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

A sustainable two-step protocol was developed forthe synthesis of the antihistamine drug Thenfadil by combining areductive amination process with a Cu-catalyzed Ullmann-type C-N coupling reaction run in environmentally responsible deepeutectic solvents (DESs), constructed from biobased compounds.Under optimized conditions, both reactions proceed smoothlyunder aerobic conditions and in the absence of any additionalligand, with the desired active pharmaceutical ingredient isolated inan overall reaction yield of 39% with an effective suppression of theside products arising from competitive Cu-catalyzed C-O couplingreactions. A novel and simplified workup procedure has also beenset 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 therobustness 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'sanalogs) like tripelennamine, methaphenilene, and thonzylamine in 39%-44% overall yield. Typical metrics applied at First andSecond Pass, according to the CHEM21 Metrics Toolkit, have been calculated as well for the whole synthetic procedure of Thenfadiland results compared with those of the classical procedure.

Automated summary

A sustainable and efficient two-step methodology for the synthesis of Thenfadil has been developed, utilizing a combination of reductive amination and Cu-catalyzed C-N coupling reactions in environmentally responsible deep eutectic solvents. Under optimized conditions, both reactions proceed smoothly with good yields and suppression of side products. A simplified workup procedure and the potential for scale-up and synthesis of analogs have also been demonstrated.