Bayesian Optimization-Assisted Screening to Identify Improved Reaction Conditions for Spiro-Dithiolane Synthesis.

Bayesian optimization (BO)-assisted screening was applied to identify improved reaction conditions toward a hundred-gram scale-up synthesis of 2,3,7,8-tetrathiaspiro[4.4]nonane (1), a key synthetic intermediate of 2,2-bis(mercaptomethyl)propane-1,3-dithiol [tetramercaptan pentaerythritol]. Starting from the initial training set (ITS) consisting of six trials sampled by random screening for BO, suitable parameters were predicted (78% conversion yield of spiro-dithiolane 1) within seven experiments. Moreover, BO-assisted screening with the ITS selected by Latin hypercube sampling (LHS) further improved the yield of 1 to 89% within the eight trials. The established conditions were confirmed to be satisfactory for a hundred grams scale-up synthesis of 1.

Aiming for More Sustainable Cross-Coupling Chemistry by Employing Single-Atom Catalysis on Scale.

Scaling up syntheses from mg to kg quantities is a complex endeavor. Besides adapting laboratory protocols to industrial processes and equipment and thorough safety assessments, much attention is paid to the reduction of the process' environmental impact. For processes including transition metal catalyzed steps, e.g. cross-coupling chemistry, this impact strongly depends on the identity of the metal used. As such, a key approach is the replacement of single-use with reusable heterogeneous catalysts. Transition metal single-atom heterogeneous catalysts (SAC), a novel class of catalytic materials, might exhibit all the necessary properties to step up to this task. This article shall discuss current applications of SAC in cross-coupling chemistry from the point of a process chemist and shed light on the NCCR Catalysis contribution to the field. Investigations of the stability-activity-selectivity relationship of SACs in combination with early-stage life-cycle assessments (LCA) of potential processes lay the foundation for large-scale application tailored catalyst synthesis. Ultimately, prevailing challenges are highlighted, which need to be addressed in future research.

Emerging Landscape of Computational Modeling in Pharmaceutical Development.

Computational chemistry applications have become an integral part of the drug discovery workflow over the past 35 years. However, computational modeling in support of drug development has remained a relatively uncharted territory for a significant part of both academic and industrial communities. This review considers the computational modeling workflows for three key components of drug preclinical and clinical development, namely, process chemistry, analytical research and development, as well as drug product and formulation development. An overview of the computational support for each step of the respective workflows is presented. Additionally, in context of solid form design, special consideration is given to modern physics-based virtual screening methods. This covers rational approaches to polymorph, coformer, counterion, and solvent virtual screening in support of solid form selection and design.

Development of Scaled-Up Synthetic Method for Retinoid X Receptor Agonist NEt-3IB Contributing to Sustainable Development Goals.

Small-molecular drugs, which are generally inexpensive compared with biopharmaceuticals and can often be taken orally, may contribute to the Sustainable Development Goals (SDGs) adopted by the United Nations. We previously reported the retinoid X receptor (RXR) agonist 4-(ethyl(3-isobutoxy-4-isopropylphenyl)amino)benzoic acid (NEt-3IB, 1) as a small-molecular drug candidate to replace biopharmaceuticals for the treatment of inflammatory bowel disease. The previous synthetic method to 1 required a large amount of organic solvent and extensive purification. In line with the SDGs, we aimed to develop an environmentally friendly, inexpensive method for the large-scale synthesis of 1. The developed method requires only a hydrophobic ether and EtOH as reaction and extraction solvents. The product was purified by recrystallization twice to afford 99% pure 1 at 100 mmol scale in about 30% yield. The optimized process showed a 35-fold improvement of the E-factor (an index of environmental impact) compared to the original method. This work, which changes the solvent used to environmentally preferable ones based on the existing synthetic method for 1, illustrates how synthetic methods for small-molecular drugs can be adapted and improved to contribute to the SDGs.

Estimating thermodynamic equilibrium solubility and solute-solvent interactions of niclosamide in eight mono-solvents at different temperatures.

