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

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.


Introduction
In recent years, growing environmental awareness has led chemists to consider the sustainability of a chemical process as a "key driver for innovation" in the pharmaceutical industry [1]. In order to develop greener and more effective methods to produce active pharmaceutical ingredients (APIs), Anastas and Warner's 12 Principles of Green Chemistry became the guidelines for building an environmentally responsible manufacturing process [2,3]. Recently, the direct or accidental release of treated solvent waste and toxic chemicals into the environment, as well as hazardous work conditions, have led to the implementation of environmental directives and legislation (Clean Air Act of 1990 and the European Union Solvents Emission Directive 1999/13/EC) and the regulation of the usage of potentially harmful or environmentally damaging chemical substances (Registration, Evaluation, Authorisation, and Restriction of Chemicals (REACH)) [4]. These governmental regulations, in addition to many others, have created widespread interest in green chemistry and sustainable technology [5].
During pharmaceutical process development, a solvent selection analysis is pivotal for determining the sustainability of future production lines. Toxic and harmful volatile organic compounds (VOCs) (50-100 • C) (e.g., dichloromethane (DCM) and toluene), traditionally employed as solvents by organic and industrial chemists, have been severely curtailed and blacklisted. In this vein, the whole question of solvents requires rethinking and has 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].  (6).

Alternative Retrosynthetic Approaches to Dimethindene
Inspired by these results, the synthesis of dimethindene was then planned according to the retrosynthetic approach depicted in Scheme 2. It involved two different steps: (i) the addition of 2-ethylpyridine to the carbonyl moiety of 5a, followed by (ii) the dehydration of the corresponding intermediate tertiary alcohol. 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]. Beaton and co-workers [13] synthesized the intermediate 5b (30% yield) by preliminary treating a THF solution of 1-indanone (7) with LDA at -78 • C and then quenching the resulting enolate with 2-chloro-N,N-dimethylacetamide (f ) (Scheme 1B). After the reduction of carbonyl groups of 5b followed by acid-mediated dehydration of secondary alcohol 8 (g,h), n-BuLi and 4-fluorobenzyl bromide were sequentially added to a solution of 9 (i). The desired product 10 (a dimethindene analog) was isolated with an overall yield of 14%. In 2010, the same authors developed another synthetic approach to dimethindene analogs (Scheme 1C) [14]. In this case, 7 was first converted into 5b by a four-step process involving condensation with glycolic acid (j) followed by reduction with Zn in acetic acid (k), acyl chloride formation catalyzed by dimethylformamide (DMF) in DCM (l), and reaction with dimethylamine in DCM (m). Simultaneous reduction of the amide and ketone moieties of 5b with LiAlH 4 led to alcohol 8, which was oxidized to produce 5a. Lithium salts from various alkyl heteroaryls, generated by the treatment of alkyl heteroarenes with LDA, were finally added to 5a, followed by acid-mediated dehydration to afford dimethindene analogs 11. Of note, among the various VOCs, experts particularly recommend avoiding dimethylacetamide and DMF, as they bear a risk of nitrosamine formation [15].
With the aim of minimizing the environmental impact of pharmaceutical processes, herein, we report a forward-looking approach for sustainable and more effective synthesis of dimethindene (6). Upon a careful solvent selection based on the replacement of VOCs with more environmentally friendly solvents, such as 2-MeTHF [16] and cyclopentyl methyl ether (CPME) [17], we were able to successfully modify the current industrial process (vide infra), not only decreasing the waste of solvents/materials but also improving the overall yield of the process, which increased from 10% in VOCs to 21-22% in 2-MeTHF/CPME.

