Development Of Synthetic Processes Research Articles

Identification, Synthesis, and Characterization of Process Related Impurities in the Synthesis of Boc‐L‐Lys(Boc)‐OSu

ABSTRACTProtected lysine esters (Boc‐L‐Lys(Boc)‐OSu) an intermediate of high repute in the peptide synthesis and diverse chemical synthetic applications, was the subject of synthetic process development studies, unveiling process‐related impurities. These impurities were synthesized, characterized, and identified by different analytical tools, with their retention times verified by HPLC co‐injection with commercial products. Detailed discussions ensued on the potential formation pathways and synthetic strategies of these process‐related impurities.

Mo@PANI-catalyzed oxidative deoximation reaction

Deoximation is an important transformation in synthetic industry. It can be employed in protection, characterization and purification of the carbonyls, and in the synthesis of ketones from non-carbonyl molecules. In the field, oxidative deoximation reaction can utilize the driving force caused by the oxidation process so that the reaction can occur under relatively mild conditions. Recently, we designed and prepared polyaniline-supported molybdenum (Mo@PANI) just by immersing PANI into the EtOH/H2O solution of MoCl5. The material was successfully applied as the efficient catalyst for oxidative deoximation reactions, which were performed in ethanol using H2O2 as the clean oxidant. The substrate scope of the reaction was wide. It could be applied on heterocycle-containing substrates, making this protocol preferable for pharmaceutical intermediate synthesis. Since Mo is a necessary trace element for both animals and plants, this method is environment-friendly and is suitable for large-scale preparation. This work as the first example of Mo-catalyzed oxidative deoximation reaction may inspire novel ideas for both catalyst design and synthetic process development.

Solubility Model to Guide Solvent Selection in Synthetic Process Development

Solubility Model to Guide Solvent Selection in Synthetic Process Development

Artificial Enzymes for Diels-Alder Reactions.

The Diels-Alder (DA) reaction is a cycloaddition of a conjugated diene and an alkene (dienophile) leading to the formation of a cyclohexene derivative through a concerted mechanism. As DA reactions generally proceed with a high degree of regio- and stereoselectivity, they are widely used in synthetic organic chemistry. Considering eco-conscious public and governmental movements, efforts are now directed towards the development of synthetic processes that meet environmental concerns. Artificial enzymes, which can be developed to catalyze abiotic reactions, appear to be important synthetic tools in the synthetic biology field. This review describes the different strategies used to develop protein-based artificial enzymes for DA reactions, including for in cellulo approaches.

Microwave-based fast synthesis of clear-cut hollow spheres with mesoporous wall of silica nanoparticles as excellent drug delivery vehicles

Over the past few decades, hollow-structured silica particles have attracted significant interest from material’s scientists due to their unique properties and morphologies related to biomedical applications. This interest has spurred the development of synthetic processes of silica particles and in this paper we report on the microwave-based synthesis of nano-silica hollow spheres (NSHS) with uniform shape and size. This synthetic process produces NSHS in more efficient and swifter manner than previously reported approaches. TEM, SEM, TGA, and BET analysis revealed that the particles produced are hollow, uniform, porous spheres with high water retention capabilities. To explore the drug delivery capability of these spheres, Ibuprofen, as the model drug, was loaded into the NSHS to explore the drug load capacity and the drug release action of these NSHS. The findings of this study signal that the reported microwave-based NSHS has interesting practical relevance as promising drug delivery vehicles.

Recent Advances in Synthesis of Benzothiazole Compounds Related to Green Chemistry.

Benzothiazoles have played an important role in the field of biochemistry and medicinal chemistry due to their highly pharmaceutical and biological activity. The development of synthetic processes is undoubtedly one of the most significant problems facing researchers. In this review paper, we provided recent advances in the synthesis of benzothiazole compounds related to green chemistry from condensation of 2-aminobenzenethiol with aldehydes/ketones/acids/acyl chlorides and the cyclization of thioamide or carbon dioxide (CO2) as raw materials, and the future development trend and prospect of the synthesis of benzothiazoles were anticipated.

Synthesis and characterization of oxitropium bromide related substances and novel stability indicating HPLC methods

The European Pharmacopoeia (Ph. Eur.) described two separate HPLC methods for determination of organic impurities in oxitropium bromide, a synthetic anticholinergic agent used by inhalation in the treatment of asthma and other bronchial disorders, and a potentiometric titration assay method which is not a stability indicating method. During synthetic process development and analytical studies of oxitropium; besides known Ph. Eur.-impurities new process related and degradation impurities were determined, identified by LC–MS, synthesized, characterized, and then used in development and validation studies of oxitropium analytical methods. As a result of these studies, a single HPLC related substances method was developed and validated according to international conference on harmonisation (ICH) guidelines for determination of all oxitropium related substances by using an inertsil ODS-4 (250 mm × 4.6 mm, 5 μm) column at 15 °C with 50 μL injection volume at a wavelength of 210 nm with gradient elution of phosphate-buffer/acetonitrile mixture flowing at a rate of 1.2 mL/min during 60 min. Also, a stability indicating HPLC assay method was developed and validated by using an XBridge C18 (150 mm × 4.6 mm, 3.5 μm) column at 25 °C with 10 μL injection volume at a wavelength of 210 nm and with phosphate-buffer/acetonitrile (85/15) mixture flowing at a rate of 1.0 mL/min during 10 min. Stress-testing and stability studies of oxitropium bromide was carried out and samples were analyzed by using newly developed stability-indicating HPLC assay and related substances methods.

