N-selective ‘one pot’ synthesis of highly N-substituted trimethyl chitosan (TMC)

Trimethylated chitosan (TMC) is a well-studied N-quaternary chitosan derivative that is promising for various pharmaceutical applications. The most commonly-used procedure today to obtain these derivatives is based on the reaction with methyl iodide as reagent and N-methylpyrrolidone as solvent. This procedure is not N-selective and significant O-methylation is observed in highly trimethylated material. The O-methylation reduces solubility of the TMC derivatives and therefore limits the use of highly N-quaternised products. Here we report a study of a ‘one-pot’ synthesis procedure based on a new solvent system. We obtained readily-soluble TMC derivatives with a degree of N-quaternisation between 0.81 and 0.88 without any O-methylation. The uniformity of these compounds was confirmed with 1D, 2D NMR and IR spectroscopy.