Niclosamide is an FDA-approved oral anthelmintic drug currently being repurposed for COVID-19 infection. Its interesting applicability in multiple therapeutic indications has sparked interest in this drug/ scaffold. Despite its therapeutic use for several years, its detailed solubility information from Chemistry Manufacturing & Controls perspective is unavailable. Thus, the present study is intended to determine the mole fraction solubility of niclosamide in commonly used solvents and cosolvents at a temperature range of 298.15-323.15 K. The polymorphic changes from crystalline to monohydrate forms post-equilibration in various solvents were observed. The maximum mole fraction solubility of niclosamide at 323.15 K is 1.103 × 10-3 in PEG400, followed by PEG200 (5.272 × 10-4), 1-butanol (3.047 × 10-4), 2-propanol (2.42 × 10-4), ethanol (1.66 × 10-4), DMSO (1.52 × 10-4), methanol (7.78 × 10-5) and water (3.27 × 10-7). The molecular electrostatic potential showed a linear correlation with the solubility. PEG400 has higher electrostatic potential, and H-bond acceptor count, which forms a hydrogen bond with phenolic -OH of niclosamide and thus enhances its solubility. This data is valuable for the drug discovery and development teams working on the medicinal chemistry and process chemistry of this scaffold.

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries.

Due to their intrinsic physical properties, which includes being able to perform as volatile liquids at room and biological temperatures, fragrance ingredients/intermediates make ideal candidates for continuous-flow manufacturing. This review highlights the potential crossover between a multibillion dollar industry and the flourishing sub-field of flow chemistry evolving within the discipline of organic synthesis. This is illustrated through selected examples of industrially important transformations specific to the fragrances and flavours industry and by highlighting the advantages of conducting these transformations by using a flow approach. This review is designed to be a compendium of techniques and apparatus already published in the chemical and engineering literature which would constitute a known solution or inspiration for commonly encountered procedures in the manufacture of fragrance and flavour chemicals.

Chiral syntheses of methyl (R)-2-Sulfanylcarboxylic esters and acids with optical purity determination using HPLC.

Accessible chiral syntheses of 3 types of (R)-2-sulfanylcarboxylic esters and acids were performed: (R)-2-sulfanylpropanoic (thiolactic) ester (53%, 98%ee) and acid (39%, 96%ee), (R)-2-sulfanylsucciinic diester (59%, 96%ee), and (R)-2-mandelic ester (78%, 90%ee) and acid (59%, 96%ee). The present practical and robust method involves (i) clean SN 2 displacement of methanesulfonates of (S)-2-hydroxyesters by using commercially available AcSK with tris(2-[2-methoxyethoxy])ethylamine and (ii) sufficiently mild deacetylation. The optical purity was determined by the corresponding (2R,5R)-trans-thiazolidin-4-one and (2S,5R)-cis-thiazolidin-4-one derivatives based on accurate high-performance liquid chromatography analysis with high-resolution efficiency. Compared with the reported method utilizing AcSCs (generated from AcSH and CsCO3 ), the present method has several advantages, that is, the use of odorless AcCOSK reagent, reasonable reaction velocity, isolation procedure, and accurate, reliable optical purity determination. The use of accessible AcSK has advantages because of easy-to-handle odorless and hygroscopic solid that can be used in a bench-top procedure. The Ti(OiPr)4 catalyst promoted smooth trans-cyclo-condensation to afford (2R,5R)-trans-thiazolidin-4-one formation of (R)-2-sulfanylcarboxylic esters with available N-(benzylidene)methylamine under neutral conditions without any racemization, whereas (2S,5R)-cis-thiazollidin-4-ones were obtained via cis-cyclo-condensation and no catalysts. Direct high-performance liquid chromatography analysis of methyl (R)-mandelate was also performed; however, the resolution efficiency was inferior to that of the thaizolidin-4-one derivatizations.

Patented Farnesoid X receptor modulators: a review (2019 - present).

