Active esters of N-substituted piperazine acetic acids, including isotopically enriched versions thereof

• US 8,569,304 B2
• Filed: 03/05/2009
• Issued: 10/29/2013
• Est. Priority Date: 01/05/2004
• Status: Active Grant

• Current Assignee: DH Technologies Development Pte. Ltd. (Danaher Corporation)
• Original Assignee: DH Technologies Development Pte. Ltd. (Danaher Corporation)
• Inventors: Dey, Subhakar, Pappin, Darryl J. C., Purkayastha, Subhasish, Pillai, Sasi, Coull, James M.
• Primary Examiner(s): Leeser, Erich A
• Application Number:
  US12/398,920
• Publication Number:
  US 20090227791A1
• Time in Patent Office: 1,699 Days
• Field of Search: 544/358, 544/372
• US Class Current: 514/252.12
• CPC Class Codes: C07D 207/46 with hetero atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 241/08 with oxygen atoms directly attached to ring carbon atoms
• CPC Class Codes: C07D 253/08 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 295/03 with the ring nitrogen atoms directly attached to acyclic carbon atoms
• CPC Class Codes: C07D 295/15 to an acyclic saturated chain

Abstract

In some embodiments, this invention pertains to active esters of N-substituted piperazine acetic acid, including isotopically enriched versions thereof. In some embodiments, this invention pertains to methods for the preparation of active esters of N-substituted piperazine acetic acid, including isotopically enriched versions thereof.

Claims

1. An N-substituted piperazine acetic acid active ester compound of the formula:

2. The compound of claim 1, wherein the N-substituted piperazine acetic acid active ester is isotopically enriched with three or more heavy atom isotopes.

3. The compound of claim 1, wherein LG is:

4. The compound of claim 1, wherein LG is:

5. The compound of claim 1, wherein LG is N-hydroxysuccinimide.

6. The compound of claim 1, wherein each Z is independently hydrogen, deuterium, fluorine, chlorine, bromine or iodine.

7. The compound of claim 1, wherein each Z is independently hydrogen, methyl or methoxy.

8. The compound of claim 1, wherein Y is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

9. The compound of claim 1, wherein X is ¹⁶O or ¹⁸O.

10. The compound of claim 1, wherein each nitrogen atom of the piperazine ring is independently ¹⁴N or ¹⁵N.

11. The compound of claim 1 of the formula:

12. The compound of claim 1, of the formula:

13. The compound of claim 12, wherein the compound is a mono-TFA salt, a mono-HCl salt, a bis-TFA salt or a bis-HCl salt.

14. The compound of claim 12, wherein each incorporated heavy atom isotope is present in at least 80 percent isotopic purity.

15. The compound of claim 12, wherein each incorporated heavy atom isotope is present in at least 93 percent or isotopic purity.

16. The compound of claim 12, wherein each incorporated heavy atom isotope is present in at least 96 percent or isotopic purity.

17. The compound of claim 12, wherein LG is N-hydroxysuccinimide.

18. The compound of claim 12, wherein LG is:

19. The compound of claim 12, wherein LG is:

20. The compound of claim 1, wherein the N-substituted piperazine acetic acid active ester is a mono-TFA salt, a mono-HCl salt, a bis-HCl salt or a bis-TFA salt.

21. The compound of claim 1, wherein each incorporated heavy atom isotope is present in at least 80 percent isotopic purity.

22. The compound of claim 1, wherein each incorporated heavy atom isotope is present in at least 93 percent isotopic purity.

23. The compound of claim 1, wherein each incorporated heavy atom isotope is present in at least 96 percent isotopic purity.

40. The method of claim 22, wherein the product of the reaction is an N-methyl piperazine acetic acid active ester of the formula:

41. The method of claim 40, wherein each incorporated heavy atom isotope is present in at least 80 percent isotopic purity.

42. The method of claim 40, wherein each incorporated heavy atom isotope is present in at least 93 percent isotopic purity.

43. The method of claim 40, wherein each incorporated heavy atom isotope is present in at least 96 percent isotopic purity.

44. The method of claim 40, wherein LG is:

45. The method of claim 40, wherein LG is:

46. The method of claim 40, wherein LG is N-hydroxysuccinimide.

47. The method of claim 40, wherein the N-substituted piperazine acetic acid active ester is a mono-TFA salt, a mono-HCl salt, a bis-HCl salt or a bis-TFA salt.

24. A method comprising:

reacting an N-substituted piperazine acetic acid compound of the formula;

25. The method of claim 24, wherein the N-substituted piperazine acetic acid active ester is isotopically enriched with one or more heavy atom isotopes.

26. The method of claim 24, wherein the N-substituted piperazine acetic acid active ester is isotopically enriched with three or more heavy atom isotopes.

27. The method of claim 24, wherein the acid is HCl or TFA.

28. The method of claim 25, wherein each incorporated heavy atom isotope is present in at least 80 percent isotopic purity.

29. The method of claim 24, wherein each incorporated heavy atom isotope is present in at least 93 percent isotopic purity.

30. The method of claim 25, wherein each incorporated heavy atom isotope is present in at least 93 percent isotopic purity.

31. The method of claim 24, wherein LG is:

32. The method of claim 24, wherein LG is:

33. The method of claim 24, wherein LG is N-hydroxysuccinimide.

34. The method of claim 24, wherein each Z is independently hydrogen, deuterium, fluorine, chlorine, bromine or iodine.

35. The method of claim 24, wherein each Z is independently hydrogen, methyl or methoxy.

36. The method of claim 24, wherein Y is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

37. The method of claim 24, wherein X is ¹⁶O or ¹⁸O.

38. The method of claim 24, wherein each nitrogen atom of the piperazine ring is independently ¹⁴N or ¹⁵N.

39. The method of claim 24, wherein the compound to be reacted has the formula:

48. The method of claim 24, wherein the N-substituted piperazine acetic acid active ester is a mono-TFA salt, a mono-HCl salt, a bis-HCl salt or a bis-TFA salt.