Ethenzamide (2-ethoxybenzamide), besides acetylsalicylic acid, is one of the mostly used salicylic acid derivatives in pharmaceuticals. It has analgesic and anti-inflammatory effects that originate from the inhibition of cyclooxygenase (COX-1) activity, thus blocking prostaglandin synthesis. In this work, efficient and eco-friendly methods were developed for the synthesis of ethenzamide via the O-alkylation reaction of salicylamide. The reactions were carried out under conventional conditions in a solvent-free system using variant solvents and different phase transfer catalysts (PTC) in the presence of microwave radiation or ultrasonic conditions. It was shown that in solvent-free conditions using TBAB as a catalyst, ethenzamide can be obtained within 15 min at 80 °C with 79% yield. Meanwhile, using microwave radiation under the same conditions, the reaction time can be shortened to 90 s with 92% yield. Notably, high yields can be achieved under PTC in water (or organic solvent-free) conditions using microwave radiation (2 min, 94%) or ultrasound (10 min, 95% efficiency). The studies prove that the PTC synthesis process of ethenzamide can be conducted under mild conditions, with a shorter reaction time and remarkably lower energy consumption in comparison to conventional processes, thus actualizing “green chemistry” for practical ethenzamide preparation.

Ethenzamide (2-ethoxybenzamide), besides acetylsalicylic acid, is one of the mostly used salicylic acid derivatives in pharmaceuticals. It has analgesic and anti-inflammatory effects that originated from the inhibition of cyclooxygenase (COX-1) activity, thus blocking prostaglandin synthesis. In this work, efficient and eco-friendly methods were developed for the synthesis of ethenzamide via the O-alkylation reaction of salicylamide. The reactions were carried out under conventional conditions in a solvent-free system using variant solvents and different phase transfer catalysts (PTC) in the presence of microwave radiation or ultrasonic conditions. It was shown that in solvent-free conditions using TBAB as a catalyst, ethenzamide can be obtained within 15 min at 80°C with 79% yield. Meanwhile, using microwave radiation under the same conditions, the reaction time can be shortened to 90 s with 92% yield. Notably, high yields can be achieved under PTC in water (or organic solvent-free) conditions using microwave radiation (2 min, 94%) or ultrasound (10 min, 95% efficiency). The studies prove that the PTC synthesis process of ethenzamide can be conducted under mild conditions, with a shorter reaction time and remarkably lower energy consumption in comparison to conventional processes, thus actualizing the ‘green chemistry’ for practical ethezamide preparation.