Method of synthesis of substituted hexitols such as dianhydrogalactitol

摘要

The present invention provides an efficient method of synthesizing and purifying dianhydrohexitols such as dianhydrogalactitol. In general, as applied to dianhydrogalactitol, the method comprises: (1) reacting dulcitol with a concentrated solution of hydrobromic acid at a temperature of about 80° C. to produce dibromogalactitol; (2) reacting the dibromogalactitol with potassium carbonate in t-butanol to produce dianhydrogalactitol; and (3) purifying the dianhydrogalactitol using a slurry of ethyl ether to produce purified dianhydrogalactitol. Another method produces dianhydrogalactitol from dulcitol; this method comprises: (1) reacting dulcitol with a reactant to convert the 1,6-hydroxy groups of dulcitol to an effective leaving group to generate an intermediate; and (2) reacting the intermediate with an inorganic weak base to produce dianhydrogalactitol through an intramolecular SN2 reaction. Other methods for the synthesis of dianhydrogalactitol from dulcitol are described.

主权项

1. A process for synthesizing and recrystallizing a dianhydrohexitol comprising the steps of:
(a) converting dulcitol to dibromodulcitol by reaction of dulcitol with hydrobromic acid for from about 12 hours to about 36 hours at an elevated temperature, wherein the hydrobromic acid is at a concentration of from about 30% to about 35%, and wherein the elevated temperature is from about 35° C. to about 45° C.; (b) precipitating the product of step (a) with water; (c) washing the precipitated product of step (b) with an aliphatic ether; (d) drying the washed product of step (c) under nitrogen and vacuum; (e) converting the dibromodulcitol from step (d) to dianhydrogalactitol by reacting with a base selected from the group consisting of potassium carbonate, N,N-diisopropylethylamine (DIPEA), triethanolamine (TEA), and 1,8-diazabicycloundec-7-ene (DBU) in a polar aprotic solvent at a temperature of from about 35° C. to 45° C. for from about 16 hours to about 20 hours; (f) washing the product of step (e) with tetrahydrofuran and then with water; and (g) recrystallizing the product of step (f) from an aliphatic ketone to produce dianhydrogalactitol, and wherein the dianhydrogalactitol resulting from step (g) of the process is at a purity of at least 99.80%.