An interesting review article from Prof Yujiro Hayashi of the University of Tohoku in Japan discusses the characteristics and limitations of one-pot synthetic approaches to complex molecules (Chemical Science, 2016, 7,866). He gives many examples, mostly from his own work on organocatalysis using nitro-olefins.
Process chemists are always trying to squeeze a few extra % yield from a reaction or improve the quality of the product, particularly enantiomeric purity. A new review from a group of Chinese academics gives some hints as to how this can be achieved, by looking at additive effects in asymmetric catalysis.
At the recent 'Scale Up of Chemical Processes Conference' in Baveno, Italy, Charles Papageorgiu of Eisai described the optimization of a borylation process to prepare boronic acid ML-826 (see Scheme 1)
At the recent 'Scale Up of Chemical Processes Conference' in Baveno, Italy, Wim Dermaut from Agfa presented some case studies where problems have occurred as a result of reactive chemicals present in waste streams. In the first case study a drum containing a waste stream including diethylhydroxylamine exploded. The most likely cause was caustic present in the empty drum which initially raised the temperature of the waste to a temperature that interaction with Zn led to the runaway reaction (the waste drum was galvanized).
At the recent 'Scale Up of Chemical Processes Conference' in Baveno, Italy, John Snoonian of Sunovion discussed the development and scale up of a manufacturing route to make a 5HT4 partial agonist containing a 1,2,4-oxadiazole ring. During route scouting studies on the synthesis of the benzopyrazole an interesting solvent effect was observed – see Scheme 2. As the ketone was the desired product this was manufactured via ortho-metalation of 1,2-difluorobenzene followed by reaction with isobutyryl chloride.
Louis Diorazio and co-workers at AstraZeneca recently published an article entitled “Toward a More Holistic Framework for Solvent Selection”, which describes the development of a solvent selection tool. Most solvent guides concentrate on Health and Environmental aspects of solvents, but where this new solvent selection tool differs is that it takes in to account issues that affect the success (conversion, selectivity and so on) of the reaction.
Another paper on the theme of solvents, is from Paul Murray working with the University College London and concerns the use of solvent maps and design of experiments (DoE). IN DoE solvent is usually considered to be a discrete or categorical variable, but by applying principle components analysis one can generate solvent maps so that solvent maps can be generated and this allows solvents to be considered as continuous variables albeit in a quantized form. This idea is not new but this paper makes available a new 3 dimensional solvent map with 136 solvents included.
GSK were one of the first companies to publish a solvent selection guide and they have updated this gradually over the years, with the latest version of their guide being published just recently in Green Chemistry1. The new guide contains 44 more solvents taking the total number of solvents covered to 154.
A recent paper from the University of York Green Chemistry Centre of excellence and Eastman Chemical proposes a new solvent, n-butylpyrrolidinone (NBP), as a replacement for common dipolar aprotics such as DMF, DMAc, and NMP which are under severe pressure from legislation such as REACH, and the updated TSCA regulations in the USA. The big advantage of NBP is that it is non-reproductively toxic, non-mutagenic, and also inherently biodegradable, however it is more acutely toxic (LD50 rat oral 300-2000 mg/kg) than NMP (~4000 mg/kg). Physically it is similar to NMP and other dipolar aprotics as can be seen in Figure 1.