Sustainable and Scalable Two-Step Synthesis of Thenfadil and Some Analogs in Deep Eutectic Solvents: From Laboratory to Industry

Abstract

A sustainable two-step protocol was developed for the synthesis of the antihistamine drug Thenfadil by combining a reductive amination process with a Cu-catalyzed Ullmann-type C− N coupling reaction run in environmentally responsible deep eutectic solvents (DESs), constructed from biobased compounds. Under optimized conditions, both reactions proceed smoothly under aerobic conditions and in the absence of any additional ligand, with the desired active pharmaceutical ingredient isolated in an overall reaction yield of 39% with an effective suppression of the side products arising from competitive Cu-catalyzed C−O coupling reactions. A novel and simplified workup procedure has also been set up, which avoids the need for chromatographic purification, while allowing the recovery and the recycling of the unreacted intermediate secondary amine. The potential application and the robustness of the proposed methodology has been demonstrated (a) in scale-up studies up to 50 g of substrate in 0.5 kg of DES, taking place with no decrease in the reaction yield, and (b) in the synthesis of three other ethylenediamine derivatives (Thenfadil's analogs) like tripelennamine, methaphenilene, and thonzylamine in 39%−44% overall yield. Typical metrics applied at First and Second Pass, according to the CHEM21 Metrics Toolkit, have been calculated as well for the whole synthetic procedure of Thenfadil and results compared with those of the classical procedure.

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

“…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.…”

Deep Eutectic Solvents as à-la-Carte Medium for Transition-Metal-Catalyzed Organic Processes

“…The first step is based on a reductive amination between an aldehyde and a primary amine using NaBH 4 , and then an Ullman coupling takes places on the generated secondary amine to afford the desired compounds. It is worth noting that no chromatographic steps were required to purify the products and that the reaction was scaled up to 50 g [ 78 ] ( Figure 27 ). Other C-N coupling transformations based on supported heterogeneous catalysts include: Cu-NPs-carboxamide- f -GO@Fe 3 O 4 [ 79 ], Cu(I)-creatine@Fe 3 O 4 [ 80 ], Cu(I)-Si(CH 2 ) 3 N -acyclovir-SiO 2 @Fe 3 O 4 [ 81 ] and Pd(II)-vitamin B6@Fe 3 O 4 [ 82 ].…”

Unconventional and Sustainable Synthesis of Polymethine Dyes: Critical Overview and Perspectives within the Framework of the Twelve Principles of Green Chemistry

“…With more strict regard to the employment of more sustainable solvents, a special mention is deserved by alternative and new generation reaction media, such as Deep Eutectic Solvents (DESs). This class of eutectic mixtures, for which the discussion concerning their strict classification is still open, [27] has recently gained spotlights because of interesting properties such as nonvolatility, recyclability, durability, low polarity, easiness of preparation and naturally available cheap precursors [28] and has found widespread use in organic synthesis, including simple transformations, [29] reactions with harmful organometallic reagents [30] preparation of APIs, [31] and catalytic methodologies, [32] in some of which the DES plays an active role [33]…”

“…generation reaction media, such as Deep Eutectic Solvents (DESs). This class of eutectic mixtures, for which the discussion concerning their strict classification is still open, [27] has recently gained spotlights because of interesting properties such as nonvolatility, recyclability, durability, low polarity, easiness of preparation and naturally available cheap precursors [28] and has found widespread use in organic synthesis, including simple transformations, [29] reactions with harmful organometallic reagents [30] preparation of APIs, [31] and catalytic methodologies, [32] in some of which the DES plays an active role. [33] In a work by Shankarling, a wide series of symmetrical squaraines 3 a-o is synthesized in one of the very first DESs to be prepared from quaternary ammonium salts, i. e. choline chloride/urea 1 : 2 by molar ratio.…”