Up-scaling a Sol-Gel Process for the Production of a Multi-Component Xerogel Powder.

A sol-gel process for the synthesis of a multi-component oxide material from the system SiO2-ZrO2-Al2O3underwent optimization and up-scaling. Initially, on a laboratory scale, components including precursors, catalysts, and additives were methodically evaluated to ensure a safe and efficient transition to larger volumes. Subsequently, the equipment for the whole setup of the sol-gel process was strategically selected. Leveraging insights from these optimizations, the process was successfully scaled-up to pilot-scale operation, conducting hydrolysis, condensation reactions, gelation, aging, and drying within a single, integrated conical dryer system for an 80 L batch. A visual test and FTIR spectroscopy were applied for process control and monitoring.

Education in Flow Chemistry.

Flow chemistry is a growing and promising technology that can be used in research, development, and production. Nowadays, properly trained staff in flow chemistry is lacking in industry. To efficiently work with this technology, a mix of engineering and chemical skills is required. Although, this dual education is well addressed in the chemistry major given at the Haute Ecole d'Ingénierie et d'Architecture de Fribourg, a school of the University of Applied Sciences and Arts, Western Switzerland, the teaching in flow chemistry should be enhanced and reinforced.

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.

Melt Polycondensation for the Synthesis of Polyester Amides using Kneader Reactor Technology.

In this work, we discuss the process development and scale-up of the melt polycondensation of polyester amides from a laboratory scale to kg-scale in a kneader reactor. We identified and optimized the most important critical parameters and produced kg-quantities of polyester amides with Mn up to 25'000 g/mol and reproducible thermal and mechanical properties. The special kneader reactor allows safe and efficient scale-up of polymerisation reactions at high temperature and viscous melts due to good mixing and efficient mass transfer.

The Vitamin C Analogue 2-O-ß-D-Glucopyranosyl-L-ascorbic Acid in Rhizomes, Stems and Leaves of Lycium barbarum.

Awareness of health benefits of goji berries coming from their bioactive compounds, mostly antioxidants like ascorbic acid, has grown. Recently, an ascorbic acid analogue from goji berries, the 2-O-ß-D-glucopyranosyl-L-ascorbic acid has been reported. In rats, the analogue is absorbed intact and in the form of free vitamin C and consequently has been proposed as a provitamin C. Synthesis of the analogue is demanding and laborious and therefore reliable natural sources are searched. Knowledge concerning the analogue's occurrence in other parts of goji plant is lacking. The aim of this study was to evaluate the contents of 2-O-ß-D-glucopyranosyl-L-ascorbic acid in rhizomes, stems and leaves from Lycium barbarum. Rhizomes, stems and leaveswere extracted and the content of 2-O-ß-D-glucopyranosyl-L-ascorbic acid and non glucosylated, free ascorbic acid was determined by HPLC-DAD. 2-O-ß-D-glucopyranosyl-L-ascorbic acid was found in all goji plant tissues investigated. Based on dry weight, 3.34 mg/100 g were found in the leaves, 4.05 mg/100 g in the stems and up to 12.6 mg/100 g in the rhizomes. Nevertheless, the analogue content in goji berries is much higher (40 to 280 mg/100 g dry weight). The present study confirmed the presence of 2-O-ß-D-glucopyranosyl-L-ascorbic acid in rhizomes, stems and leaves of Lycium barbarum. However, their content compared to goji berries is considerably lower.

One-Pot Synthesis of Trifluoromethylated Quinazolin-4(3 H)-ones with Trifluoroacetic Acid as CF3 Source.

A novel and convenient one-pot sequential cascade method for the preparation of 2-trifluoromethylquinazolin-4(3 H)-ones is described. Trifluoroacetic acid (TFA) was employed as inexpensive and readily available CF3 source, which in the presence of T3P was condensed with a variety of anthranilic acids and amines to provide the products in up to 75% yield. The protocol was proved to be robust on 80 g scale, and the synthetic versatility of the prepared quinazolinon-4-ones was demonstrated by derivatization to further useful building blocks.

4-epi-Isofagomine derivatives as pharmacological chaperones for the treatment of lysosomal diseases linked to ß-galactosidase mutations: Improved synthesis and biological investigations.

