Preparation of Grignard reagents using a fluidized bed

1. A process of preparing a Grignard reagent comprising the steps of creating a fluid of magnesium particulates and a solvent in a reactor; and contacting the magnesium particulates with at least one organohalide to form the Grignard reagent; wherein the fluid comprises the solvent flowing against gravity through a bed of magnesium particulates ranging in size from 10 to 1000 μm when added, with a flow rate ranging from 0.1 to 0.3 cm/s to create a fluidized bed of magnesium particulates in the solvent.

2. The process of claim 1 , wherein the solvent comprises the at least one organohalide.

3. The process according to claim 1 , wherein the solvent is a liquid.

4. The process according to claim 1 , wherein the solvent is a gas.

5. The process according to claim 1 , wherein the particulates range in size from 100 to 500 μm.

6. The process according to claim 5 , wherein the particulates range in size from 200 to 400 μm.

7. The process according to claim 2 , wherein the solvent further comprises at least one ether solvent.

8. The process according to claim 7 , wherein the ether solvent is selected from the group consisting of cyclopentyl methyl ether (CPME), tetrahydrofuran, methyltetrahydrofuran, dioxane and dimethoxyethane.

9. The process according to claim 1 , wherein the solvent flows at a rate higher than the settling velocity of the magnesium particulates in at least a part of the process.

10. The process according to claim 1 , wherein the flow rate is in the range of 0.1 to 0.2 cm/s in a part of the process where magnesium particulates create the fluidized bed.

11. The process according to claim 1 , wherein the magnesium is contained in a reactor column, and wherein a solvent is pumped into the reactor to contact the magnesium, and wherein such contact has a residence time that ranges from 0.1 to 10 minutes.

12. The process according to claim 11 , wherein the residence time is in the range from 0.5 to 3 minutes.

13. The process according to claim 11 , wherein the reactor is maintained at temperatures in the range of 50° C. to 150° C.

14. The process according to claim 13 , wherein the reactor is maintained at a temperature in the range of 75° C. to 125° C.

15. The process according to claim 1 , wherein the process is continuous.

16. A continuous process comprising the steps of: creating a fluid of magnesium particulates and a solvent in a reactor column; contacting the magnesium particulates with at least one organohalide to form the Grignard reagent; wherein the fluid comprises the solvent flowing against gravity through a bed of magnesium particulates that range in size from about 10 μm to about 1,000 μm when added, with a flow rate ranging from about 0.1 to about 0.3 cm/s in at least a part of the process to create a fluidized bed of magnesium particulates in the solvent; and contacting the Grignard reagent with a substrate.

17. The process of claim 16 , wherein the solvent comprises the at least one organohalide.

18. The process according to claim 16 , wherein Grignard reagent flows into contact with the substrate, which is stationary.

19. The process according to claim 18 , wherein the fluid of magnesium particulates and solvent continuously replenish Grignard reagent.

20. The process according to claim 16 , wherein the solvent is a liquid.

21. The process according to claim 16 , wherein the solvent is a gas.

22. The process according to claim 16 , wherein the particulates range in size from about 100 to about 500 μm.

23. The process according to claim 16 , wherein the particulates range in size from about 200 to about 400 μm.

24. The process according to claim 17 , wherein the solvent further comprises at least one ether solvent.

25. The process according to claim 24 , wherein the ether solvent is selected from the group consisting of cyclopentyl methyl ether (CPME), tetrahydrofuran, methyltetrahydrofuran, dioxane and dimethoxyethane.

26. The process according to claim 16 , wherein the flow rate is in the range of about 0.1 to about 0.2 cm/s in at least a part of the process where magnesium particulates create the fluidized bed.

27. The process according to claim 1 , wherein the magnesium is contained in a reactor, and wherein the solvent is introduced into the reactor to contact the magnesium, and wherein such contact has a residence time that is long enough to activate the Grignard reagent.

28. The process according to claim 27 , wherein the residence time ranges from 0.1 to 10 minutes.

29. The process according to claim 27 , wherein the residence time is in the range from 0.5 to 3 minutes.

30. The process according to claim 27 , wherein the reactor is maintained at a temperature in the range of 50° C. to 150° C.

31. The process according to claim 30 , wherein the reactor is maintained at a temperature in the range of 75° C. to 125° C.

32. The process according to claim 1 , wherein a uniform temperature gradient during preparation of a Grignard reagent is maintained by reacting the magnesium particulates with the organohalide in a fluid bed reactor.

33. The process according to claim 16 , wherein a uniform temperature gradient during preparation of a Grignard reagent is maintained by reacting the magnesium particulates with the organohalide in a fluid bed reactor.

34. The process according to claim 4 , wherein the gas is methylchloride.

35. The process according to claim 16 , wherein the Grignard reagent reacts with a substrate to produce an active drug product.

36. The process of claim 35 , wherein the reaction occurs in a microreactor.

37. The process of claim 36 , wherein the microreactor may be heated or cooled to yield the active drug product.

38. The process according to claim 16 , wherein the magnesium is contained in a reactor, and wherein the solvent is introduced into the reactor to contact the magnesium, and wherein such contact has a residence time that is long enough to activate the Grignard reagent.