Identification of an Unexpected Impurity in a New Improved Synthesis of Lesinurad

An unexpected phenomenon concerning an otherwise common impurity of lesinurad has been observed in the context of synthetic process development. A new industrial process was designed as a chlorine-...

Designing hybrid materials with multifunctional interfaces for wound dressing, electrocatalysis, and chemical separation

An infinite number of possibilities can emerge from the combination of phases in hybrid systems. Interfacing phases is a strategy to obtain a set of properties in one system that are beyond the abilities of single phases. Herein, the progress in materials science exploring hybrid systems are discussed from the point of view of three important applications: wound dressing; electrocatalysis; and chemical separation. These three unrelated applications exemplify the broad impact of hybrid materials, which can be coherently designed to achieve outstanding performance. Many inspiring works have been published in the last few years, remodeling the edges of human knowledge on hybrid materials. However, the challenges in the coherent design seem to rely on the development of synthetic processes to achieve stronger integration among the phases in a hybrid material.

N,N-二烷基乙醇胺的合成工艺研究进展

N,N-二烷基乙醇胺是一种重要的精细化工中间体，在纺织、医药、农用化学品等方面具有广泛的应用。本文根据起始原料不同将其合成路线分为两大类，即：仲胺的羟乙基化和乙醇胺的N-烷基化，并较系统地归纳总结了各不同合成路线的特点，对N,N-二烷基乙醇胺的合成路线优化与生产工艺改进具有指导意义。 N,N-dialkylethanolamine is an important intermediate in fine chemical industries, especially in textile, pharmaceuticals, and agrochemicals. According to different starting material, the synthetic route can be divided into two categories: Hydroxyethylation of secondary amines and N-alkylation of ethanolamine. The characteristic features of each route are summarized in this paper systematically. And it is important for the optimization and development of synthetic process of N,N- dialkylethanolamine.

Synthesis, Characterization, Identification and Quantification of Sertraline Hydrochloride Related Impurities

Sertraline hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class, is synthesized for commercial use as a drug substance in highly pure form. During the synthetic process development studies of Sertraline hydrochloride, an impurity was detected in the final product at levels ranging from 0.05% to 0.15% in Gas Chromatography (GC) method and its molecular weight was determined by LC-MS analysis. The impurity was identified as 4-(4-chlorophenyl)-3,4-dihydronaphthalen-1(2H)-ol impurity, synthesized and characterized, the process of its formation was discussed in detail. After qualification of impurity standard, it was used as a reference standard for development of quantification by High Performance Liquid Chromatography (HPLC) method.

Identification, synthesis and characterization of process related desfluoro impurity of ezetimibe and HPLC method validations

Ezetimibe, which selectively inhibits cholesterol absorption across the intestinal wall and is used as an antihyperlipidemic agent, is synthesized for commercial use as a drug substance in highly pure form. During the synthetic process development studies of ezetimibe, an impurity was detected in the final product at levels ranging from 0.05% to 0.15% in reverse phase gradient high performance liquid chromatography (HPLC) method and its molecular weight was determined by LC–MS analysis. The impurity was identified as (3R,4S)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-(4-hydroxyphenyl)-1-phenylazetidin-2-one which is called desfluoro ezetimibe (lactam-related) impurity, synthesized and characterized, the mechanism of its formation was discussed in detail. After all standardization procedures, it was used as a reference standard during validation of HPLC method and routine analyses. In addition, content of Eze-1 desfluoro impurity in Eze-1 intermediates was specified as 0.10% to keep the formation of desfluoro ezetimibe impurity under control and the related substances HPLC method was validated accordingly.

Identification, synthesis and characterization of process related impurities of benidipine hydrochloride, stress-testing/stability studies and HPLC/UPLC method validations

Benidipine hydrochloride, used as an antihypertensive agent and long-acting calcium antagonist, is synthesized for commercial use as a drug substance in highly pure form. During the synthetic process development studies of benidipine, process related impurities were detected. These impurities were identified, synthesized and characterized and mechanisms of their formation were discussed in detail. After all standardization procedures, they were used as reference standards for analytical studies. In addition, a separate HPLC method was developed and validated for detection of residual 1-benzylpiperidin-3-ol (Ben-2), which is used during benidipine synthesis and controlled as a potential process related impurity. As complementary of this work, stress-testing studies of benidipine were carried out under specified conditions and a stability-indicating UPLC assay method was developed, validated and used during stability studies of benidipine.

