In recent years,
the development of continuous-flow reactors has
attracted growing attention from the synthetic community. Moreover,
findings in the precise control of the reaction parameters and improved
mass/heat transfer have made the flow setup an attractive alternative
to batch reactors, both in academia and industry, enabling safe and
easy scaling-up of synthetic processes. Even though a majority of
the pharmaceutical industry currently rely on batch reactors or semibatch
reactors, many are integrating flow technology because of easier maintenance
and lower risks. Herein, we demonstrate an operationally simple flow
setup for homogeneous ring-closing metathesis, which is applicable
to the synthesis of active pharmaceutical ingredients precursors or
analogues with high efficiency, low residence time, and in a green
solvent. Furthermore, through the addition of a soluble metal scavenger
in the subsequent step within the flow system, the level of ruthenium
contamination in the final product can be greatly reduced (to less
than 5 ppm). To ensure that this method is applicable for industrial
usage, an upscale process including a 24 h continuous-flow reaction
for more than 60 g of a Sildenafil analogue was achieved in a continuous-flow
fashion by adjusting the tubing size and flow rate accordingly.
Easy and efficient method for preparation of all-chloro ruthenium catalysts bearing a quaternary ammonium tag was developed. The key anion metathesis reaction was made with AgCl, and the facile recycling of silver wastes was demonstrated. The developed method transforms more accessible, yet poorly characterised mixed chloro/iodo Ru complexes into valuable all-chloro catalysts, useful in aqueous metathesis. Practical utility of the developed anion metathesis reaction was demonstrated by preparation of a commercial Ru catalyst, StickyCat™, on a 5 gram scale.
Promoted by homogeneous Ru-benzylidene complexes, the olefin metathesis reaction is a powerful methodology for C-C double bonds formation that can find a number of applications in green chemical production. A set of heterogeneous olefin metathesis pre-catalysts composed of ammonium-tagged Ru-benzylidene complexes 4 (commercial FixCat™ catalyst) and 6 (in-house made) immobilized on solid supports such as 13X zeolite, metal-organic framework (MOF), and SBA-15 silica were obtained and tested in catalysis. These hybrid materials were doped with various amounts of ammonium-tagged styrene derivative 5—a precursor of a spare benzylidene ligand—in order to enhance pre-catalyst regeneration via the so-called release-return “boomerang effect”. Although this effect was for the first time observed inside the solid support, we discovered that non-doped systems gave better results in terms of the resulting turnover number (TON) values, and the most productive were hybrid catalysts composed of 4@MOF, 4@SBA-15, and 6@SBA-15.
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