Study and Characterization of Nitration of Isovanillic Acid Derivatives using NMR and Mass Spectroscopy

Abstract

Isovanillic acid and its derivatives serve as precursors in the synthesis of EGFR tyrosine kinase inhibitors, which are used to treat cancer cell lines. A crucial step in this process is the nitration of isovanillic acid through nucleophilic aromatic substitution, resulting in 6-nitroisovanilic acid and its derivatives, which act as intermediates for forming a quinazolinone ring. However, this study revealed that direct nitration of isovanillic acid derivatives led to unexpected products, such as 3-hydroxy-4-methoxy-2,6-dinitrobenzoic acid (1) and 4-(3-(2-methoxy-4-nitrophenoxy)propyl)morpholine (4). Additionally, the optimal conditions for etherification of 2 with N-(3-chloropropyl)morpholine to produce 3 involved using Cs2CO3 in DMF and refluxing for 7 hours, achieving an 89% yield. All synthesized compounds were characterized using NMR spectroscopy, and mass spectrometry was employed for two compounds (3, 4). Compound 1 represents the first report of direct nitration of isovanillic acid. Compound 4 was synthesized for the first time from 3 through a one-pot process involving hydrolysis and decarboxylation, followed by nitration at carbon C-1 without metal catalysis, as confirmed by a NOESY 1D experiment. Moreover, the application of 4 could hold promise for future advancements in medicinal chemistry.