Olefin Metathesis in Continuous Flow Reactor Employing Polar Ruthenium Catalyst and Soluble Metal Scavenger for Instant Purification of Products of Pharmaceutical Interest

Abstract

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.

Testing enabling techniques for olefin metathesis reactions of lipophilic substrates in water as a diluent

“…2, 131.6, 130.7, 128.1, 126.5, 74.9, 48.5, 38.5, 23.0. Presented analytical data are consistent with literature (Rodriguez et al, 2020;Toh et al, 2021). 2, 136.2, 125.9, 125.8, 124.7, 124.2, 123.2, 122.3, 111.6, 54.0, 53.4; melting point: 216 C. Presented analytical data are consistent with literature (Nienałtowski et al, 2020b).…”

“…13 C NMR (101 MHz, CDCl 3 ) d 156.2, 156. 1, 137.2, 137.1, 131.7, 131.4, 128.4, 128.3, 127.8, 127.7, 127.6, 127.4, 66.9, 66.7, 52.5, 52.3, 39.4, 39.1, 34.0, 33.9, 27.1, 26.9, 19.6, 19.1.Presented analytical data are consistent with literature (Szczepaniak et al, 2019;Toh et al, 2021). 2, 131.6, 130.7, 128.1, 126.5, 74.9, 48.5, 38.5, 23.0.…”

“…Fortunately, simple recrystallization of the crude product from a mixture of ethyl acetate and ethanol resulted in significant decrease of product contamination (Table 5, entry 3). An alternative purification protocol, consisting of the use of a ruthenium scavenger developed in our laboratories (Szczepaniak et al, 2019;Toh et al, 2021) (recently commercialized under the trade name SnatchCat), led to 5 ppm of ruthenium residue (Table 5, entry 4). Interestingly, similar results were obtained after treatment of crude compound 24 (containing 1,032 of ruthenium) with active charcoal (Table 5, entry 5).…”

Organometallic flow chemistry: solvento complexes

“…The removal of gaseous products in organometallic flow chemistry is relevant to the deployment of alkene metathesis processes in flow, where the inability to remove ethene from micro-reactor tubing compromises conversion. 13…”

“…The removal of gaseous products in organometallic flow chemistry is relevant to the deployment of alkene metathesis processes in flow, where the inability to remove ethene from micro-reactor tubing compromises conversion. 13 It is important to note that the intensities of infrared absorbances vary with the symmetry of each vibrational mode, such that peak height or integrated area are inappropriate for estimating relative concentrations of species of different symmetry (O h -[W(CO) 6 ] vs. C 4v -[W(THF)(CO) 5 ]) but useful for an estimation of conversion. To provide a more practically useful assay of productive conversion, the sample was dispensed into the theoretical equimolar amount of triphenylphosphine (Scheme 1).…”