Selective O‑Alkylation of 2,2′-Bis(hydroxymethyl)propionic Acid to Synthesize Biodegradable Polymers for Drug Delivery Applications

• Published in: ACS applied polymer materials 2020-08, Vol.2 (8), p.3465-3473
• Main Authors: Santra, Santimukul, Shaw, Zachary, Narayanam, Raghunath, Jain, Vedant, Banerjee, Tuhina
• Format: Article
• Language: English
• ISSN: 2637-6105; 2637-6105
• DOI: 10.1021/acsapm.0c00509

A facile synthetic approach to the selective mono- and di-O-alkylation of a β,β-disubstituted hydroxy compound has been demonstrated and applied to the field of polymer chemistry and drug delivery. 2,2′-Bis­(hydroxymethyl) propionic acid (bis-MPA) is a β,β-disubstituted hydroxy compound with one carboxylic acid group (AB2 system); therefore, it is a very important starting material in the synthesis of functional aliphatic macromolecules. The etherification (O-alkylation) of bis-MPA was successful with different alkyl functionalities using this facile approach, where 1,4-diazabicyclo [2.2.2] octane was used as a catalyst. This method successfully prevented the reported internal cyclization of bis-MPA, allowing for selective functionalization. Mono- and di-O-alkylated bis-MPA were synthesized selectively in high yields by controlling the equivalent ratio of the reactants and reaction time. Nonuniform bifunctional O-alkylated bis-MPA with different alkyl halides were prepared using the same reaction conditions and have been used for the synthesis of functional polyester polymers. Postsurface functionalization by the means of bromination was demonstrated on the allyl-functionalized linear polyester. All the compounds were characterized by 1H and 13C Nuclear Magnetic Resonance, Fourier transform infrared, thermogravimetric analysis, differential scanning calorimetry, size exclusion chromatography, and electrospray and matrix-assisted laser desorption/ionization–time of flight mass spectroscopic techniques. The synthesized functional polyester polymer was able to formulate stable polymeric nanoparticles using the solvent diffusion method and encapsulate therapeutic drug doxorubicin with higher encapsulation efficiency (EEDoxo = 71%). This facile synthetic approach of O-alkylation provides direction for the synthesis of bis-MPA-based functional linear and dendritic macromolecules for drug delivery and other biomedical applications.