations in supporting their expanded applications and use.

2,5-Dihydro-1H-pyrrol-3-yl Boronic Derivatives: Multigram Synthesis and Coupling Reactions

2,5-Dihydro-1<i>H</i>-pyrrol-3-yl Boronic Derivatives: Multigram Synthesis and Coupling Reactions

Multigram Synthesis of Chiral Cyclopropane Carboxylic Acids via Tandem Diastereoselective Wadsworth–Emmons Cyclopropanation-Hydrolysis in Continuous Flow

Multigram Synthesis of Chiral Cyclopropane Carboxylic Acids via Tandem Diastereoselective Wadsworth–Emmons Cyclopropanation-Hydrolysis in Continuous Flow

A Metallomicellar Catalyst for Controlled Oxidation of Alcohols and Lignin Mimics in Water using Open Air as Oxidant.

Alcohol groups and β-O-4 (C-C) linkages are widespread in biomass feedstock that are abundant renewable resource for value-added chemicals. The development of sustainable protocols for direct oxidation or oxidative cleavage of feedstock materials in a controlled fashion, using open air as an oxidant is an intellectually stimulating task to produce industrially important value-added carbonyls. Further, the oxidative depolymerization of lignin into fine chemicals has evoked interest in recent times. Herein, we report the first example of a catalyst system that could activate molecular oxygen from atmospheric air for controlled oxidation and oxidative cleavage/depolymerization of feedstock materials such as alcohols, β-O-4 (C-C) linkages and real lignin in water under open air conditions. The selectivity of carbonyl products is controlled by altering the pH between ~7.0 and ~12.0. The current strategy highlights the non-involvement of any external co-catalyst, oxidant, radical additives, and/or destructive organic solvents. The catalyst shows a wide substrate scope and eminent functional group tolerance. The upscaled multigram synthesis using an inexpensive catalyst and easily available oxidant evidences the practical utility of the developed protocol. A plausible mechanism has been proposed with the help of a few controlled experiments, and kinetic and computational studies.

Bicyclo[m.n.k]alkane Building Blocks as Promising Benzene and Cycloalkane Isosteres: Multigram Synthesis, Physicochemical and Structural Characterization.

Electrophilic double bond functionalization - intramolecular enolate alkylation sequence was used to obtain a series of bridged and fused bicyclo[m.n.k]alkane derivatives (i. e., bicyclo[4.1.1]octanes, bicyclo[2.2.1]heptanes, bicyclo[3.2.1]octanes, bicyclo[3.1.0]hexanes, and bicyclo[4.2.0]heptanes). The scope and limitations of the method were established, and applicability to the multigram synthesis of target bicyclic compounds was illustrated. Using the developed protocols, over 50 mono- and bifunctional building blocks relevant to medicinal chemistry were prepared. The synthesized compounds are promising isosteres of benzene and cycloalkane rings, which is confirmed by their physicochemical and structural characterization (pKa , LogP, and exit vector parameters (EVP)). "Rules of thumb" for the upcoming isosteric replacement studies were proposed.

Sequence-Defined Tertiary Amine-Based Oligomer Employing a Scalable, Support-Free, and Protection/Deprotection-Free Iterative Strategy.

Sequence-defined oligomers (SDOs) with their unique monomeric sequence and customizable nature are attracting the attention of researchers globally. The structural and functional diversity attainable in SDOs makes this platform promising, albeit with challenges in the synthesis. Herein, we report the design and synthesis of a novel class of SDO by incorporating tertiary amines into the backbone from commercially available inexpensive materials. Tertiary amines were selected due to their various material and biomedical applications. Even though the synthesis and purification of amine compounds are challenging, their various significant applications, such as pharmaceuticals, catalysts, surfactants, corrosion inhibitors, dye intermediates, polymer additives, rubber accelerators, gas treating agents, agriculture, and analytical chemistry, make them fascinating. The synthetic strategy that is designed here is extremely efficient and economical for the scalable synthesis of the SDO and is support-free, protection-deprotection chemistry-free, and catalyst/template-free. Most importantly, no extra design and synthesis of the monomer is required here. The key reactions employed for the SDO synthesis are (i) transformation of the hydroxy group to a halide and (ii) substitution of the halide by the secondary amine units. Including the purifying processes, the multigram synthesis of 4-mer was completed in 12-14 h. The synthetic strategy was established by synthesizing two different sequences of SDOs. The SDOs are characterized by 1H NMR and LC-MS. The tandem MS (MS/MS) experiment was conducted in order to validate the sequences over the SDO chain. Furthermore, the SDO platform was advanced in two ways: (i) by increasing the chain length via attaching a linker, which provides a rapid method for increasing the tertiary amine over the SDO chain, and (ii) postsynthetic modification of SDO with other functional groups, including guanidine for biological importance and a well-known fluorophore dansyl group for material significance.