An Environmentally Sustainable Process for the Industrial Synthesis of Dimethindene (6)
A large amount of waste produced (80%) from the API manufacturing process is estimated to be solvent-related [24,25]. Thus, the selection, use, and recovery of solvents would contribute significantly to alleviating this problem. The shift toward greener solvents in the industrial synthesis of APIs is one of the main goals of pharmaceutical companies [26]. According to a recent ICH guidance Q3C (R8) [27], 2-MeTHF and CPME belong to solvent classes 3 and 2, respectively. Thus, they are recognized as "greener alternatives" to VOCs [28,29], and their use has been strongly advocated in the synthesis of drugs and drug intermediates by the ACS Green Chemistry Pharmaceutical Roundtable [30][31][32]. On this basis, we focused on the use of these solvents for the total synthesis of dimethindene (6). Moreover, to quantify the eco-sustainability of the synthesis of 6, when using 2-MeTHF or CPME as the solvent, we made use of the First Pass CHEM21 Metrics Toolkit developed by Clark et al. [33][34][35], calculating atom economy (AE), reaction mass efficiency (RME), optimum efficiency (OE), effective mass yield (EM), and mass intensity (MI) of each step, along with process mass intensity (PMI) metrics, the latter taking into account the reactants, reagents, and solvents of the whole process (PMI RXN ) or the solvents and reagents used in the work-up procedure (PMI WU ), and we compared these values with the corresponding ones related to the classical synthetic procedure for 6 (see Supplementary Materials for details). In addition, some metrics typical of the Second Pass CHEM21 Metrics Toolkit, which quantify the use of material from renewable sources, such as renewables intensity (RI) and renewables percentage (RP), were also calculated.
The new approach followed for the synthesis of 6 comprised 4 steps and started from commercially available benzyl malonic diethyl ester 2 ( Table 1). The latter (1.0 g, 4 mmol) was added to a refluxing suspension of NaH (1 equiv) in CPME or 2-MeTHF (10 mL each). After 1 h, 2-chloro-N,N-dimethylethan-1-amine (1 equiv) was added, and the reaction was refluxed for an additional 6 h. Compound 3 could finally be isolated at an 80% yield from 2-MeTHF and a 90% yield from CPME. Conversely, the yield of 3 was only 63% when using toluene as the solvent and 2 equiv of amine (Table 1, step 1). This allowed a significant improvement in reaction efficiency indicators, such as RME, OE, and E factor (Table 1, step 1). Furthermore, the use of CPME or 2-MeTHF as the reaction solvent and for the work-up step decreased the mass of non-benign reagents (and thus the indicator EM) while improving the recyclability of the process (RI and RP indicators).
The saponification of malonic ester 3 with an aqueous NaOH solution furnished the amino diacid 4 at a 75% yield, and the E factor for this step was very low (9.8). This reaction step was also characterized by a good RP value (90.1%) ( Table 1, step 2). The ring closure reaction (Friedel-Craft acylation) to produce the indanone skeleton is generally carried out using an excess of PPA (which also acts as a reaction medium), affording 5a at only a 20% yield. Conversely, a stoichiometric amount of PPA (1 equiv) in CPME or 2-MeTHF was enough to isolate 5a at a 50% yield in CPME and a 55% yield in 2-MeTHF, with a safer and operationally easier work-up procedure, thereby decreasing the amount of mass of non-benign reagents (higher EM value), improving the efficiency of the reaction (higher RME and OE values), and reducing the MI WU to a third compared with that of the classic procedure. The RP indicator for both reactions run in CPME and 2-MeTHF was very high (87-91.8%) ( Table 1, step 3).
Finally, by carrying out the nucleophilic addition of the benzylic-type anion of 2ethylpyridine to the carbonyl moiety of 5a in CPME or 2-MeTHF at 0 • C, followed by dehydration of the corresponding tertiary alcohol in refluxing HCl, dimethindene (6) was isolated at a 65% yield, regardless of whether CPME or 2-MeTHF was used as the solvent. On the other hand, the employment of a VOC, such as Et 2 O, as an alternative solvent, required the cooling of the system to −78 • C and led to the isolation of 6 at a 60% yield (Table 1, step 4). Again, the use of green solvents improved the efficiency and the sustainability of the reaction as results of the quantitative metrics calculated, particularly for the EM indicator (Table 1, step 4). Table 1. Quantitative metrics for each step a of the classical synthesis of dimethindene (6) in VOCs or in CPME or in 2-MeTHF.
In summary, the use of eco-sustainable solvents, such as CPME and 2-MeTHF, made it possible to improve the efficiency and sustainability of the entire synthetic process of dimethindene (6). The overall yield of the isolated product was twice that of the yield obtained through the current synthetic procedure using VOCs, with improvements in all quantitative metrics, especially the RP indicator (Table 2). Furthermore, the use of CPME or 2-MeTHF as the solvent allowed the reaction to be carried out under milder conditions (step 4) and avoided the use of toxic reagents in excess ( Table 1, steps 1 and 3). Table 1. Quantitative metrics for each step a of the classical synthesis of dimethindene (6) in VOCs or in CPME or in 2-MeTHF.

RP (%) E-Factor e
Step  Table 2. Quantitative metrics for the process of synthesis of dimethindene (6) in VOCs or in CPME or in 2-MeTHF.

