Synthesis of labeled metabolites

Details Synthesis of labeled metabolites Synthesis of labeled metabolites

2003-04-18

2004-03-23

Vollano, Jean F. (Department: 1621)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

C568S027000, C568S028000, C568S032000, C568S579000, C568S606000, C568S613000, C568S671000

Reexamination Certificate

active

06709645

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to labeled compounds and more particularly to isotopically enriched mustard gas metabolites labeled with carbon-13 or with carbon-13 and hydrogen-2.
BACKGROUND OF THE INVENTION
Several mass spectral screening procedures have been developed for the detection and identification of metabolic products resulting from exposure to chemical warfare (CW) agents (e.g., vesicants such as mustard gas and other mustard agents, nerve agents such as the organic esters of substituted phosphoric acid including tabun, sarin and the like, and incapacitants such as BZ (3-quinuclidinyl benzilate)). In order to positively identify the suspected metabolites, an isotopically enriched sample of the metabolite must be available. The amount, or in some cases the presence, of the suspected metabolite is derived by isotope dilution (ID) mass spectrometry. Isotope dilution mass spectrometry is based on the addition of isotopically enriched sample to the unknown samples. The equilibration of the samples, including both the isotopically labeled material and the unknown material) alters the isotope ratio that would normally be measured for the native sample alone. This ratio can then be used to establish the presence of a suspected metabolite which can then indicate which CW agent is present.
2,2′-dichloroethyl sulfide, commonly referred to as mustard gas or mustard, was first used by the Germans during World War I. It is a heavy, oily liquid and is nearly colorless and odorless when pure. Other compounds such as (ClCH
2
CH
2
)
2
NEt, (ClCH
2
CH
2
)
2
NMe and (ClCH
2
CH
2
)
3
N also fall within the class of compounds known and used as mustard gases. Even today, with the availability of more advanced chemical technologies, mustard gas may still be the war gas of choice due largely to its ease of manufacture.
It is an object of the present invention to provide isotopically enriched mustard gas metabolites.
SUMMARY OF THE INVENTION
In accordance with the purposes of the present invention, as embodied and broadly described herein, the present invention provides labeled compounds of the formula
where Q
1
is sulfide (—S—), sulfone (—S(O)—), sulfoxide (—S(O
2
)—) or oxide (—O—), at least one C* is a carbon-13, i.e.,
13
C, X is a hydrogen (H) or deuterium (D), and Z is hydroxide (—O—), or —Q
2
—R where Q
2
is sulfide (—S—), sulfone(—S(O)—), sulfoxide (—S(O
2
)—) or oxide (—O—), and R is hydrogen, a C
1
to C
4
lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and t-butyl, or an amino acid moiety, with the proviso that where Z is a hydroxide and Q
1
is a sulfide then at least one X is deuterium. Preferably, each C* is a carbon-13, i.e.,
13
C. In specific embodiments, the labeled compounds include [1,1′,2,2′-
13
C
4
]ethane, 1,1′-sulfonylbis[2-(methylthio); [1,1′,2,2′-
13
C
4
]ethane, 1-[[2-(methylsulfinyl)ethyl]sulfonyl]-2-(methylthio); [1,1′,2,2′-
13
C
4
]ethane, 1,1′-sulfonylbis[2-(methylsulfinyl)]; and, 2,2′-sulfinylbis([1,2-
13
C
2
]ethanol.
The present invention further provides processes of preparing labeled compounds of the formula
where Q
1
is sulfide (—S—), sulfone (—S(O)—), sulfoxide (—S(O
2
)—) or oxide (—O—), at least one C* is a carbon-13, i.e.,
13
C, X is a hydrogen (H) or deuterium (D), and Z is hydroxide (—OH), or —Q
2
—R where Q
2
is sulfide (—S—), sulfone(—S(O)—), sulfoxide (—S(O
2
)—) or oxide (—O—), and R is a hydrogen, C
1
to C
4
lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and t-butyl, or an amino acid moiety. In specific embodiments those labeled compounds include [1,1′,2,2′-
13
C
4
