# Environmentally Friendly Green \(O\)-Alkylation Reaction for Ethenzamide Synthesis
## 1 Introduction  
Salicylic acid (**1**) derivatives are one of the oldest active substances used in pharmacy, initially isolated mainly from willlow bark (_Salix alba_). The first records of the therapeutic analgesic properties of willow bark extracts were described by [PERSON] in the 5 th century BC, but it is known that the anti-inflammatory properties of this plant were also known in ancient Egypt and China [1, 2, 3]. Currently, both salicylic acid and its derivatives are obtained mainly chemically, although herbal medicines based on salicates are still very popular. Salicylic acid was first obtained in the Kolbe reaction from phenol and carbon dioxide, and then there was a development in the synthesis of other derivatives of this acid such as acetylsalicylic acid (**2**), \(p\)-aminosalicylic acid (**3**), methyl salicate (**4**), salicamide (**5**), or ethenzamide (**6**) (Figure 1). Most derivatives of salicylic acid possess analgesic, anti-inflammatory, and antipyretic effects and are classified as non-steroidal anti-inflammatory drugs (NSAIDs). This group includes salicamide (5), which, even though this compound is not as effective as the popular acetylsalicylic acid (2), is still used as an analgesic, antipyretic, antirheumatic, and as a fungicide [4]. Interestingly, \(O\)-derivatives of salicylic acid are a common building block of bioactive compounds tested for their potential use as new anticancer drugs [5; 6; 7; 8; 9] and antihistamines [10], and are also being explored for the treatment of schizophrenia and depression [11; 12; 13], tuberculosis [14], bacterial infections [15], and cardiovascular diseases [16]. Ethenzamide (6) is one of the most pharmaceutically interesting derivatives of salicamide: it has analgesic and anti-inflammatory effects and reduces skeletal muscle tension [17; 18; 19; 20; 21; 22]. Most often, in combination with paracetamol or acetylsalicylic acid and caffeine, it is recommended for colds, headaches, toothaches, menstrual cramps, or fever. Ethenzamide, like other \(O\)-alkyl derivatives of salicamide, is most often obtained via Williamson synthesis in the presence of sodium, sodium or potassium hydroxide, or potassium carbonate in solvents such as acetone, ethanol, or dimethylformamide, and the process usually takes at least several hours [23]. Considering that ethenzamide is a widely used active pharmaceutical ingredient (API) worldwide, we decided to develop a new ecological-friendly and efficient method for the synthesis of this compound. Based on literature data from recent years on the synthesis of heterocyclic organic compounds, a clear trend of searching for new environmentally friendly technologies is observed. It is worth emphasizing that the concept of green chemistry is already important at the stage of process planning, and its purpose is to make industrial chemistry safer, cleaner, and more energy-efficient throughout the entire product life cycle, i.e., from synthesis, through purification, to disposal. An important aspect is using renewable raw materials wherever possible and minimizing or eliminating toxic waste from the beginning [24]. Undoubtedly, an important aspect in the case of environmentally friendly processes is the use of appropriate catalysts that are non-toxic and significantly affect the selectivity and efficiency of the process. It seems that all these aspects are met in the case of conducting processes under phase transfer catalysis (PTC) conditions. A wide range of reactions such as alkylation, oxidation, reduction, elimination, hydrolysis, esterification, polymerization, aliphatic or aromatic substitution, and many others can be carried out under PTC conditions. This is a method that allows for the synthesis to be carried out under mild conditions, while at the same time with high efficiency and selectivity.