Non-cryogenic process for forming glycosides

1. A method of making glycosides using a non-cryogenic process comprising, in a continuous process, the steps of:

(a) lithiating an aromatic reactant having a leaving group using a lithium reagent in a first microreactor at non-cryogenic temperatures to form a lithiated anion species; and

(b) coupling the lithiated anion species with a carbonyl substituted reactant at non-cryogenic temperatures to form a glycoside.

2. The method according to claim 1 , wherein said lithiating step is performed at a temperature of from about −10° C. to about 20° C.

3. The method according to claim 2 , wherein said lithiating step is performed at a temperature of from about −10° C. to about 5° C.

4. The method according to claim 1 , wherein the residence time in said first microreactor is from about 2 seconds to about 3 seconds.

5. The method according to claim 1 , wherein said aromatic reactant is a halide.

6. The method according to claim 1 , where said lithium reagent is selected from the group consisting of n-BuLi and t-BuLi.

7. The method according to claim 1 , wherein said coupling step is performed in a second microreactor under non-cryogenic conditions.

8. The method according to claim 7 , wherein said coupling step is performed at a temperature of from about −20° C. to about 20° C.

9. The method according to claim 8 , wherein said coupling step is performed at a temperature of about −10° C.

10. The method according to claim 7 , wherein the residence time in said second microreactor is from about 2 seconds to about 3 seconds.

11. The method according to claim 7 , wherein a yield of said glycoside is greater than about 70%.

12. A method of making glycosides using a non-cryogenic process comprising, in a continuous process, the steps of:

(a) lithiating an aromatic reactant having a leaving group wing a lithium reagent at non-cryogenic temperatures to form a lithiated anion species; and

(b) coupling the lithiated anion species with a carbonyl substituted reactant according to formula IV

wherein

X 1 is a heteroatom;

R 2 is a substituted or unsubstituted alkyl group; and

PG is a protective group, in a microreactor under non-cryogenic temperatures to form a glycoside.

13. The method according to claim 12 , wherein said coupling step is performed at a temperature of from about −10° C. to about 200° C.

14. The method according to claim 12 , wherein said coupling step is performed at a temperature of from about −10° C. to about 5° C.

15. The method according to claim 12 , wherein the residence time in said microreactor is from about 2 seconds to about 3 seconds.

16. The method according to claim 12 , further comprising the step of:

(c) deprotecting the glycoside.

17. A continuous process for making a glycoside having the general structural formula [I]:

wherein: R 1 is hydrogen, NO 2 , OR 4 , a halogen, or a substituted or non-substituted alkyl , aryl, or heterocycle; R 2 is a substituted or non-substituted alkyl group; R 4 is a substituted or non-substituted alkyl or aryl; X 1 is a heteroatom; and PG is a protective group, the method including the steps of:

(a) reacting an aromatic reactant having general structural formula [II]:

wherein: R 1 is as defined previously and X 2 is a leaving group, in a first microreactor with an organo lithium reagent at non-cryogenic temperatures to form a lithiated anion species having general structural formula [III]:

wherein R 1 is as defined previously, and

(b) coupling the lithiated anion species [III] with a carbonyl substituted compound having general structural formula [IV]:

wherein: R 2 , X 1 and PG are as described previously, at non-cryogenic temperatures to form the compound having general structural formula [I].

18. The method of claim 17 wherein the lithiating step is performed at a temperature of from about −10° C. to 20° C.

19. The method of claim 18 wherein the coupling step is performed in a second microreactor at non-cryogenic temperatures.

20. The method of claim 18 wherein the lithiating step is conducted in a solvent selected from THF/toluene or THF/heptane.

21. The method of claim 18 wherein the coupling step is performed in a second microreactor at non-cryogenic temperatures.

22. The method of claim 21 wherein the coupling step is performed at a temperature of from about −20° C. to 20° C.

23. The method of claim 12 wherein PG is a per(silyl) group.

24. The method of claim 23 wherein PG is Me 3 Si, Et 3 Si or Me 2 SiBu-t.

25. The method of claim 17 wherein PG is a per(silyl) group.

26. The method of claim 25 wherein PG is Me 3 Si, Et 3 Si or Me 2 SiBu-t.