(5aR)-5a-C-pentyl-4-epi-isofagomine 1 is a powerful inhibitor of lysosomal ß-galactosidase and a remarkable chaperone for mutations associated with GM1-gangliosidosis and Morquio disease type B. We report herein an improved synthesis of this compound and analogs (5a-C-methyl, pentyl, nonyl and phenylethyl derivatives), and a crystal structure of a synthetic intermediate that confirms its configuration resulting from the addition of a Grignard reagent. These compounds were evaluated as glycosidase inhibitors and their potential as chaperones for mutant lysosomal galactosidases determined. Based on these results and on docking studies, the 5-C-pentyl derivative 1 was selected as the optimal structure for further investigations: this compound induces the maturation of mutated ß-galactosidase in fibroblasts of a GM1-gangliosidosis patient and promote the decrease of keratan sulfate and oligosaccharide load in patient cells. Compound 1 is clearly capable of restoring ß-galactosidase activity and of promoting maturation of the protein, which should result in significant clinical benefit. These properties strongly support the development of compound 1 for the treatment of GM1-gangliosidosis and Morquio disease type B patients harboring ß-galactosidase mutations sensitive to pharmacological chaperoning.

Biofilm Formation Potential of Heat-Resistant Escherichia coli Dairy Isolates and the Complete Genome of Multidrug-Resistant, Heat-Resistant Strain FAM21845.

We tested the biofilm formation potential of 30 heat-resistant and 6 heat-sensitive Escherichia coli dairy isolates. Production of curli and cellulose, static biofilm formation on polystyrene (PS) and stainless steel surfaces, biofilm formation under dynamic conditions (Bioflux), and initial adhesion rates (IAR) were evaluated. Biofilm formation varied greatly between strains, media, and assays. Our results highlight the importance of the experimental setup in determining biofilm formation under conditions of interest, as correlation between different assays was often not a given. The heat-resistant, multidrug-resistant (MDR) strain FAM21845 showed the strongest biofilm formation on PS and the highest IAR and was the only strain that formed significant biofilms on stainless steel under conditions relevant to the dairy industry, and it was therefore fully sequenced. Its chromosome is 4.9 Mb long, and it harbors a total of five plasmids (147.2, 54.2, 5.8, 2.5, and 1.9 kb). The strain carries a broad range of genes relevant to antimicrobial resistance and biofilm formation, including some on its two large conjugative plasmids, as demonstrated in plate mating assays.IMPORTANCE In biofilms, cells are embedded in an extracellular matrix that protects them from stresses, such as UV radiation, osmotic shock, desiccation, antibiotics, and predation. Biofilm formation is a major bacterial persistence factor of great concern in the clinic and the food industry. Many tested strains formed strong biofilms, and especially strains such as the heat-resistant, MDR strain FAM21845 may pose a serious issue for food production. Strong biofilm formation combined with diverse resistances (some encoded on conjugative plasmids) may allow for increased persistence, coselection, and possible transfer of these resistance factors. Horizontal gene transfer may conceivably occur in the food production setting or the gastrointestinal tract after consumption.

Continuous Processes and Flow Chemistry at the Universities of Applied Sciences in Switzerland.

This article provides an overview of activities in the fields of continuous processes, flow chemistry and microreactors at the Universities of Applied Sciences in Switzerland.

Short communication: Heat-resistant Escherichia coli as potential persistent reservoir of extended-spectrum ß-lactamases and Shiga toxin-encoding phages in dairy.

