4-Methyltetrahydropyran as a Convenient Alternative Solvent for Olefin Metathesis Reaction: Model Studies and Medicinal Chemistry Applications

Abstract

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.

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

“…Green chemistry is an increasing trend not only in chemical industry but also in academia. 59 − 62 Despite the environmental needs and the availability of many alternative solvents such as water, 63 ethyl acetate, 64 , 65 dimethyl carbonate, 66 , 67 2-MeTHF, 68 , 69 and 4-MeTHP, 61 , 70 the usage of green solvent for olefin metathesis is relatively scarce. We therefore screened both the general-purpose Hoveyda–Grubbs second-generation catalyst ( Ru1 , see Figure 1 ) and the tagged StickyCat PF 6 ( Ru2 ) in RCM of diethyl diallylmalonate ( 1 ) used as a model substrate, in two solvent systems—DCM (not green) and EtOAc (green).…”

“…Notably, previously published process for 16 manufacturing at a scale of 33 g that uses a standard batch reactor required up to 1 mol % of catalyst loading to yield 16 in 88% with ruthenium content in product equal 88 ppm. 61 …”

Ruthenium Complexes Featuring Unsymmetrical N‐Heterocyclic Carbene Ligands–Useful Olefin Metathesis Catalysts for Special Tasks

“…(2-MeTHF), [58] 4-methyltetrahydropyran (4-MeTHP), [62] and dimethyl carbonate (DMC). [54] For example, a collection of polyfunctional substrates including active pharmaceutical ingredients (API), such as modafinil (46) and SUAM 1221 (47) derivatives have been successfully obtained in RCM reaction (Scheme 12a).…”

“…Scheme 12. Selected applications of Ru52 in medicinal chemistry context in green solvents a) RCM reactions, [54,62] b) self-CM of estrone derivative. [54] DMC = dimethyl carbonate, 4-MeTHP = 4-metyltetrahydropyran.…”

Potential Degradation of 4‐Methyltetrahydropyran (4‐MeTHP) under Oxidation Conditions

“…4‐Methyltetrahydropyran (4‐MeTHP) is a recently‐developed ethereal solvent that can be applied to a broad range of organic reactions [1,2] . The inherent hydrophobicity permits easy recycle of the solvent by distillation after extractive workup, which makes the solvent more environmentally benign than water‐miscible tetrahydrofuran (THF) [3] .…”