Green Solvents for Eco-Friendly Synthesis of Dimethindene: A Forward-Looking Approach
Andrea Francesca Quivelli,
Federico Vittorio Rossi,
Chiara Alario,
Francesco Sannicolò,
Paola Vitale,
Joaquín García-Álvarez,
Filippo Maria Perna,
Vito Capriati
Affiliations
Andrea Francesca Quivelli
Dipartimento di Farmacia—Scienze del Farmaco, Università degli Studi di Bari “Aldo Moro”, Consorzio C.I.N.M.P.I.S., Via E. Orabona 4, I-70125 Bari, Italy
Federico Vittorio Rossi
Laboratori Alchemia S.r.l., Via San Faustino 68, I-20134 Milan, Italy
Chiara Alario
Laboratori Alchemia S.r.l., Via San Faustino 68, I-20134 Milan, Italy
Francesco Sannicolò
Laboratori Alchemia S.r.l., Via San Faustino 68, I-20134 Milan, Italy
Paola Vitale
Dipartimento di Farmacia—Scienze del Farmaco, Università degli Studi di Bari “Aldo Moro”, Consorzio C.I.N.M.P.I.S., Via E. Orabona 4, I-70125 Bari, Italy
Joaquín García-Álvarez
Laboratorio de Química Sintética Sostenible (QuimSisSos), Departamento de Química Orgánica e Inorgánica, (IUQOEM), Centro de Innovación en Química Avanzada (ORFEO-CINQA), Facultad de Química, Julián Clavería, 8, 33006 Oviedo, Spain
Filippo Maria Perna
Dipartimento di Farmacia—Scienze del Farmaco, Università degli Studi di Bari “Aldo Moro”, Consorzio C.I.N.M.P.I.S., Via E. Orabona 4, I-70125 Bari, Italy
Vito Capriati
Dipartimento di Farmacia—Scienze del Farmaco, Università degli Studi di Bari “Aldo Moro”, Consorzio C.I.N.M.P.I.S., Via E. Orabona 4, I-70125 Bari, Italy
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.