Here we report the isolation of heat-resistant Escherichia coli from raw milk cheeses. Detection of the heat-resistance markers clpK and orfI by PCR was followed by phenotypical confirmation of increased heat-resistance. These strains were Shiga toxin-negative and, although several were found to be multidrug resistant, no plasmids encoding extended-spectrum ß-lactamases (ESBL) were found in any of the isolates. The aim of this study was to assess the potential of these strains to acquire ESBL plasmids and a modified Shiga toxin-encoding phage. Only 4 ESBL-encoding, heat-sensitive E. coli strains were isolated from 1,251 dairy samples (2/455 raw milk and 2/796 raw milk cheese samples). One incompatibility group FII plasmid (CTX-M-14, 79.0 kb) and 3 incompatibility group I1 plasmids (CTX-M-15, 95.2, 96.1, and 97.8 kb) were fully sequenced and de novo assembled. All 4 plasmids are readily transferred to heat-resistant E. coli isolates in plate matings (9.7×10-5 to 3.7×10-1 exconjugants per recipient) and, to a lesser extent, in milk (up to 7.4×10-5 exconjugants per recipient). Importantly, the plasmids are stably maintained during passaging in liquid media without antimicrobial pressure. The heat-resistant isolate FAM21805 was also shown to be capable of acting as donor of all 4 ESBL plasmids. In addition, 3 of 11 tested ESBL exconjugants of heat-resistant strains were lysogenized by the modified Shiga toxin-encoding phage 933W ∆stx::gfp::cat. The higher fraction of heat-resistant E. coli (93 of 256 isolates) compared with the estimated 2% previously predicted based on genomic prevalence of heat resistance genes seems to indicate a selection advantage in the raw milk cheese production environment. The combination of 2 factors may lead to said advantage: increased survival during thermization of raw milk (heating to subpasteurization temperatures) and increased survival rates during cheese ripening. Should these strains acquire ESBL-encoding plasmids, Shiga toxin-encoding phages, or both, these genetic elements would profit from the selection advantage of their host and become more abundant in this particular environment, which in turn could lead to an increased threat to consumers of raw milk products.

International Relations at Universities of Applied Sciences.

An overview of international relations at the Universities of Applied Sciences in Switzerland is presented.

International Relations at Universities of Applied Sciences.

An overview of international relations at the Universities of Applied Sciences in Switzerland is presented.

Daring the Challenge and Thinking Big: The Value of Early Process R&D.

The production of the L/T channel blocker ACT-280778 required the enantiomerically pure 5-phenylbicyclo[2.2.2]oct-5-en-2-one (1) as key building block. As the published routes towards 1 are very low yielding (<0.5% yield) and comprise many steps that are not acceptable for scale-up, a series of processes to 1 was developed to match the increasing requirements from first kg-batches to clinical supplies. The three routes are characterized by an individual asset. (1) The first route contains a scale-up of a Diels-Alder reaction with highly reactive reagents and afforded 90 kg enantiomerically pure 1. To mitigate safety risks, a flow reactor was developed for the high-temperature Diels-Alder reaction. This route relied on an efficient enantiomer separation on a »-ton scale by HPLC. (2) A Crystallization Induced Diastereomer Transformation (CIDT) during an intramolecular aldol reaction was the pivotal step of a first enantioselective route that starts with the Shibasaki reaction. (3) The 2(nd) enantioselective route represents a rare example of organocatalysis on scale and allowed to skip six out of nine steps with a significant impact on the cost of goods. This simple way to 1 opened up a short synthesis of Hayashi's chiral diene ligands (bod*) that were so far lacking an affordable access. Some of these novel C1-symmetrical dienes have shown very high enantioselectivities in Rh-catalyzed additions of arylboronates.

New t-butyl based aspartate protecting groups preventing aspartimide formation in Fmoc SPPS.

Obtaining homogenous aspartyl-containing peptides via Fmoc/tBu chemistry is often an insurmountable obstacle. A generic solution for this issue utilising an optimised side-chain protection strategy that minimises aspartimide formation would therefore be most desirable. To this end, we developed the following new derivatives: Fmoc-Asp(OEpe)-OH (Epe = 3-ethyl-3-pentyl), Fmoc-Asp(OPhp)-OH (Php = 4-n-propyl-4-heptyl) and Fmoc-Asp(OBno)-OH (Bno = 5-n-butyl-5-nonyl). We have compared their effectiveness against that of Fmoc-Asp(OtBu)-OH and Fmoc-Asp(OMpe)-OH in the well-established scorpion toxin II model peptide variants H-Val-Lys-Asp-Asn/Arg-Tyr-Ile-OH by treatments of the peptidyl resins with the Fmoc removal reagents containing piperidine and DBU at both room and elevated temperatures. The new derivatives proved to be extremely effective in minimising aspartimide by-products in each application.

