Synthesis of Phthaloylglycyl Hydrazide Derivatives: Selective Protection of Phthalimide Group from Hydrazinolysis

Abstract

Background: N-phthalimide amino acid hydrazide is a class of compounds that have the potential therapeutic use. In general, hydrazinolysis of N-substituted amino acid(s) ester removes the ester group and yields the corresponding hydrazide. However, in case if N-substitution group is phthalimide, phthalimide group is cleaved and not the ester group. The resulted compound, therefore, is amino acid ester rather than Nphthalimide amino acid hydrazide. The above class of compounds, because of susceptibility of phthalimide group to hydrazinolysis, has previously been synthesized by a lengthy three-step procedure. Objective: N-phthaloylglycyl hydrazide was synthesized by using new efficient, simplified, one step process. Hydrazone derivatives from substituted benzaldehydes, and substituted furaldehyde were also synthesized. Method: N-phthaloylglycyl hydrazide was synthesized from the corresponding carboxylic acid using 1-Ethyl- 3-(3-dimethylaminopropyl)carbodiimide (EDC) as a coupling agent and hydroxybenzotriazole (HOBt) as an activator. Hydrazone derivatives were synthesized by condensation of N-phthaloylglycyl hydrazide with substituted benzaldehyde/substituted furaldehydes. All the compounds were characterized by IR, 1H-NMR, 13CNMR, mass spectroscopy and elemental analysis. Results: The presence of EDC/HOBt resulted in hydrazinolysis of the carboxylic acid group and not the phthalimide group. N-phthaloylglycyl hydrazide was synthesized in good yield. Conclusion: We report the improved process of the synthesis of N-phthaloylglycyl hydrazide. This is the first report where stability of phthaloyl amino acid compound to hydrazine is demonstrated. The reaction may be explored for the reaction schemes where stability of phthalimide group to hydrazinolysis is required.

Synthesis, in silico Study and Antimicrobial Evaluation of New Diesters Derived from Phthaloylglycine

“…9 In the second step, phthaloylglycine (5) was prepared by the condensation reaction of the phthalic anhydride (4) with glycine (3) in glacial acetic acid as solvent. 10 Potassium phthaloylglycinate (6) was obtained by an acid-base reaction in an ethanolic solution of potassium hydroxide. The final diester products (7a-7i) were prepared from the nucleophilic substitution reaction S N 2 of the 2-chloroacetate esters (2a-2i) with potassium phthaloylglycinate (6) using dimethylformamide (DMF) as solvent, catalyzed by 1% sodium iodine in reflux, with yields ranging 38-75% at this stage.…”