Granted Patent B2

US 9,434,680 · App. 12/110,627 · Granted Sep 6, 2016

Abstract

Claims (54)

1. A method for the synthesis of a 9-aminomethyl minocycline compound of the following structural formula:

the method comprising:

a) contacting minocycline with a N-hydroxymethyl pthalimide compound (Pht) in the presence of a water scavenger and an acid under a reaction temperature of 20-35° C. to form a first 9-aminomethyl minocycline intermediate of the following structural formula:

b) reacting said first 9-aminomethyl minocycline intermediate formed in step a) with methylamine in the presence of ether and alkyl alcohol to form a second 9-aminomethyl minocycline intermediate of the following structural formula:

 and

c) treating said second 9-aminomethyl minocycline intermediate formed in step b) through hydrogenation to form said 9-aminomethyl minocycline compound.

2. The method of claim 1 , wherein said water scavenger is an acid chloride or an acid anhydride.

3. The method of claim 2 , wherein said acid anhydride is methylsulfonic anhydride.

4. The method of claim 1 , wherein said acid is triflic acid or methane sulfonic acid.

5. The method of claim 1 , wherein said first 9-aminomethyl minocycline intermediate is no more than 10% tris-alkylated.

6. The method of claim 1 , wherein said first 9-aminomethyl minocycline intermediate is dissolved in acetone before step b).

7. The method of claim 1 , wherein step b) comprises an inert atmosphere.

8. The method of claim 1 , further comprising purifying said second 9-aminomethyl minocycline intermediate by forming a hydrochloride salt of said second 9-aminomethyl minocycline intermediate.

9. The method of claim 8 , wherein said hydrochloride salt is formed in an alkyl alcohol followed by precipitation with an alkyl ether.

10. The method of claim 1 , wherein step c) comprises a Pd/C or Pd/C/S catalyst.

11. The method of claim 1 , wherein step c) comprises methanol and an aldehyde.

12. The method of claim 1 , wherein step c) comprises hydrogen gas.

13. The method of claim 1 , further comprising reacting said 9-aminomethyl minocycline compound with an aldehyde to form a substituted 9-aminomethyl minocycline compound of the formula

14. The method of claim 13 , wherein said reaction comprises a Pd/C or Pd/C/S catalyst.

15. The method of claim 13 , wherein said reaction comprises methanol and an aldehyde.

16. The method of claim 13 , wherein said reaction comprises hydrogen gas.

17. The method of claim 13 , wherein said substituted 9-aminomethyl minocycline compound is formed substantially free of over hydrogenated impurities.

18. The method of claim 13 , wherein said substituted 9-aminomethyl minocycline compound comprises less than 10% β isomer.

19. The method of claim 18 , wherein said substituted 9-aminomethyl minocycline compound comprises less than 5% β isomer.

20. The method of claim 4 , wherein said acid is triflic acid.

21. The method of claim 1 , wherein said ether is an alkyl ether or a cyclic ether.

22. The method of claim 1 , wherein step a) comprises a reaction time of 1-2 hours.

23. The method of claim 1 , wherein step a) is carried out under a reaction temperature of 20-25° C.

24. A method for the synthesis of a 9-aminomethyl minocycline compound of the following structural formula:

the method comprising:

a) contacting minocycline with a N-hydroxymethyl pthalimide compound (Pht) in the presence of an acid under a reaction temperature of 20-35° C. to form a first 9-aminomethyl minocycline intermediate of the following structural formula:

b) reacting said first 9-aminomethyl minocycline intermediate formed in step a) with methylamine in the presence of ether and alkyl alcohol to form a second 9-aminomethyl minocycline intermediate of the following structural formula:

 and

c) treating said second 9-aminomethyl minocycline intermediate formed in step b) through hydrogenation to form said 9-aminomethyl minocycline compound.

25. The method of claim 24 , wherein said acid is triflic acid or methane sulfonic acid.

26. The method of claim 24 , wherein said first 9-aminomethyl minocycline intermediate is no more than 10% tris-alkylated.

27. The method of claim 24 , wherein said first 9-aminomethyl minocycline intermediate is dissolved in acetone before step b).

28. The method of claim 24 , wherein step b) comprises an inert atmosphere.

29. The method of claim 24 , further comprising purifying said second 9-aminomethyl minocycline intermediate by forming a hydrochloride salt of said second 9-aminomethyl minocycline intermediate.

30. The method of claim 29 , wherein said hydrochloride salt is formed in an alkyl alcohol followed by precipitation with an alkyl ether.

31. The method of claim 24 , wherein step c) comprises a Pd/C or Pd/C/S catalyst.

32. The method of claim 24 , wherein step c) comprises methanol and an aldehyde.

33. The method of claim 24 , wherein step c) comprises hydrogen gas.

34. The method of claim 24 , further comprising reacting said 9-aminomethyl minocycline compound with an aldehyde to form a substituted 9-aminomethyl minocycline compound of the formula

35. The method of claim 34 , wherein said reaction comprises a Pd/C or Pd/C/S catalyst.

36. The method of claim 34 , wherein said reaction comprises methanol and an aldehyde.

37. The method of claim 34 , wherein said reaction comprises hydrogen gas.

38. The method of claim 34 , wherein said substituted 9-aminomethyl minocycline compound is formed substantially free of over hydrogenated impurities.

39. The method of claim 34 , wherein said substituted 9-aminomethyl minocycline compound comprises less than 10% β isomer.

40. The method of claim 39 , wherein said substituted 9-aminomethyl minocycline compound comprises less than 5% β isomer.

41. The method of claim 25 , wherein said acid is triflic acid.

42. The method of claim 24 , wherein said ether is an alkyl ether or a cyclic ether.

43. The method of claim 24 , wherein step a) comprises a reaction time of 1-2 hours.

44. The method of claim 24 , wherein step a) is carried out under a reaction temperature of 20-25° C.

Assignments (12)