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

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

or a salt thereof, wherein;

LG is the leaving group of an active ester;

X is O or S;

Y is a straight chain or branched C1-C6 alkyl group or a straight chain or branched C1-C6 alkyl ether group wherein the carbon atoms of the alkyl group or alkyl ether group each independently comprise linked hydrogen, deuterium or fluorine atoms;

each Z is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, an amino acid side chain, a straight chain or branched C1-C6 alkyl group that may optionally contain a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups each independently comprise linked hydrogen, deuterium or fluorine atoms, a straight chain or branched C1-C6 alkyl ether group that may optionally contain a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups each independently comprise linked hydrogen, deuterium or fluorine atoms or a straight chain or branched C1-C6 alkoxy group that may optionally contain a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups each independently comprise linked hydrogen, deuterium or fluorine atoms; and

the N-substituted piperazine acetic acid active ester is isotopically enriched with one or more heavy atom isotopes.

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:

and wherein X is O or S.

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

and wherein X is O or S.

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 16 O or 18 O.

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

11. The compound of claim 1 of the formula:

wherein

each C* is independently 12 C or 13 C;

LG is the leaving group of an active ester;

X is O or S;

Y is a straight chain or branched C1-C6 alkyl group or a straight chain or branched C1-C6 alkyl ether group wherein the carbon atoms of the alkyl group or alkyl ether group each independently comprise linked hydrogen, deuterium or fluorine atoms;

each Z is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, an amino acid side chain, a straight chain or branched C1-C6 alkyl group that may optionally contain a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups each independently comprise linked hydrogen, deuterium or fluorine atoms, a straight chain or branched C1-C6 alkyl ether group that may optionally contain a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups each independently comprise linked hydrogen, deuterium or fluorine atoms or a straight chain or branched C1-C6 alkoxy group that may optionally contain a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups each independently comprise linked hydrogen, deuterium or fluorine atoms.

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

wherein, LG is the leaving group of an active ester.

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:

and wherein X is O or S.

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

and wherein X is O or S.

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.

24. A method comprising:

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

or a salt thereof, with:

1) a compound of the formula:

and, if the piperazine compound is a salt,

2) optionally with a base strong enough to deprotonate the basic nitrogen atoms of the piperazine ring; to thereby form an N-substituted piperazine acetic acid active ester of the formula:

or a salt thereof wherein;

Hal is a fluorine, chlorine, bromine or iodine;

LG is the leaving group of an active ester;

X is O or S;

Y is a straight chain or branched C1-C6 alkyl group or a straight chain or branched C1-C6 alkyl ether group wherein the carbon atoms of the alkyl group or alkyl ether group each independently comprise linked hydrogen, deuterium or fluorine atoms;

each Z is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, an amino acid side chain, a straight chain or branched C1-C6 alkyl group that may optionally contain a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups each independently comprise linked hydrogen, deuterium or fluorine atoms, a straight chain or branched C1-C6 alkyl ether group that may optionally contain a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups each independently comprise linked hydrogen, deuterium or fluorine atoms or a straight chain or branched C1-C6 alkoxy group that may optionally contain a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups each independently comprise linked hydrogen, deuterium or fluorine atoms; and optionally the N-substituted piperazine acetic acid moiety comprises one or more heavy atom isotopes; and

optionally treating the N-substituted piperazine acetic acid active ester with an acid.

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:

and wherein X is O or S.

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

and wherein X is O or S.

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 16 O or 18 O.

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

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

wherein,

each C* is independently 12 C or 13 C,

LG is the leaving group of an active ester;

X is O or S;

Y is a straight chain or branched C1-C6 alkyl group or a straight chain or branched C1-C6 alkyl ether group wherein the carbon atoms of the alkyl group or alkyl ether group each independently comprise linked hydrogen, deuterium or fluorine atoms;

each Z is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, an amino acid side chain, a straight chain or branched C1-C6 alkyl group that may optionally contain a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups each independently comprise linked hydrogen, deuterium or fluorine atoms, a straight chain or branched C1-C6 alkyl ether group that may optionally contain a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups each independently comprise linked hydrogen, deuterium or fluorine atoms or a straight chain or branched C1-C6 alkoxy group that may optionally contain a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups each independently comprise linked hydrogen, deuterium or fluorine atoms.

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

wherein, LG is the leaving group of an active ester.

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:

and wherein X is O or S.

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

and wherein X is O or S.

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.

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.