Process for the preparation of 2,4-dideoxyhexoses and 2,4,6-trideoxyhexoses
View Patent ↗The invention relates to a process for the preparation of a 2,4-dideoxyhexose or a 2,4,6-trideoxyhexose from a substituted or unsubstituted carbonyl compound with at least 2 carbon atoms and at least one α-hydrogen atom and a substituted or unsubstituted aldehyde in the presence of an aldolase and water, the reaction between the substituted or unsubstituted carbonyl compound with at least 2 carbon atoms and at least one α-hydrogen atom and the substituted or unsubstituted aldehyde being carried out at a carbonyl concentration of at most 6 moles/l of reaction mixture and the final concentration of the 2,4-dideoxyhexose or the 2,4,6-trideoxyhexose being at least 2 mass % of the reaction mixture. The invention also relates to the use of a 2,4-dideoxyhexose or a 2,4,6-trideoxyhexose obtained by means of a process according to the invention in the preparation of a medicine, particularly in the preparation of a statine.
1. A process of making 4-hydroxy-tetrahydropyran-2-one comprising converting 2,4-dideoxyhexose or 2,4,6-trideoxyhexose into the corresponding 4-hydroxy-tetrahydropyran-2-one wherein the 2,4-dideoxyhexose and 2,4,6-trideoxyhexose is obtained from the process comprising
providing a reaction mixture of a substituted or unsubstituted carbonyl compound containing at least 2 carbon atoms and at least one α-hydrogen atom and
a substituted or unsubstituted aldehyde
in the presence of an aldolase and water, wherein the carbonyl concentration is at most 6 moles/liter of the reaction mixture to form 2,4-dideoxyhexose or 2,4,6-trideoxyhexose, and
wherein the final concentration of the 2,4-dideoxyhexose or the 2,4,6-trideoxyhexose is at least 2 mass % of the reaction mixture, and
wherein the substituted or unsubstituted aldehyde is of the formula HC(O)CH 2 X, where X represents a leaving group.
2. The process of claim 1 , which further comprises converting the 4-hydroxy-tetrahydropyran-2-one to a 2-(1,3-dioxane-4-yl)acetic acid derivative.
3. The process of claim 2 , which further comprises converting the 2-(1,3-dioxane-4-yl)acetic acid derivative to the corresponding 2-(6-hydroxymethyl-1,3-dioxane-4-yl)acetic acid derivative.
4. The process of claim 2 , in which the 2-(1,3-dioxane-4-yl)acetic acid derivative is the t-butylester of the 2-(1,3-dioxane-4-yl) acetic acid.
5. The process of claim 1 , wherein the substituted or unsubstituted carbonyl compound is acetaldehyde.
6. The process of claim 1 , wherein the leaving group is a halogen, a tosylate group, or a mesylate group.
7. The process of claim 1 , wherein the final concentration of the 2,4-dideoxyhexose or the 2,4,6-trideoxyhexose is 5 to 50 mass % of the reaction mixture.
8. The process of claim 7 , wherein the final concentration of the 2,4-dideoxyhexose or the 2,4,6-trideoxyhexose is 10 to 35 mass % of the reaction mixture.
9. The process of claim 1 , wherein the carbonyl concentration in the reaction mixture is 0.6 to 4 moles/liter of the reaction mixture.
10. The process of claim 1 , wherein the reaction mixture comprises at least 0.1 mole/liter of the substituted or unsubstituted aldehyde.
11. The process of claim 1 , wherein the substituted or unsubstituted carbonyl compound containing at least 2 carbon atoms and at least one α-hydrogen atom and/or the substituted or unsubstituted aldehyde are added to the reaction mixture in at least two portions.
12. The process of claim 1 , wherein the substituted or unsubstituted carbonyl compound containing at least 2 carbon atoms and at least one α-hydrogen atom and/or the substituted or unsubstituted aldehyde are metered to the reaction mixture over time.
