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

Öz

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.

Anahtar Kelimeler

• Esterification
• N-hydroxy succinimide
• Folic Acid
• 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide.
• 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide.

Folik Asit N-Hidroksisüksinimid Ester Sentezinde Farklı Çözücü Tiplerinin Ester Oluşumuna Etkisi

Öz

Folik asit, hücrelerin hayati fonksiyonları için önemli bir B9 vitaminidir. Folik asit reseptörleri tarafından hücre içine pH'a bağlı Michaelis-Menten kinetiği ile alınan folik asit, bu reseptörlerin aşırı ifade edildiği hastalıklarda ilacın hücre içine kolay alınabilmesine imkan tanır. Folik asidin ester formunun hedefli tedavilerde kullanılması, folik asidin taşıyıcı ilaca bağlanması açısından önemlidir. N-hidroksi süksinimid, ester oluşturmak için kullanılan bir ajandır ve Steglich esterifikasyonu ile folik asitten ester oluşumuna katkıda bulunur. Birçok sentezde, çözücü olarak dimetil sülfoksit (DMSO) ve reaktif olarak ise N, N'-disiklohekzilkarbodiimid (DCC) kullanılır. Bu maddelerle etkili bir sentez gerçekleştirilmesine rağmen, olası safsızlıklar nedeniyle sonraki çalışmalarda başka analizler yapılmalıdır. Diklorometan veya dimetil formamid gibi çözücüler daha az safsızlık üretmeleri ve 1-Etil-3-(3-dimetilaminopropil) karbodiimid (EDC)’in reaktif olarak daha kolay bir şekilde uzaklaştırılabilen ara ürün oluşturması sebebiyle bu reaksiyon için daha uygun olabilir. Araştırmamız sonucunda dimetil formamid ile yapılan sentezde aşırı miktarda folik asit bulunması, sonraki çalışmalarda N-hidroksi süksinimid ve EDC'nin molar oranlarının artırılması gerektiğini göstermektedir. Diklorometan ile yapılan sentezde ester oluşumu tespit edilmiş ancak sonuç UV-Vis deneyi ile doğrulanamamıştır. Ayrıca EDC kullanımının ara ürün oluşturmadığı ve bunun reaksiyonun safsızlığına katkıda bulunduğu gözlenmiştir. Sonuç olarak EDC, DCC yerine ara ürün olarak safsızlıklardan kurtulmada etkili bir rol oynamıştır. Bu nedenle reaksiyonda DCC/EDC kombinasyonunun daha verimli reaksiyon saflığı oluşturduğu tartışılmıştır.

Anahtar Kelimeler

• Esterifikasyon
• N-hidroksisüksinimid
• Folik Asit
• 1-Etil-3-(3-dimetilaminopropil)karbodiimid.

Kaynakça

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