Gas–liquid tubular continuous-flow Pd-catalysed aminocarbonylation process for scalable synthesis of carboxamides

We report an efficient continuous flow process, integrating a custom-designed gas input control system coupled with a tubular reactor, for Pd-catalysed aminocarbonylation, which leads to the multigram synthesis of biologically relevant carboxamides.

Triptycene-like naphthopleiadene as a readily accessible scaffold for supramolecular and materials chemistry.

Triptycene derivatives are used extensively in supramolecular and materials chemistry, however, most are prepared using a multi-step synthesis involving the generation of a benzyne intermediate, which hinders production on a large scale. Inspired by the ease of the synthesis of resorcinarenes, we report the rapid and efficient preparation of triptycene-like 1,6,2',7'-tetrahydroxynaphthopleiadene directly from 2,7-dihydroxynaphthalene and phthalaldehyde. Structural characterisation confirms the novel bridged bicyclic framework, within which the planes of the single benzene ring and two naphthalene units are fixed at an angle of ∼120° relative to each other. Other combinations of aromatic 1,2-dialdehydes and 2,7-disubstituted naphthalenes also provided similar triptycene-like products. The low cost of the precursors and undemanding reaction conditions allow for rapid multigram synthesis of 1,6,2',7'-tetrahydroxynaphthopleiadene, which is shown to be a useful precursor for making the parent naphthopleiadene hydrocarbon. The great potential for the use of the naphthopleiadene scaffold in supramolecular and polymer chemistry is demonstrated by the preparation of a rigid novel cavitand, a microporous network polymer, and a solution-processable polymer of intrinsic microporosity.

Multigram synthesis of β-fluorinated saturated heterocyclic methanamines

An efficient multigram synthesis of β-fluorinated saturated heterocyclic methanamines - promising building blocks for drug discovery, starting from the corresponding saturated heterocyclic ketones is described. The method includes Wittig olefination, bromofluorination, nucleophilic substitution with azide, and Staudinger reaction and works well for four- to seven-membered nitrogen- and oxygen-containing heterocyclic derivatives

W18O49 Nanowhiskers Decorating SiO2 Nanofibers: Lessons from In Situ SEM/TEM Growth to Large Scale Synthesis and Fundamental Structural Understanding.

Tungsten suboxide W18O49 nanowhiskers are a material of great interest due to their potential high-end applications in electronics, near-infrared light shielding, catalysis, and gas sensing. The present study introduces three main approaches for the fundamental understanding of W18O49 nanowhisker growth and structure. First, W18O49 nanowhiskers were grown from γ-WO3/a-SiO2 nanofibers in situ in a scanning electron microscope (SEM) utilizing a specially designed microreactor (μReactor). It was found that irradiation by the electron beam slows the growth kinetics of the W18O49 nanowhisker, markedly. Following this, an in situ TEM study led to some new fundamental understanding of the growth mode of the crystal shear planes in the W18O49 nanowhisker and the formation of a domain (bundle) structure. High-resolution scanning transmission electron microscopy analysis of a cross-sectioned W18O49 nanowhisker revealed the well-documented pentagonal Magnéli columns and hexagonal channel characteristics for this phase. Furthermore, a highly crystalline and oriented domain structure and previously unreported mixed structural arrangement of tungsten oxide polyhedrons were analyzed. The tungsten oxide phases found in the cross section of the W18O49 nanowhisker were analyzed by nanodiffraction and electron energy loss spectroscopy (EELS), which were discussed and compared in light of theoretical calculations based on the density functional theory method. Finally, the knowledge gained from the in situ SEM and TEM experiments was valorized in developing a multigram synthesis of W18O49/a-SiO2 urchin-like nanofibers in a flow reactor.