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.

Keywords: 2-Methyltetrahydrofuran; API synthesis; cyclopentyl methyl ether; deep eutectic solvents; dimethindene; green chemistry; synthetic methodologies.

Scheme 1

Current industrial synthesis of dimethindene (6) using VOCs: Path (A) [11,12]; synthesis of dimethindene analogs 10,11 using VOCs: Paths (B,C) [13,14]. (Path A) Reagents and conditions: (a) diethyl malonate, Na, and EtOH, at reflux. (b) NaH, 2-chloro-N,N-dimethylethan-1-amine, and toluene, at reflux. (c) NaOH and EtOH/water at reflux. (d) PPA, heating. (e) 2-Ethylpyridine, n-BuLi, and Et₂O, at −78 °C; HCl (20%), at reflux. Path (B) Reagents and conditions: (f) LDA and THF, at −78 °C; 2-chloro-N,N-dimethylacetamide. (g) LiAlH₄ and THF, at reflux. (h) AcOH and HCl, at reflux. (i) 4-Fluorobenzyl bromide, n-BuLi, and THF, at −78 °C. Path (C) Reagents and conditions: (j) glycolic acid (40% in H₂O), conc. H₂SO₄, and dioxane, at reflux; (k) Zn, HOAc, and H₂O, at 100 °C; (l) (COCl)₂, cat. DMF, and DCM; (m) HNMe₂, Et₃N, and DCM.

Scheme 2

An alternative retrosynthetic approach to dimethindene (6).

Scheme 3

Possible retrosynthetic approaches to 5a. (a) α-Functionalization of 1-indanone (7) with 2-chloro- or 2-iodo-N,N-dimethylethan-1-amine; base: LDA, KHMDS, and NaHMDS; solvent: THF and toluene; temperature: −78 °C or −20 °C; (b) α-functionalization of 1-indanone (7) with 2-chloro-N,N-dimethylacetamide; base: LDA and NaH; solvent: THF and CPME; temperature: −78 °C or 0 °C or 25 °C; (c) α-functionalization of 1-indanone (7) with 2-(dimethylamino)ethyl-4-methylbenzenesulfonate; base: LDA and NaH; solvent: THF, toluene, and CPME; temperature: −78 °C or −20 °C or 0 °C; (d) α-functionalization of 1-indanone (7) with 2-(dimethylamino)ethan-1-ol; Ru cat.: [Ru(p-cymene)Cl₂]₂; ligand: (oxydi-2,1-phenylene)bis(diphenylphosphine); solvent: toluene; base: CsCO₃ and NaOH; temperature: 105 °C; 8 h; (e) reaction between enamine 12 and 2-chloro- or 2-iodo-N,N-dimethylethan-1-amine or 2-chloro-N,N-dimethylacetamide; solvent: ChCl/urea; temperature: 25 °C for up to 24 h; (f) reaction between β-ketoester 13 and 2-chloro-N,N-dimethylethan-1-amine; base: LDA, KHMDS, NaMDS, and NaH; solvent: THF, toluene, CPME, and DES; temperature: −78 °C, −20 °C, or 0 °C.