INTRODUCTION: The Farnesoid X receptor (FXR) is a key transcription factor that is involved in the bile acid signaling network. The modulation of the FXR activity influences glucose and lipid homeostasis, reduces obesity and insulin resistance, as well as it regulates the pathogenesis of inflammatory and metabolic disorders. FXR ligands have therefore emerged in drug discovery as promising therapeutic agents for the prevention and treatment of gastrointestinal and liver diseases, including cancer. AREAS COVERED: Recent advances in the field of FXR modulators are reviewed, with a particular attention on patent applications filed in the past 5 years related to both the discovery and development of FXR targeting drugs. EXPERT OPINION: FXR agonists have proven their efficacy and safety in humans and have shown a significant potential as clinical agents to treat metabolic and inflammatory associated conditions. However, several challenges, including adverse events such as pruritus, remain to be solved. Current studies aim to gain insights into the pathophysiological mechanisms by which FXR regulates metabolism and inflammation in terms of tissue/organ/isoform-specificity, post-translational modifications and coregulatory proteins, on the route of novel, improved FXR modulators.

Cefonicid Benzathine Salt: A Convenient, Lean, and High-Performance Protocol to Make an Old Cephalosporin Shine.

Cefonicid is a second-generation cephalosporin sold under the brand name Sintocef™. It is an injectable drug obtained via a freeze-drying process and is also available for oral preparations. The high-quality standard required is very challenging to satisfy, and current production protocols are characterized by steps that are lengthy and cumbersome, making the product unattractive for the international market. Industrial R&D is constantly working on the process optimization for API synthesis, with the aim of increasing productivity and decreasing production costs and waste. We herein report a new and efficient method for the synthesis of the cefonicid benzathine salt that provides a good yield and high product stability. The double-nucleophilic and lipophilic nature of N',N″-dibenzylethylene diacetate enables the deformylation of the OH-protected group on the mandelic moiety and also enables product crystallization to occur. We demonstrate that the formyl group in the peculiar position has high reactivity, promoting an amidation reaction that deprotects a hydroxy group and generates a new C-N bond in the reaction by-product. Several amines and OH-protected groups have been studied, but none were able to replicate the excellent results of benzathine diacetate.

Development of 3α,7α-dihydroxy-6α-ethyl-24-nor-5ß-cholan-23-sulfate sodium salt (INT-767): Process optimization, synthesis and characterization of metabolites.

Herein we report our synthetic efforts in supporting the development of the bile alcohol sulfate INT-767, a FXR/TGR5 dual agonist with remarkable therapeutic potential for liver disorders. We describe the process development to a final route for large scale preparation and analogues synthesis. Key sequences include Grignard addition, a one-pot two-step shortening-reduction of the carboxylic side chain, and the final sulfation reaction. The necessity for additional steps such as the protection/deprotection of hydroxyl groups at the steroidal body was also evaluated for step-economy and formation of side-products. Critical bottlenecks such as the side chain degradation have been tackled using flow technology before scaling-up individual steps. The final synthetic route may be successfully employed to produce the amount of INT-767 required to support late-stage clinical development of the compound. Furthermore, potential metabolites have been synthesized, characterized and evaluated for their ability to modulate FXR and TGR5 receptors providing key reference standards for future drug investigations, as well as offering further insights into the structure-activity relationships of this class of compounds.

Generic gas chromatography flame ionization detection method using hydrogen as the carrier gas for the analysis of solvents in pharmaceuticals.

Within the pharmaceutical industry, the determination of residual solvents by Gas Chromatography Flame Ionization Detection (GC-FID) is a highly utilized analytical test that often employs helium (He) as the carrier gas. However, many do not realize that helium is a non-renewable resource that will eventually become progressively more difficult to source. In recent years, analytical chemists are increasingly adopting hydrogen (H2) in place of helium for routine GC analysis. In this study, a simple and efficient generic/universal GC-FID method using H2 as the carrier gas has been developed with the capability of baseline resolution of over 30 of the most commonly used solvents in development and manufacturing with a method run time of less than eight minutes. The use of this method for the separation and analysis of solvents within a pharmaceutical manufacturing process is demonstrated with additional method validation data presented using five different diluents as a means to increase flexibility for the chromatographer. Furthermore, it is the recommendation of the authors that the current compendia for residual solvent analysis be updated to allow for hydrogen as a carrier gas. The similarity between He and H2 observed within this study supports the use of hydrogen as a suitable replacement for helium, and an update of the EU and USP compendia for residual solvent analysis should be made to reflect this.

Process Development and Scale-up Total Synthesis of Largazole, a Potent Class I Histone Deacetylase Inhibitor.

