METHODS OF PREPARING 1-(4-((1R,2S,3R)-1,2,3,4-TETRAHYDROXYBUTYL)-1H-IMIDAZOL-2-YL)ETHANONE

1 . A method of preparing 1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone, which comprises:

contacting 2-ethoxyacrylimidate with a weak acid salt of D-glucosamine to provide a first mixture;

contacting the first mixture with a base to provide a second mixture;

adding an aqueous acid to the second mixture to provide a third mixture; and

isolating 1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone from the third mixture.

2 . The method of claim 1 , wherein the weak acid salt of D-glucosamine is D-glucosamine acetate.

3 . The method of claim 2 , wherein the base is an alkaline or alkaline earth metal alkoxide, hydroxide, carbonate, phosphate, or trialkylamine.

4 . The method of claim 3 , wherein the base is methoxide.

5 . The method of claim 1 , wherein the first mixture is maintained at a temperature of greater than 10° C. for at least 0.5 hours.

6 . The method of claim 1 , wherein the second mixture is maintained at a temperature of greater than 5° C. for at least 1 hour.

7 . The method of claim 1 , wherein the third mixture is maintained at a temperature of greater than 20° C. for at least 0.5 hours.

8 . The method of claim 1 , wherein the aqueous acid has a pK a of from 0 to 10.

9 . The method of claim 8 , wherein the aqueous acid is formic, acetic, or trichloroacetic acid.

10 . The method of claim 9 , wherein the aqueous acid is acetic acid.

11 . The method of claim 1 , wherein the 1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone is isolated by filtering a slurry prepared by concentrating, cooling and/or diluting the third mixture with water.

12 . The method of claim 1 , wherein the 1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone is isolated with a yield of greater than about 50 percent.

13 . The method of claim 1 , wherein the 2-ethoxyacrylimidate is prepared by contacting 2-ethoxyacrylonitrile with an alcohol and an alkaline or alkaline earth metal alkoxide to provide a fourth mixture.

14 . The method of claim 13 , wherein the fourth mixture is maintained at a temperature of greater than 0° C. for at least 2 hours.

15 . A method of preparing 1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone, which comprises:

contacting 2-ethoxyacrylimidate with the initial mixture at a temperature of greater than 0° C. to provide a first mixture, wherein the initial mixture comprises D-glucosamine or a salt thereof, a weak acid or a metal salt thereof, and an alcohol;

contacting the first mixture with a base to provide a second mixture;

contacting the second mixture with aqueous acid to provide a third mixture; and

isolating 1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone from the third mixture.