Granted Patent B2

US 7,812,174 · App. 12/101,410 · Granted Oct 12, 2010

Abstract

Claims (63)

1. A method of preparing a compound of formula I:

which comprises:

contacting a compound of formula II:

with a compound of formula III:

under conditions sufficient for the formation of a mixture of E and Z isomers of a compound of formula I; and

contacting the mixture of E and Z isomers with a strong acid;

wherein: X is optionally substituted alkyl; R 1 is optionally substituted alkyl; R 2 is hydrogen, halogen, nitrile, or optionally substituted alkyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heterocycle, alkylheterocycle, or heterocyclealkyl; and R 3 is hydrogen or optionally substituted alkyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heterocycle, alkylheterocycle, or heterocyclealkyl.

2. The method of claim 1 , wherein X is alkyl optionally substituted with one or more hydroxyl, acetate or halogen moieties.

3. The method of claim 1 , wherein R 2 is hydrogen.

4. The method of claim 1 , wherein R 3 is hydrogen.

5. The method of claim 1 , wherein the compound of formula I is of formula I(a):

wherein:

R 4 is OR 4A , OC(O)R 4A , N(R 4B ) 2 , NHC(O)R 4B , hydrogen, or halogen;

R 5 is OR 5A , OC(O)R 5A , N(R 5B ) 2 , NHC(O)R 5B , hydrogen, or halogen;

R 6 is OR 6A , OC(O)R 6A , N(R 6B ) 2 , NHC(O)R 6B , hydrogen, or halogen;

R 7 is alkyl, CH 2 OR 7A , CH 2 OC(O)R 7A , CH 2 N(R 7B ) 2 , CH 2 NHC(O)R 7B , hydrogen, or halogen; and

each of R 4A , R 5A , R 6A , R 5A , R 4B , R 5B , R 6B , and R 7B is independently hydrogen or optionally substituted alkyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heterocycle, alkylheterocycle, or heterocyclealkyl.

6. The method of claim 5 , wherein the compound of formula I(a) is a compound of formula I(b):

7. The method of claim 5 , wherein one or more of R 4 , R 5 , and R 6 is hydroxy or halogen.

8. The method of claim 5 , wherein all of R 4 , R 5 , and R 6 are hydroxyl or acetate.

9. The method of claim 1 , wherein the strong acid is hydroiodic, hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, alkanesulfonic, or arenesulfonic acid.

10. A method of increasing the E:Z isomer ratio in a mixture of E and Z isomers of formula I:

which comprises:

contacting a solution comprising a first mixture of E and Z isomers of formula I with a strong acid under conditions sufficient to provide a second mixture of E and Z isomers of formula I, wherein:

the E:Z isomer ratio of the first mixture is less than the E:Z isomer ratio of the second mixture;

X is optionally substituted alkyl;

R 1 is optionally substituted alkyl;

R 2 is hydrogen, halogen, nitrile, or optionally substituted alkyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heterocycle, alkylheterocycle, or heterocyclealkyl; and

R 3 is hydrogen or optionally substituted alkyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heterocycle, alkylheterocycle, or heterocyclealkyl.

11. The method of claim 10 , wherein the compound of formula I is prepared by contacting a compound of formula II:

with a compound of formula III:

under conditions sufficient for the formation of the compound of formula I.

12. The method of claim 10 , wherein X is alkyl optionally substituted with one or more hydroxyl, acetate or halogen moieties.

13. The method of claim 10 , wherein R 2 is hydrogen.

14. The method of claim 10 , wherein R 3 is hydrogen.

15. The method of claim 10 , wherein the compound of formula I is of formula II(a):

wherein:

R 4 is OR 4A , OC(O)R 4A , N(R 4B ) 2 , NHC(O)R 4B , hydrogen, or halogen;

R 5 is OR 5A , OC(O)R 5A , N(R 5B ) 2 , NHC(O)R 5B , hydrogen, or halogen;

R 6 is OR 6A , OC(O)R 6A , N(R 6B ) 2 , NHC(O)R 6B , hydrogen, or halogen;

R 7 is alkyl, CH 2 OR 7A , CH 2 OC(O)R 7A , CH 2 N(R 7B ) 2 , CH 2 NHC(O)R 7B , hydrogen, or halogen; and

each of R 4A , R 5A , R 6A , R 7A , R 4B , R 5B , R 6B , and R 7B is independently hydrogen or optionally substituted alkyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heterocycle, alkylheterocycle, or heterocyclealkyl.

16. The method of claim 15 , wherein the compound of formula I(a) is a compound of formula I(b):

17. The method of claim 15 , wherein one or more of R 4 , R 5 , R 6 , is hydroxy or halogen.

18. The method of claim 15 , wherein all of R 4 , R 5 , R 6 , are hydroxyl or acetate.

19. The method of claim 10 , wherein the solution comprises an alcohol.

20. The method of claim 19 , wherein the alcohol is methanol, ethanol, propanol or isopropanol.

21. The method of claim 10 , wherein the strong acid is hydroiodic, hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, alkanesulfonic, or arenesulfonic acid.

22. A method of increasing the E:Z isomer ratio in a mixture of (E)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)-ethanone oxime and (Z)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)-ethanone oxime, which comprises:

contacting a solution comprising a first mixture of (E)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)-ethanone oxime and (Z)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)-ethanone oxime, with a strong acid under conditions sufficient to provide a second mixture of (E)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)-ethanone oxime and (E)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)-ethanone oxime;

wherein the E:Z isomer ratio of the first mixture is less than the E:Z isomer ratio of the second mixture.

23. The method of claim 22 , wherein the first mixture is prepared by contacting 1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone with hydroxylamine under conditions sufficient for the formation of 1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)-ethanone oxime.

24. The method of claim 23 , wherein the 1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone is prepared by contacting 1-amino-1-deoxy-D-fructose with 2-ethoxyacrylonitrile under conditions sufficient for the formation of 1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone.

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

adding a first portion of sodium methoxide to a solution comprising 2-ethoxyacrylonitrile to provide a first mixture;

contacting the first mixture with 1-amino-1-deoxy-D-fructose to provide a second mixture;

adding a second portion of sodium methoxide to the second mixture to provide a third mixture;

adding acetic acid to the third mixture to provide a fourth mixture; and

mixing the fourth mixture for a time and at a temperature sufficient for the formation of 1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone;

wherein the second mixture is maintained at a temperature of greater than about 5° C.

26. The method of claim 25 , wherein the first mixture is maintained at a temperature of greater than about 5° C.

27. The method of claim 25 , wherein the first portion of sodium methoxide is added as a solution of greater than about 15 weight percent sodium methoxide in methanol.

28. The method of claim 25 , wherein the second portion of sodium methoxide is added as a solution of greater than about 15 weight percent sodium methoxide in methanol.

Assignments (6)