Herein we describe the research and development of the process for the scale-up total synthesis of largazole, a potent class I selective histone deacetylase (HDAC) inhibitor, a potential anticancer agent and also useful for the treatment of other disorders where transcriptional reprogramming might be beneficial. The synthetic route and conditions for each fragment and final product were modified and optimized to make them suitable for larger scale synthesis. With the process we developed, hundreds of grams of each fragment and decagrams of final productlargazole were synthesized in good to excellent yields. The final target largazole was obtained in 21% overall yield over eight steps based on the longest sequence with over 95% HPLC purity.

A Review of Water-Resistant Hemicellulose-Based Materials: Processing and Applications.

Hemicelluloses, due to their hydrophilic nature, may tend to be overlooked as a component in water-resistant product applications. However, their domains of use can be greatly expanded by chemical derivatization. Research in which hydrophobic derivatives of hemicelluloses or combinations of hemicelluloses with hydrophobic materials are used with to prepare films and composites is considered herein. Isolation methods that have been used to separate hemicellulose from biomass are also reviewed. Finally, the most useful pathways to change the hydrophilic character of hemicelluloses to hydrophobic are reviewed. In this way, the water resistance can be increased and applications of targeted water-resistant hemicellulose developed. Several applications of these materials are discussed.

Emulsification in novel ultrasonic cavitation intensifying bag reactors.

Cavitation Intensifying Bags (CIBs), a novel reactor type for use with ultrasound, have been recently proposed as a scaled-up microreactor with increased energy efficiencies. We now report on the use of the CIBs for the preparation of emulsions out of hexadecane and an SDS aqueous solution. The CIBs have been designed in such a way that cavitation effects created by the ultrasound are increased. It was found that the CIBs were 60 times more effective in breaking up droplets than conventional bags, therewith showing a proof of principle for the CIBs for the preparation of emulsions. Droplets of 0.2µm could easily be obtained. To our knowledge, no other technology results in the same droplet size more easily in terms of energy usage. Without depending on the wettability changes of the membrane, the CIBs score similarly as membrane emulsification, which is the most energy friendly emulsification method known in literature. Out of the frequencies used, 37kHz was found to require the lowest treatment time. The treatment time decreased at higher temperatures. While the energy usage in the current non-optimised experiments was on the order of 107-109J/m3, which is comparable to that of a high-pressure homogenizer, we expect that the use of CIBs for the preparation of fine emulsions can still be improved considerably. The process presented can be applied for other uses such as water treatment, synthesis of nanomaterials and food processing.

Hydrogen Peroxide: A Key Chemical for Today's Sustainable Development.

The global utilization of hydrogen peroxide, a green oxidant that decomposes in water and oxygen, has gone from 0.5 million tonnes per year three decades ago to 4.5 million tonnes per year in 2014, and is still climbing. With the aim of expanding the utilization of this eminent green chemical across different industrial and civil sectors, the production and use of hydrogen peroxide as a green industrial oxidant is reviewed herein to provide an overview of the explosive growth of its industrial use over the last three decades and of the state of the art in its industrial manufacture, with important details of what determines the viability of the direct production from oxygen and hydrogen compared with the traditional auto-oxidation process.

Process Chemistry in Antiviral Research.

This article reviews antiviral therapies that have been approved for human use during the last decade, with a focus on the process chemistry that enabled access to these important drugs. In particular, process chemistry highlights from the practical syntheses of the HCV drugs sofosbuvir (Gilead), grazoprevir (Merck), and elbasvir (Merck), the HIV therapy darunavir (Tibotec) and the influenza treatment peramivir (BioCryst) are presented.

Solvents and sustainable chemistry.

Solvents are widely recognized to be of great environmental concern. The reduction of their use is one of the most important aims of green chemistry. In addition to this, the appropriate selection of solvent for a process can greatly improve the sustainability of a chemical production process. There has also been extensive research into the application of so-called green solvents, such as ionic liquids and supercritical fluids. However, most examples of solvent technologies that give improved sustainability come from the application of well-established solvents. It is also apparent that the successful implementation of environmentally sustainable processes must be accompanied by improvements in commercial performance.