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.
Laboratori Alchemia S.r.l., Via San Faustino 68, I-20134 Milan, Italy.
Molecules. 2022 Nov 5;27(21):7594. doi: 10.3390/molecules27217594.
Dimethindene is a selective histamine H 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.
二甲茚定是一种选择性组胺 H 拮抗剂，商业上可作为外消旋体供应。在分析目前用于二甲茚定工业制备的合成途径时，我们为该药物的合成建立了一种可持续的方法，从基于石油的挥发性有机化合物 (VOCs) 切换到环保溶剂，如分别属于第 3 类和第 2 类的 2-甲基四氢呋喃 (2-MeTHF) 和环戊基甲基醚 (CPME)。这种转变不仅降低了合成的环境影响（E 因子：使用 VOCs 为 24.1-54.9；使用 2-MeTHF 或 CPME 为 12.2-22.1），还提高了工艺的总收率（从使用 VOCs 的 10%提高到使用 2-MeTHF 或 CPME 的 21-22%），并且显著简化了操作，在更温和的条件下进行。根据 CHEM21 指标工具包，还为二甲茚定的整个合成过程计算了首次和第二次通过的典型指标，并将结果与经典过程进行了比较。
