Effect of Solvent Type Approaches on Ester Formation in the Synthesis of Folic Acid N-Hydroxy Succinimide Ester

Folic acid is a crucial substituent compound for vital functions of cell known as vitamin B9. Folic acid, which is taken into the cell by folic acid receptors, is used for the pH-dependent Michaelis-Menten kinetics of the drug into the cell in diseases where these receptors are overexpressed. Using the ester form of folic acid in targeted treatments is important in terms of folic acid binding to the carrier drug. N-hydroxy succinimide is an agent used to form esters and contributes to the formation of esters from folic acid with Steglich esterification. In many syntheses, dimethyl sulfoxide (DMSO) is used as a solvent and N, N'-dicyclohexylcarbodiimide (DCC) represents a reagent. Although an effective synthesis is carried out with these substances, other analyses should be performed in subsequent studies due to possible impurities. Solvents such as dichloromethane or dimethyl formamide can be more suitable for this reaction as they produce fewer impurities and 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) represents a reagent and forms a more simply removable intermediate product. As a result of our research, the presence of excessive amounts of folic acid in the synthesis carried out with dimethyl formamide indicates that the molar ratios of N-hydroxy succinimide and EDC should be increased in subsequent studies. In the synthesis carried out with dichloromethane, ester formation was detected, but the result could not be matched with UV-Vis experiment. In addition, it was observed that the use of EDC did not form intermediate products, and this contributed to the impurity of the reaction. As a result, EDC has played an effective role to get rid of the impurities as intermediate product instead of DCC. Thus, the combination of DCC/EDC in reaction discussed as more efficient reaction purity and yield profile.