The GlyT1 transporter has emerged as a key novel target for the treatment of schizophrenia. Herein, we report on the optimization of the 2-alkoxy-5-methylsulfonebenzoylpiperazine class of GlyT1 inhibitors to improve hERG channel selectivity and brain penetration. This effort culminated in the discovery of compound 10a (RG1678), the first potent and selective GlyT1 inhibitor to have a beneficial effect in schizophrenic patients in a phase II clinical trial.

Azides are building blocks of increasing importance in synthetic chemistry, chemical biology, and materials science. Azidobenziodoxolone (ABX, Zhdankin reagent) is a valuable azide source, but its safety profile has not been thoroughly established. Herein, we report a safety study of ABX, which shows its hazardous nature. We introduce two derivatives, tBu-ABX and ABZ (azidobenziodazolone), with a better safety profile, and use them in established photoredox- and metal-mediated azidations, and in a new ring-expansion of silylated cyclobutanols to give azidated cyclopentanones.

Despite numerous discussions, workshops, reviews and reports about responsible development of nanotechnology, information describing health and environmental risk of engineered nanoparticles or nanomaterials is severely lacking and thus insufficient for completing rigorous risk assessment on their use. However, since preliminary scientific evaluations indicate that there are reasonable suspicions that activities involving nanomaterials might have damaging effects on human health; the precautionary principle must be applied. Public and private institutions as well as industries have the duty to adopt preventive and protective measures proportionate to the risk intensity and the desired level of protection. In this work, we present a practical, 'user-friendly' procedure for a university-wide safety and health management of nanomaterials, developed as a multi-stakeholder effort (government, accident insurance, researchers and experts for occupational safety and health). The process starts using a schematic decision tree that allows classifying the nano laboratory into three hazard classes similar to a control banding approach (from Nano 3 - highest hazard to Nano1 - lowest hazard). Classifying laboratories into risk classes would require considering actual or potential exposure to the nanomaterial as well as statistical data on health effects of exposure. Due to the fact that these data (as well as exposure limits for each individual material) are not available, risk classes could not be determined. For each hazard level we then provide a list of required risk mitigation measures (technical, organizational and personal). The target 'users' of this safety and health methodology are researchers and safety officers. They can rapidly access the precautionary hazard class of their activities and the corresponding adequate safety and health measures. We succeed in convincing scientist dealing with nano-activities that adequate safety measures and management are promoting innovation and discoveries by ensuring them a safe environment even in the case of very novel products. The proposed measures are not considered as constraints but as a support to their research. This methodology is being implemented at the Ecole Polytechnique de Lausanne in over 100 research labs dealing with nanomaterials. It is our opinion that it would be useful to other research and academia institutions as well.

The scale-up/-down of polymerization reactors has to deal with large viscosity changes during the process, addressing massand heat-transfer issues. A practical example on scale-up of styrene and methyl methacrylate free radical bulk and solution polymerization is presented. The main critical parameters are mixing at molecular level (micromixing) and heat removal capacity. The operating parameters being kept constant are: reaction conditions (temperature, pressure, chemistry) and thus the reaction time. A pilot plant issued from scale-down of possible industrial sizes was developed to represent, at best, larger scales. The main parameter being scaled-up is the heat removal capacity, which has to be maintained constant among the different sizes. New concepts are adapted to dissipate the mixing energy where it is the most suitable, and the final step is the scale-up/-down strategy. Another issue addressed in this contribution is the need for in-line analytics that could operate at different plant scales and thus give important information for process control. Scale-up/-down strategy must include the whole process, not only the reaction stage but also what happens before, after, and simultaneously, i.e., upstream, downstream, and peripheral operations. Finally the measurable success of a scale-up/-down analysis could only be proved at industrial scale, where a good agreement between pilot-and larger scale should be observed. The concepts in terms of transfer phenomena, analytics, separation, product properties, feasibility, and economics should also be included in this analysis.

No abstract

No abstract

No abstract

Summary: Several researches have dealt with the thermal initiation of methyl methacrylate (MMA) in the past. Some of them already discussed the presence of peroxide containing species that are formed from dissolved oxygen and the monomer itself as main reason for this initiation. However, a more detailed investigation as well as a kinetic description of this phenomenon is still due in literature. In this paper, the formation and decomposition of methyl methacrylate peroxides are described. MMA that has been in contact with air forms macromolecular peroxides at temperatures below 100 °C from physically dissolved oxygen. These peroxides have molecular weights of approximately 3 000–5 000 g · mol−1, depending on the temperature during formation. Above this temperature, these peroxides decompose quickly and initiate the radical polymerization. Depending on the reaction conditions, monomer conversions from 15 to 30% are obtained. In combination with additional initiators, the MMA peroxides provoke an acceleration of the reaction rate and can also lead to bimodal molecular weight distributions. An analytical method based on UV‐spectrophotometry was developed for the quantification of the peroxide content in the monomer. The kinetic rate constants for the formation were determined in batch experiments with purified, air‐saturated monomer to be kf,0 = 6.28 · 107 l2 · mol−2 · s and EA = 7.75 · 104 J · mol−1. The decomposition rate constants were determined from batch dead‐end polymerizations and found to be kd,0 = 4.73 · 107 l · mol−1 · s−1 and EA = 8.56 · 104 J · mol−1. magnified image