Reaction Solvent
Yield AE (%) RME (%) OE (%) EM (%) PMIRXN a (g g -1 ) In summary, the use of eco-sustainable solvents, such as CPME and 2-MeTHF, made it possible to improve the efficiency and sustainability of the entire synthetic process of dimethindene (6). The overall yield of the isolated product was twice that of the yield obtained through the current synthetic procedure using VOCs, with improvements in all quantitative metrics, especially the RP indicator (Table 2). Furthermore, the use of CPME or 2-MeTHF as the solvent allowed the reaction to be carried out under milder conditions (step 4) and avoided the use of toxic reagents in excess (Table 1, steps 1 and 3). Table 2. Quantitative metrics for the process of synthesis of dimethindene (6) in VOCs or in CPME or in 2-MeTHF.

General Methods
The deep eutectic solvent ChCl/urea (1:2 mol/mol) was prepared by heating under stirring at 60-80 • C for 10-30 min the corresponding individual components until a clear solution was obtained. For 1 H NMR (600 MHz) and 13 C NMR (150 MHz), CDCl 3 or D 2 O was used as the solvent; chemical shifts are reported in parts per million (δ). FT-IR spectra were recorded on a Perkin-Elmer 681 spectrometer. GC analyses were performed on an HP 6890 model Series II using an HP1 column (methyl siloxane; 30 m × 0.32 mm × 0.25 µm film thickness). Analytical thin-layer chromatography (TLC) was carried out on precoated 0.25 mm thick plates of a Kieselgel 60 F; visualization was accomplished by UV light (254 nm) or by spraying a solution of 5% (w/v) ammonium molybdate and 0.2% (w/v) cerium(III) sulfate in 100 mL 17.6% (w/v) aq. sulfuric acid and heating to 473 K until blue spots appeared. Chromatography was run using silica gel 60 with a particle size distribution of 40-63 µm and 230-400 ASTM. GC-MS analyses were performed on an HP 5995C model. Cyclopentyl methyl ether (CPME) was provided by Zeon Europe GmbH. High-resolution mass spectrometry (HRMS) analyses were performed using a Bruker microTOF QII mass spectrometer equipped with an electrospray ion source (ESI). Other reagents and solvents, unless otherwise specified, were purchased from Sigma-Aldrich (Sigma-Aldrich, St. Louis, MO, USA) and were used without further purification. The following abbreviations are used to explain the multiplicities: s = singlet, d = doublet, t = triplet, m = multiplet, br = broad, dd = double doublet. RT = room temperature.

Step 3: Synthesis of 2-[2-(Dimethylamino)ethyl]indan-1-one (5a)
Compound 4 (0.72 g, 2.71 mmol) was added to polyphosphoric acid (1.15 g) at 110 • C with overhead stirring. The resulting brown reaction mixture was heated to 140-150 • C and stirred for 20 min. The reaction was finally quenched with the cautious addition of ice chips and then with cold water (1 mL), and it was basified with an aq. sol. of K 2 CO 3 (2 M). The mixture was extracted with Et 2 O (3 × 2 mL), washed with water (5 mL), dried (Na 2 SO 4 ), and evaporated under reduced pressure to yield 5a as a yellow oil at a 20% yield (0.110 g).

Conclusions
An environmentally sustainable procedure was developed for the synthesis of the antihistamine drug dimethindene (6) using green solvents 2-MeTHF and CPME belonging to classes 3 and 2, respectively, in agreement with the principles of green chemistry and following the recommendations of the ACS GCI Pharmaceutical Roundtable to redesign the chemical manufacturing of drugs by substituting the use of hazardous chemicals and fossil fuels and/or by reducing the production of waste to a minimum. The old synthetic industrial procedure, consisting of four steps and based on VOCs and harsh reaction conditions, has been now revisited and optimized by employing stoichiometric amounts of reagents and milder conditions, and the outcome of each step was compared when alternatively using 2-MeTHF or CPME as the solvent in place of VOCs. As a result, the overall yield of the process improved from 10% (with VOCs) to 21-22% (with 2-MeTHF or CPME) with a simplified work-up procedure. The decreased environmental impact of the newly reported approach is supported by the calculation of Quantitative Metrics of the CHEM21 Metrics Toolkit. Thus, an old and hazardous industrial process for the synthesis of a drug was usefully transformed into a more environmentally friendly synthetic methodology.
Supplementary Materials: The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules27217594/s1, typical metrics applied at Zero, First, and Second pass according to the CHEM21 Metrics Toolkit; quantitative metrics of classical and eco-friendly approach for the synthesis of Dimethindene (6); E-factor calculation for the synthesis of Dimethindene (6); Tables S1-S4: various experimental procedures; 1 H and 13 C NMR spectra of compounds 3, 4, 5a, and 6.