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

• Published in: Molecules (Basel, Switzerland) Vol. 27; no. 21; p. 7594
• Main Authors: Quivelli, Andrea Francesca, Rossi, Federico Vittorio, Alario, Chiara, Sannicolò, Francesco, Vitale, Paola, García-Álvarez, Joaquín, Perna, Filippo Maria, Capriati, Vito
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01.11.2022; MDPI
• Subjects: Acids; Alcohol; Analysis; API synthesis; cyclopentyl methyl ether; deep eutectic solvents; dimethindene; Efficiency; Green chemistry; Histamine H1 receptors; Manufacturing; Methyl ether; Organic compounds; Pharmaceutical industry; Solvents; Sustainability; synthetic methodologies; VOCs; Volatile organic compounds
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27217594

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.