MIGLUSTAT N-BUTYL-1,5-DIDEOXY-1,5-IMINO-D-GLUCITOL Russian patent published in 2021 - IPC C07D211/46 

FIELD: medicine; pharmaceuticals.

SUBSTANCE: invention relates to pharmaceutics, specifically to production of a new form of miglustat of N-butyl-1,5-dideoxy-1,5-imino-D-glucitol, characterized by (i) on powder X-ray diffraction pattern corresponding to figure 1, two characteristic amorphous halos with diffraction angles (2θ) 5 degrees and 17 degrees, (ii) the IR spectrum corresponding to figure 2. Method of producing is carried out through direct alkylation, during which dimethylformamide and (2R,3R,4R,5S)-2-(hydroxymethyl) piperidine-3,4,5-triol are loaded into the reactor, after which potassium carbonate and 1-butylbromide are successively added to the suspension, then the reaction mass is stirred, cooled and filtered. Precipitate on the filter is washed with dimethylformamide, after which the mother and washing solutions are combined, and then dimethylformamide is removed. Obtained mass is heated in a mixture of methanol-ethyl acetate until formation of a formed precipitate of inorganic salts, then the suspension is filtered in a heated state, after which the mother solution is held at temperature within 0–5 °C and filtering the precipitate. Then the mother solution is passed through the layer of ion-exchange resin KU-2-8 h (H-form), the end product is washed off with the resin with methanolic solution of aqueous ammonia and a precipitate is obtained, after recrystallisation from methanol-ethyl acetate mixture, obtained precipitate is treated with mixture of distilled water and propanol-2 at temperature within 40–50 °C, after which cooling to temperature within 20–25 °C and left to settle for a day. Top layer is decanted, and from bottom layer after evaporation and drying during 24 hours at temperature within 63–67 °C and low pressure produce amorphous miglustat powder. Also, amorphous form of N-butyl-1,5-dideoxy-1,5-imino-D-glucitol is obtained with said characteristics through reductive amination of (2R,3R,4R,5S)-2-(hydroxymethyl) piperidine-3,4,5-triol, which is carried out in a mixture of methanol and acetic acid in the presence of sodium cyanoborohydride, the mixture of reagents is mixed, to extract the target product, the reaction mass is added to a mixture of ion-exchange resin KU-2-8 h and distilled water. Obtained suspension is stirred until the hydrogen evolution is completed, after which the resin with the target product sorbed thereon is filtered out. Then the target product is washed off resin with 5 % aqueous ammonia solution, then the solution is evaporated in a vacuum, then propanol-2 is added to the residue and evaporation is repeated. Obtained syrupy residue is treated with a mixture of distilled water and propanol-2 at temperature within range of 40–50 °C, after which cooling to temperature within 20–25 °C and left to settle for a day. Then upper layer is decanted, and from lower one after evaporation and drying during 24 hours at temperature within 63–67°C and low pressure produce amorphous miglustat powder.

EFFECT: technical result is obtaining amorphous form of miglustat, having less electricity.

2 cl, 2 tbl, 2 dwg, 6 ex