A number of metathesis reactions were successfully conducted in 4-methyltetrahydropyran, including both standard model dienes, as well as more complex substrates, such as analogues of biologically active compounds and active pharmaceutical ingredients. To place this solvent in a context of pharmaceutical R + D, larger-scale syntheses of SUAM 1221, a prolyl endopeptidase inhibitor with potential application in Alzheimer disease treatment, and a derivative of sildenafil, an analogue of the popular Viagra drug, were executed. In the latter case, despite all the setup being made in air, the metathesis reaction at a 33 g scale proceeded very well with relatively low catalyst loading and without need of aqueous workup or column chromatography.

Al arge-scale synthesis of knownR uo lefin metathesis catalyst VII featuring an unsymmetrical N-heterocyclic carbene (NHC) ligand with one 2,5-diisopropylphenyl (DIPP) and one thiophenylmethylene N-substituent is reported. The optimised procedure does not requirec olumnc hromatography in any step and allows forp reparation of up to 0.5 kg batches of the catalystf rom simple precursors.T he application profile of the obtainedc atalystw as studied in environmentally friendly dimethyl carbonate (DMC). Although VII exhibited low efficiency in cross-metathesis (CM) with electron deficient partners, good to excellent results were noted for substrates featuring easyt oi somerise CÀCd ouble bonds. This includes polyfunctional substrates of medicinal chemistry interest, such as analogues of psychoactive 5F-PB-22 and NM-2201 and two PDE5i nhibitors-Sildenafil and Vardenafil. Finally,al arger scale ring-closing metathesis (RCM) of aV ardenafil derivativew as conducted in DMC, allowing for straightforwardi solation of the expectedp roduct (23 g) in high yield and with low Ru contamination level (7.7 ppm).

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.