Large‐Scale Synthesis of a Niche Olefin Metathesis Catalyst Bearing an Unsymmetrical N‐Heterocyclic Carbene (NHC) Ligand and its Application in a Green Pharmaceutical Context

Abstract

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).

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).…”

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

“…However, first, to show a perspective for a large-scale production, we undertook a half-kilogram scale synthesis of this complex which has been obtained in 15 % yield over 12 steps from commercially available and cost-efficient precursors, such as RuCl 3 , 2,6-diisopropylaniline, and salicylic aldehyde. [54] Next, we found that this complex is stable under air in non-degassed common organic solvents (DCM, toluene), as well as in so-called "green solvents" [55] such as 2-MeTHF or dimethyl carbonate (DMC) usually leading to very good results in a range of metathesis reactions. [56] What is more, high selectivity of complex Ru52 has been demonstrated in ethenolysis of ethyl oleate (27) and in a set of self-CM reactions of various terminal olefins (Scheme 10).…”

“…(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). Of note, the corresponding products 44-47 were obtained in excellent yield with only 0.4-0.5 mol % of Ru52.…”

“…The reaction required the sequential addition of 0.8 mol % of the catalyst (in two portions 0.4 mol % each) but eventually led to the isolation of the expected product 49 in 80 % yield and no signs of CÀ C double bond isomerization (selectivity of 99 %). [54] It shall be however noted that in CM reactions with partners bearing electron-deficient CÀ C double bond, such as acrylic esters, acrylonitrile, and other α,β-unsaturated compounds, the uNHC catalysts are typically giving worse results than the general purpose symmetrical NHC bearing variants. [54] In cooperation with a pharmaceutical company, the thiophene uNHC catalyst was utilized in a larger scale (> 30 gram/batch) metathesis of two drugs analogues used in treatment of erectile dysfunction and pulmonary arterial Scheme 10.…”

“…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.…”