Green Solvents for Eco-Friendly Synthesis of Dimethindene: A Forward-Looking Approach

Abstract

Dimethindene is a selective histamine H1 antagonist and is commercially available as a racemate. Upon analyzing the synthetic pathways currently available for the industrial preparation of dimethindene, we set up a sustainable approach for the synthesis of this drug, switching from petroleum-based volatile organic compounds (VOCs) to eco-friendly solvents, such as 2-methyltetrahydrofuran (2-MeTHF) and cyclopentyl methyl ether (CPME) belonging to classes 3 and 2, respectively. Beyond decreasing the environmental impact of the synthesis (E-factor: 24.1–54.9 with VOCs; 12.2–22.1 with 2-MeTHF or CPME), this switch also improved the overall yield of the process (from 10% with VOCs to 21–22% with 2-MeTHF or CPME) and remarkably simplified the manual operations, working under milder conditions. Typical metrics applied at the first and second pass, according to the CHEM21 metrics toolkit, were also calculated for the whole synthetic procedure of dimethindene, and the results were compared with those of the classical procedure.

Introducing Water and Deep Eutectic Solvents in Organosodium Chemistry: Chemoselective Nucleophilic Functionalizations in Air

“…These values are in line with those obtained in the synthesis of other active pharmaceutical ingredients (APIs) using environmentally responsible/ nature-inspired solvents. [27] Calculated production costs of 6, with reference to raw materials only, are 2.6 E/g (for details, see Supporting Information). [28]…”

A Sustainable Synthetic Approach to Tacrine and Cholinesterase Inhibitors in Deep Eutectic Solvents under Aerobic Conditions

“…DESs have been widely used in organic synthesis [ 9 ], in particular for the preparation of N -containing heterocyclic scaffolds because of their dual solvent–catalyst role [ 10 , 11 , 12 ]. Over the last decade, valuable sustainable methodologies have been introduced in the literature, both by our group and others, for the synthesis of pharmacologically active heterocycles with central nervous system activity or anti-inflammatory or antiproliferative properties (e.g., functionalized triazoles, pyrimidines, imidazoles, pyrazones, benzoxazines, tetrahydrofuran, and tetrahydropyran derivatives) [ 13 , 14 , 15 , 16 , 17 , 18 ] and of Active Pharmaceutical Ingredients (APIs) like COX-1 inhibitors [ 19 ] and antihistamine drugs (e.g., thenfadyl and some analogs, such as dimethindene) [ 20 , 21 ].…”