Active esters of N-substituted piperazine acetic acids, including isotopically enriched versions thereof
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.
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
optionally the N-substituted piperazine acetic acid active ester comprises 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 one or more heavy atom isotopes.
3 . The compound of claim 1 , wherein the N-substituted piperazine acetic acid active ester is isotopically enriched with three or more heavy atom isotopes.
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:
and wherein X is O or S.
6 . The compound of claim 1 , wherein LG is N-hydroxysuccinimide.
7 . The compound of claim 1 , wherein each Z is independently hydrogen, deuterium, fluorine, chlorine, bromine or iodine.
8 . The compound of claim 1 , wherein each Z is independently hydrogen, methyl or methoxy.
9 . The compound of claim 1 , wherein Y is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
10 . The compound of claim 1 , wherein X is 16 O or 18 O.
11 . The compound of claim 1 , wherein each nitrogen atom of the piperazine ring is independently 14 N or 15 N.
12 . 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.
13 . The compound of claim 2 of the formula:
wherein, LG is the leaving group of an active ester.
14 . The compound of claim 13 , wherein the compound is a mono-TFA salt, a mono-HCl salt, a bis-TFA salt or a bis-HCl salt.
15 . The compound of claim 13 , wherein each incorporated heavy atom isotope is present in at least 80 percent isotopic purity.
16 . The compound of claim 13 , wherein each incorporated heavy atom isotope is present in at least 93 percent or isotopic purity.
17 . The compound of claim 13 , wherein each incorporated heavy atom isotope is present in at least 96 percent or isotopic purity.
18 . The compound of claim 13 , wherein LG is N-hydroxysuccinimide.
19 . The compound of claim 13 , wherein LG is:
and wherein X is O or S.
20 . The compound of claim 13 , wherein LG is:
and wherein X is O or S.
21 . 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.
22 . The compound of claim 2 , wherein each incorporated heavy atom isotope is present in at least 80 percent isotopic purity.
23 . The compound of claim 2 , wherein each incorporated heavy atom isotope is present in at least 93 percent isotopic purity.
24 . The compound of claim 2 , wherein each incorporated heavy atom isotope is present in at least 96 percent isotopic purity.
25 . 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.
26 . The method of claim 25 , wherein the N-substituted piperazine acetic acid active ester is isotopically enriched with one or more heavy atom isotopes.
27 . The method of claim 25 , wherein the N-substituted piperazine acetic acid active ester is isotopically enriched with three or more heavy atom isotopes.
28 . The method of claim 25 , wherein the acid is HCl or TFA.
29 . The method of claim 26 , wherein each incorporated heavy atom isotope is present in at least 80 percent isotopic purity.
30 . The method of claim 26 , wherein each incorporated heavy atom isotope is present in at least 93 percent isotopic purity.
31 . The method of claim 26 , wherein each incorporated heavy atom isotope is present in at least 93 percent isotopic purity.
32 . The method of claim 25 , wherein LG is:
and wherein X is O or S.
33 . The method of claim 25 , wherein LG is:
and wherein X is O or S.
34 . The method of claim 25 , wherein LG is N-hydroxysuccinimide.
35 . The method of claim 25 , wherein each Z is independently hydrogen, deuterium, fluorine, chlorine, bromine or iodine.
36 . The method of claim 25 , wherein each Z is independently hydrogen, methyl or methoxy.
37 . The method of claim 25 , wherein Y is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
38 . The method of claim 25 , wherein X is 16 O or 18 O.
39 . The method of claim 25 , wherein each nitrogen atom of the piperazine ring is independently 14 N or 15 N.
40 . The method of claim 25 , 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.
41 . The method of claim 23 , 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.
42 . The method of claim 41 , wherein each incorporated heavy atom isotope is present in at least 80 percent isotopic purity.
43 . The method of claim 41 , wherein each incorporated heavy atom isotope is present in at least 93 percent isotopic purity.
44 . The method of claim 41 , wherein each incorporated heavy atom isotope is present in at least 96 percent isotopic purity.
45 . The method of claim 41 , wherein LG is:
and wherein X is O or S.
46 . The method of claim 41 , wherein LG is:
and wherein X is O or S.
47 . The method of claim 41 , wherein LG is N-hydroxysuccinimide.
48 . The method of claim 41 , 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.
49 . The method of claim 25 , 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.