13. The process of claim 1 , wherein the molar ratio between the total quantity of substituted or unsubstituted carbonyl compound containing at least 2 carbon atoms and at least one α-hydrogen atom that is added and the total quantity of substituted or unsubstituted aldehyde that is added lies between 1.5:1 and 4:1.
14. The process of claim 1 , wherein the aldolase comprises a 2-deoxyribose-5-phosphate aldolase.
15. The process of claim 14 , wherein the 2-deoxyribose-5-phosphate aldolase is derived from Escherichia coli.
16. A process of making 4-hydroxy-tetrahydropyran-2-one comprising
providing a reaction mixture of a substituted or unsubstituted carbonyl compound containing at least 2 carbon atoms and at least one α-hydrogen atom and
a substituted or unsubstituted aldehyde
in the presence of an aldolase and water, wherein the carbonyl concentration is at most 6 moles/liter of the reaction mixture to form 2,4-dideoxyhexose or 2,4,6-trideoxyhexose, and
wherein the final concentration of the 2,4-dideoxyhexose or the 2,4, 6-trideoxyhexose is at least 2 mass % of the reaction mixture;
wherein the substituted or unsubstituted aldehyde is of the formula HC(O)CH 2 X, where X represents a leaving group which is a halogen, a tosylate group, or a mesylate group; and
converting the 2,4-dideoxyhexose or 2,4,6-trideoxyhexose into the corresponding 4-hydroxy-tetrahydropyran-2-one.
17. The process of claim 16 , which further comprises converting the 4-hydroxy-tetrahydropyran-2-one to a 2-(1,3-dioxane-4-yl)acetic acid derivative.
18. The process of claim 17 , which further comprises converting the 2-(1,3-dioxane-4-yl)acetic acid derivative to the corresponding 2-(6-hydroxymethyl-1,3-dioxane-4-yl)acetic acid derivative.
19. The process of claim 17 , in which the 2-(1,3-dioxane-4-yl)acetic acid derivative is the t-butylester of the 2-(1,3-dioxane-4-yl)acetic acid.
20. The process of claim 16 , wherein the substituted or unsubstituted carbonyl compound is acetaldehyde.
21. The process of claim 16 , wherein the leaving group is a halogen, a tosylate group, or a mesylate group.
22. The process of claim 16 , wherein the final concentration of the 2,4-dideoxyhexose or the 2,4,6-trideoxyhexose is 5 to 50 mass % of the reaction mixture.
23. The process of claim 22 , wherein the final concentration of the 2,4-dideoxyhexose or the 2,4,6-trideoxyhexose is 10 to 35 mass % of the reaction mixture.
24. The process of claim 16 , wherein the carbonyl concentration in the reaction mixture is 0.6 to 4 moles/liter of the reaction mixture.
25. The process of claim 16 , wherein the reaction mixture comprises at least 0.1 mole/liter of the substituted or unsubstituted aldehyde.
26. The process of claim 16 , wherein the substituted or unsubstituted carbonyl compound containing at least 2 carbon atoms and at least one α-hydrogen atom and/or the substituted or unsubstituted aldehyde are added to the reaction mixture in at least two portions.
27. The process of claim 16 , wherein the substituted or unsubstituted carbonyl compound containing at least 2 carbon atoms and at least one α-hydrogen atom and/or the substituted or unsubstituted aldehyde are metered to the reaction mixture over time.
28. The process of claim 16 , wherein the molar ratio between the total quantity of substituted or unsubstituted carbonyl compound containing at least 2 carbon atoms and at least one α-hydrogen atom that is added and the total quantity of substituted or unsubstituted aldehyde that is added lies between 1.5:1 and 4:1.
29. The process of claim 16 , wherein the aldolase comprises a 2-deoxyribose-5-phosphate aldolase.
30. The process of claim 29 , wherein the 2-deoxyribose-5-phosphate aldolase is derived from Escherichia coli .