]ethane, 1,1′-sulfonylbis[2-(methylthio); [1,1′,2,2′-
13
C
4
]ethane, 1-[[2-(methylsulfinyl)ethyl]sulfonyl]-2-(methylthio); [1,1′,2,2′-
13
C
4
]ethane, 1,1′-sulfonylbis[2-(methylsulfinyl)]; and, 2,2′-sulfinylbis([1,2-
13
C
2
]ethanol.
DETAILED DESCRIPTION
The present invention is concerned with isotopically enriched mustard gas metabolites labeled with carbon-13. By “isotopically enriched” is meant that the common naturally occurring isotope of one or more element have been deliberately enriched with a less common isotope of the same element, e.g., carbon-12 (
12
C) can be replaced with carbon-13 (
13
C) or hydrogen (
1
H) can be replaced by deuterium (
2
H). Particularly, the present invention is concerned with labeled compounds of the formula
where Q
1
is sulfide (—S—), sulfone (—S(O)—), sulfoxide (—S(O
2
)—) or oxide (—O—), at least one C* is a carbon-13, i.e.,
13
C, X is a hydrogen (H) or deuterium (D), and Z is hydroxide (—OH), or —Q
2
—R where Q
2
is sulfide (—S—), sulfone(—S(O)—), sulfoxide (—S(O
2
)—) or oxide (—O—), and R is hydrogen, a C
1
to C
4
lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and t-butyl, or an amino acid moiety, with the proviso that when Z is a hydroxide and Q
1
is a sulfide then at least one X is deuterium. Preferably, each C* is a carbon-13, i.e.,
13
C.
By the term “amino acid moiety” is meant to portions of, e.g., cysteine or serine such as —CH
2
CH(NH
2
)COOH. These may be added through the sulfur (for cysteine) or through the oxygen (for serine).
Among particular isotopically enriched mustard gas metabolites are included: [1,1′,2,2′-
13
C
4
]ethane, 1,1′-sulfonylbis[2-(methylthio); [1,1′,2,2′-
13
C
4
]ethane, 1-[[2-(methylsulfinyl)ethyl]sulfonyl]-2-(methylthio); [1,1′,2,2′-
13
C
4
]ethane, 1,1′-sulfonylbis[2-(methylsulfinyl)]; and, 2,2′-sulfinylbis([1,2-
13
C
2
]ethanol.
Each of these labeled metabolites can be synthesized from the same common intermediate, namely, ethyl [1,2-
13
C
2
] bromoacetate although other starting materials may be employed. In a process of the present invention, two equivalents of an alkyl bromoacetate such as ethyl [1,2-
13
C
2
] bromoacetate can be reacted with one equivalent of sodium sulfide (Na
2
S) in ethanol to form an intermediate addition product (I). The intermediate product can then be reacted with lithium aluminum hydride (LAH) or lithium aluminum deuteride (LAD) in THF depending upon whether a deuterium label is desired on the outermost carbons in relation to the central sulfur atom. Alternatively, a bromoacetaldehyde may be hydrogenated or deuterated to place a deuterium label and after a similar subsequent reaction with sodium sulfide, the innermost carbons in relation to the central sulfur atom may contain a deuterium label. In yet another alternative, deuterium labeling may be carried out at all the carbon sites by both of these processes.
Following hydrogenation or deuteration of the intermediate product (I), the resultant material can be reacted hydrogen peroxide in ethanol to form 2,2′-sulfinylbis([1,2-13C
2
]ethanol or deuterated products thereof.
Alternatively, following hydrogenation or deuteration of the intermediate product (I), the resultant material can be reacted with tosyl chloride (TsCl) in, e.g., 90 percent dichloromethane/10 percent pyridine to form a next intermediate product (II).
This next intermediate product (II) can be be reacted with Oxone® in a biphasic mixture of dichlromethane and water followed by reaction with sodium methyl sulfide (NaSCH
3
) in ethanol to form, e.g., [1,1′,2,2′-
13
C
4
]ethane, 1,1′-sulfonylbis[2-(methylthio) or deuterated products thereof.
Reaction of [1,1′,2,2′-
13
C
4
]ethane, 1,1′-sulfonylbis[2-(methylthio) or deuterated products thereof with hydrogen peroxide in ethanol can then form a mixture of [1,1′,2,2′-
13
C
4
]ethane, 1-[[2-(methylsulfinyl)ethyl]sulfonyl]-2-(methylthio) and [1,1′,2,2′-
13
C
4
]ethan

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