PAT at the Universities of Applied Sciences.

An overview of activities in the field of Process Analytical Technologies (PAT) at the Universities of Applied Sciences in Switzerland is presented.

PAT at the Universities of Applied Sciences.

An overview of activities in the field of Process Analytical Technologies (PAT) at the Universities of Applied Sciences in Switzerland is presented.

Long tail fibres of the novel broad-host-range T-even bacteriophage S16 specifically recognize Salmonella OmpC.

We report isolation and characterization of the novel T4-like Salmonella bacteriophage vB_SenM-S16. S16 features a T-even morphology and a highly modified 160 kbp dsDNA genome with 36.9 mol % G+C, containing 269 putative coding sequences and three tRNA genes. S16 is a virulent phage, and exhibits a maximally broad host range within the genus Salmonella, but does not infect other bacteria. Synthesis of functional S16 full-length long tail fibre (LTF) in Escherichia coli was possible by coexpression of gp37 and gp38. Surface plasmon resonance analysis revealed nanomolar equilibrium affinity of the LTF to its receptor on Salmonella cells. We show that OmpC serves as primary binding ligand, and that S16 adsorption can be transferred to E. coli by substitution of ompC with the Salmonella homologue. S16 also infects 'rough' Salmonella strains which are defective in lipopolysaccharide synthesis and/or its carbohydrate substitution, indicating that this interaction does not require an intact LPS structure. Altogether, its virulent nature, broad host range and apparent lack of host DNA transduction render S16 highly suitable for biocontrol of Salmonella in foods and animal production. The S16 LTF represents a highly specific affinity reagent useful for cell decoration and labelling, as well as bacterial immobilization and separation.

Development of Lab-Scale Continuous Stirred-Tank Reactor as Flow Process Tool for Oxidation Reactions Using Molecular Oxygen.

The use of sustainable oxidants is of great interest to the chemical industry, considering the importance of oxidation reactions for the manufacturing of chemicals and society's growing awareness of its environmental impact. Molecular oxygen (O2), with an almost optimal atom efficiency in oxidation reactions, presents one of the most attractive alternatives to common reagents that are not only toxic in most cases but produce stoichiometric amounts of waste that must be treated. However, fire and explosion safety concerns, especially when used in combination with organic solvents, restrict its easy use. Here, we use state-of-the-art 3D printing and experimental feedback to develop a miniature continuous stirred-tank reactor (mini-CSTR) that enables efficient use of O2 as an oxidant in organic chemistry. Outstanding heat dissipation properties, achieved through integrated jacket cooling and a high surface-to-volume ratio, allow for a safe operation of the exothermic oxidation of 2-ethylhexanal, surpassing previously reported product selectivity. Moving well beyond the proof-of-concept stage, we characterize and illustrate the reactor's potential in the gas-liquid-solid triphasic synthesis of an endoperoxide precursor of antileishmanial agents. The custom-designed magnetic overhead stirring unit provides improved stirring efficiency, facilitating the handling of suspensions and, in combination with the borosilicate gas dispersion plate, leading to an optimized gas-liquid interface. These results underscore the immense potential that lies within the use of mini-CSTR in sustainable chemistry.

Sustainable One-Pot Production and Scale-Up of the New Platform Chemical Diformylxylose (DFX) from Agricultural Biomass.

The large-scale production of platform chemicals from biomass requires efficient, cost-effective, and sustainable methods. Here, we present three one-pot synthesis routes for producing diformylxylose (DFX), a sugar-based solvent and platform chemical, using d-xylose or corncobs as feedstocks. With yields of approximately 80%, these routes were seamlessly scaled from lab to kilogram-scale in a 15 L batch reactor. Techno-economic assessment demonstrates the competitiveness of the proposed methods against fossil- and biobased analogues. Life-cycle analysis shows the potential of these processes to reduce environmental and societal impacts from cradle to gate. At the "end of life", DFX is demonstrated to be inherently biodegradable. Overall, we present a compelling case study of scaling a novel platform chemical guided by techno-economic and environmental concerns leading to balanced cost-competitiveness and life-cycle sustainability.