Synthetic Process Development of BMS-599793 Including Azaindole Negishi Coupling on Kilogram Scale

A new approach to the synthesis of 1 (DS003, BMS-599793), a small-molecule HIV entry inhibitor, is described. The initial medical chemistry route has been modified by rearranging the sequence of synthetic steps followed by replacement of the Suzuki coupling step by the Negishi conditions. Acylation of the resulting azaindole 7 under the Friedel–Crafts conditions is studied using monoesters of chlorooxalic acid in the presence of aluminum chloride. Polymorphism of 1 is also investigated to develop conditions suitable for preparation of the desired Form 1 of the target compound. The new route is further optimized and scaled up to establish a new process that is applied to the synthesis of kilogram quantites of the target active pharmaceutical ingredient.

Facile Fabrication of Ultrafine Hollow Silica and Magnetic Hollow Silica Nanoparticles by a Dual-Templating Approach.

The development of synthetic process for hollow silica materials is an issue of considerable topical interest. While a number of chemical routes are available and are extensively used, the diameter of hollow silica often large than 50 nm. Here, we report on a facial route to synthesis ultrafine hollow silica nanoparticles (the diameter of ca. 24 nm) with high surface area by using cetyltrimethylammmonium bromide (CTAB) and sodium bis(2-ethylhexyl) sulfosuccinate (AOT) as co-templates and subsequent annealing treatment. When the hollow magnetite nanoparticles were introduced into the reaction, the ultrafine magnetic hollow silica nanoparticles with the diameter of ca. 32 nm were obtained correspondingly. Transmission electron microscopy studies confirm that the nanoparticles are composed of amorphous silica and that the majority of them are hollow.

Extracellular Biosynthesis of Magnetite using Fungi

The development of synthetic processes for oxide nanomaterials is an issue of considerable topical interest. While a number of chemical methods are available and are extensively used, the collaborations are often energy intensive and employ toxic chemicals. On the other hand, the synthesis of inorganic materials by biological systems is characterized by processes that occur at close to ambient temperatures and pressures, and at neutral pH (examples include magnetotactic bacteria, diatoms, and S-layer bacteria). Here we show that nanoparticulate magnetite may be produced at room temperature extracellularly by challenging the fungi, Fusarium oxysporum and Verticillium sp., with mixtures of ferric and ferrous salts. Extracellular hydrolysis of the anionic iron complexes by cationic proteins secreted by the fungi results in the room-temperature synthesis of crystalline magnetite particles that exhibit a signature of a ferrimagnetic transition with a negligible amount of spontaneous magnetization at low temperature.

Synthetic Process Development and Scale-Up of the Oxidative Cleavage of a Double Bond Catalyzed by Ruthenium Trichloride

Using statistical experimental tools, a relatively complex process for the oxidative cleavage of a double bond catalyzed by a ruthenium catalyst was studied. A good understanding of the influence of the reaction parameters led to the development of a technically feasible process which was successively scaled up to kilogram-laboratory facilities and finally to the launch plant facilities.

Synthetic Processes via Complex Precursors of Rare Earth Manganites with the Perovskite and its Related Structures

A development of synthetic process via rare earth complex precursors was applied to a formation of rare earth manganites which can not be easily formed by conventional (normal) process. Several compounds of rare earth manganites with various structures were successfully synthesized by this method and their crystal structures were identified by powder X-ray diffractometry. Both of the orthorhombic and rhombohedral LaMnO3 phases were prepared. LnMn2 O5 phase was more easily prepared by this method than by another method. The solid solution of (Sr,La)2 MnO4 phase for various compositions were tried to prepare a single phase, especially for a composition region Sr/La ratio < 1. since this phase is normally formed for only region of Sr/La ratio .. 1 by the solid state reaction method.

Synthetic Process Development and Scale Up of Palladium-Catalyzed Alkoxycarbonylation of Chloropyridines

2,3-Dichloropyridines undergo a mono- or a dicarbonylation in the presence of carbon monoxide, an alc., and a palladium catalyst, affording selectively either alkyl 3-chloropyridine-2-carboxylates or dialkyl pyridine-2,3-dicarboxylates in good yields, depending on the reaction conditions. For instance, the process could be scaled up for the monoalkoxycarbonylation of 2,3-dichloro-5-(trifluoromethyl)pyridine, affording in high yield and selectivity the corresponding 3-chloro-5-(trifluoromethyl)pyridine-2-carboxylate. [on SciFinder (R)]

Synthetic Process Development of Antitumor Agent KT6587, an Indolocarbazole Alkaloid K252a Derivative

A facile and large-scale preparation process of an antitumor agent KT6587 (2), derived from an indolocarbazole alkaloid K252a (1), has been developed. The new synthetic process requires four steps: (i) selective N-silylation of the amide group of 1 with tert-butyldimethylsilyl chloride, (ii) methylation of the hydroxy group, (iii) deprotection under aqueous acidic conditions to afford 3, and (iv) reduction of the methoxycarbonyl group to obtain 2. The key strategic improvement is to obtain fine quality of the intermediate 3 in a reasonable yield with reproducibility. This new process improves the overall yield from 33% to 70% without tedious chromatographic separations and hazardous conditions. Multikilogram quantities of KT6587 (2) for early clinical evaluation have been obtained by this method.