Efficient mechanochemical synthesis of regioselective persubstituted cyclodextrins

Abstract

A number of per-6-substituted cyclodextrin derivative syntheses have been effectively carried out in a planetary ball mill under solvent-free conditions. The preparation of Bridion^® and important per-6-amino/thiocyclodextrin intermediates without polar aprotic solvents, a source of byproducts and persistent impurities, could be performed. Isolation and purification processes could also be simplified. Considerably lower alkylthiol/halide ratio were necessary to reach the complete reaction in comparison with thiourea or azide reactions. While the presented mechanochemical syntheses were carried out on the millimolar scale, they are easily scalable.

Keywords: green chemistry; nucleophilic substitution; planetary ball mill; siRNA delivery intermediate; sugammadex.

Scheme 1

Synthesis of per-6-derivatized CDs. Ball milling conditions: 1500 steel balls of 1 mm diameter and 50 steel balls of 5 mm diameter, sun wheel speed 650 min⁻¹, 2 h grinding.