A Switchable Oxidation Process Leading to Two Various Versatile Pharmaceutical Intermediates

Abstract

An efficient high-yielding and environmentally benign switchable oxidation process that can selectively produce two different versatile synthetic intermediates is disclosed. One of the two intermediates, 2,3-dimethoxy-5-methylcyclohexa-2,5-diene-1,4-dione (coenzyme Q0), is obtained by means of a telescoped two-step synthetic protocol that in the first step involves treatment of the substrate (1,2,3-trimethoxy-5-methylbenzene) with hydrogen peroxide in acetic acid with p-toluene sulphonic acid present as a Brønsted acid catalyst, succeeded by a telescoped second step that entails treatment with fuming nitric acid to achieve the target molecule in an excellent isolated yield (88%). If the substrate is treated directly with nitric acid (65%) in glacial acetic acid two different products can be obtained, namely acetic acid 3,4,5-trimethoxybenzyl ester in a superb isolated yield (93%) or, under slightly altered reaction conditions, 1,2,3-trimethoxy-5-(nitromethyl)benzene in a moderate to low yield (35%) and low selectivity. The two pathways leading to the two different products in the nitric acid oxidation protocol were investigated by means of DFT calculations as an aid to elaborate a proposal for the reaction mechanism.

Synthesis of coenzyme Q0 through divanadium-catalyzed oxidation of 3,4,5-trimethoxytoluene with hydrogen peroxide

“…In most procedures reported in the literature for TMT oxidation with H 2 O 2 , the reaction proceeds in acidic medium, such as acetic or formic acid. [9][10][11]13,15,16 Some of them require addition of mineral acid in catalytic amounts to accelerate the formation of peroxy acid, which is the real oxidizing species in these systems. 10,15,16 In view of our interest in the development of a more safe and environmentally friendly approach to the synthesis of CoQ 0 , we have checked whether a mineral acid can play a role of the sole catalyst in a less corrosive and harmful solvent, for example, MeCN.…”

“…7 Several synthetic methods were reported for the production of CoQ 0 through the oxidation of commercially available 3,4,5-trimethoxytoluene (TMT) with the green oxidanthydrogen peroxide. [8][9][10][11][12][13][14][15][16] Among catalysts applied were potassium hexacyanoferrate(III), 8 methyltrioxorhenium(VII) (MTORe), 11,12 mineral acids (H 2 SO 4 10,16 or HNO 3 15 ), and heteropolyacids of the general formula H n XM 12 O 40 (where X = P or Si, n = 3 (P) or 4 (Si), and M = Mo or W). 13,14 So far, the best yields of CoQ 0 have been claimed for systems that employed formic acid as a solvent and phosphomolybdic heteropolyacid as a catalyst 14 or a mixture of acetic and formic acids without any catalysts.…”

Single-step Syznthesis of Coenzyme Q0

“…Among metal catalysts applied were potassiumhexacyanoferrate(III) K 3 Fe(CN) 6 [6], methyltrioxorhenium (CH 3 ReO 3 ) [7], ruthenium complex-bound norvaline [8] and γ-Keggin divanadium-substituted phosphotungstate [9]. Recently, Bjørsvik et al utilized hydrogen peroxide in combination with mineral acids (HNO 3 ) [10] to produce CoQ 0 , which imposed practical problems related to reactor corrosion and safety risks. Based on our previous study [11], here we described a single step synthesis of CoQ 0 by treatment of 3,4,5-Trimethoxytoluene 1 with persulfate (…”

The Baeyer‐Villiger oxidation versus aromatic ring hydroxylation: competing organic peracid oxidation mechanisms explored by multivariate modelling of designed multi‐response experiments

“…The research activity included (1) preparation of methoxy‐substituted phenols by oxidation of the corresponding benzenes in one synthetic step, path (iv) of Scheme , and (2) synthesis of 2‐methoxy‐3‐methyl‐benzo‐quinone 6 by means of a two‐step telescoped process, where the phenol was generated in the first step (not isolated), whereupon the phenolic hydroxyl group was further oxidized by a second oxidant to induce the formation of the resultant quinone derivate . This latter process was afterward adapted for the synthesis of the 2,3‐dimethoxy‐5‐methylcyclohexa‐2,5‐diene‐1,4‐dione (also known as CoQ 0 ) that is an essential building block in the synthesis of ubiquinones (also known as coenzyme Q n , n = 1,…, 12, and mitoquinones), and the synthetic analogue idebenone …”

“…The research activity included (1) preparation of methoxy-substituted phenols by oxidation of the corresponding benzenes in one synthetic step, path (iv) of Scheme 1, and (2) synthesis of 2-methoxy-3-methyl- [1,4] benzo-quinone 6 by means of a two-step telescoped process, where the phenol was generated in the first step (not isolated), whereupon the phenolic hydroxyl group was further oxidized by a second oxidant to induce the formation of the resultant quinone derivate. [11] This latter process was afterward adapted for the synthesis of the 2,3dimethoxy-5-methylcyclohexa-2,5-diene-1,4-dione (also known as CoQ 0 ) [12] that is an essential building block in the synthesis of ubiquinones (also known as coenzyme Q n , n = 1,…, 12, and mitoquinones), and the synthetic analogue idebenone. [13] Direct hydroxylation of the benzene ring, step (iv) of Scheme 1, can be of pronounced importance from an industrial point of view when focusing process efficacy, process economy and environmental issues, because an operating alternative encompassing the steps (i-iii) of Scheme 1 that involves a Friedel-Crafts acylation, [14] a Baeyer-Villiger oxidation [8] and an ester hydrolysis.…”