Synthesis of labeled oxalic acid derivatives

Details Synthesis of labeled oxalic acid derivatives Synthesis of labeled oxalic acid derivatives

2003-06-05

2004-06-22

Shippen, Michael L. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S190000, C558S255000

Reexamination Certificate

active

06753446

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to labeled compounds and more particularly to isotopically enriched acetic acid, (dialkylamino)oxo-, alkyl esters labeled with carbon-13 or with carbon-13 and hydrogen-2.
BACKGROUND OF THE INVENTION
Diethyloxalate is an extremely useful synthon for the synthesis of many important biochemicals and pharmaceuticals. It can be used as a labeling synthon but has limitations in that it can only be used as a symetrically labeled compound. A new synthon has now been developed that has the synthetic utility of diethyl oxalate and allows the differentiation of each of the carbons.
It is an object of the present invention to provide labeled compounds useful for synthetic chemistry development.
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 each C* is selected from the group consisting of a carbon-12, i.e.,
12
C, or a carbon-13, i.e.,
13
C and at least one C* is
13
C, R
1
is selected from the group of C
1
-C
4
lower alkyl and aryl, and X is selected from the group of —NR
2
R
3
where R
2
and R
3
are each independently selected from the group of C
1
-C
4
lower alkyl, alkoxy and aryl, —SR
4
where R
4
is selected from the group of C
1
-C
4
lower alkyl, alkoxy and aryl, and —OR
5
where R
5
is selected from the group of C
1
-C
4
lower alkyl, alkoxy and aryl with the proviso that when R
1
is methyl then R
5
is other than methyl, when R
1
is ethyl then R
5
is other than ethyl, and when R
1
is benzyl then R
5
is other than benzyl. In specific embodiments, the labeled compounds include [1-
13
C]acetic acid, (dimethylamino)oxo-, ethyl ester, [2-
13
C]acetic acid, (dimethylamino)oxo-, ethyl ester, and [1,2-
13
C
2
]acetic acid, (dimethylamino)oxo-, ethyl ester.
DETAILED DESCRIPTION
The present invention is concerned with diethyl oxalate analogs useful for assymetric labeling of synthetic compounds. Generally, the compounds are labeled with carbon-13, although they may be labeled with deuterium (
2
H) as well.
Particularly, the present invention is concerned with labeled compounds of the formula
where each C* is selected from the group consisting of a carbon-12, i.e.,
12
C, or a carbon-13, i.e.,
13
C and at least one C* is
13
C, R
1
is selected from the group of C
1
-C
4
lower alkyl and aryl, and X is selected from the group of —NR
2
R
3
where R
2
and R
3
are each independently selected from the group of C
1
-C
4
lower alkyl, alkoxy and aryl, —SR
4
where R
4
is selected from the group of C
1
-C
4
lower alkyl, alkoxy and aryl, and —OR
5
where R
5
is selected from the group of C
1
-C
4
lower alkyl, alkoxy and aryl with the proviso that when R
1
is methyl then R
5
is other than methyl, when R
1
is ethyl then R
5
is other than ethyl, and when R
1
is benzyl then R
5
is other than benzyl.
As used herein, the term “lower alkyl” refers to C
1
-C
4
alkyl such as methyl, ethyl, n-propyl, iso-propyl, butyl, isobutyl, and tert-butyl while the term “aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms, and optionally substituted independently with one, two, three, four or five substituents selected from alkyl, haloalkyl, cycloalkyl, halo, nitro, cyano, —OR (where R is hydrogen, alkyl, haloalkyl, cycloalkyl, optionally substituted phenyl), acyl, and —COOR (where R is hydrogen or alkyl). More specifically, the term “aryl” includes, but is not limited to 1-naphthyl, substituted 1-naphthyl, 2-naphthyl, substituted 2-naphthyl, and phenyl groups with the structure
wherein R
11
, R
12
, R
13
, R
14
and R
15
are each independently a lower alkyl, i.e., a C
1
-C
4
alkyl such as methyl, ethyl, n-propyl, iso-propyl, butyl, isobutyl, and tert-butyl, a halogen such as chloro, bromo or iodo, an amino group such as NH
2
, NHR or NRR′ where R and R′ are each a lower alkyl or aryl as described above, or an alkoxy group such as O-alkyl or O-aryl where the alkyl is a lower alkyl as described above or an aryl as described above. Additionally, the aryl group may be a benzyl group.
Among particular labeled compounds are included [1-
13
C]acetic acid, (dimethylamino)oxo-, ethyl ester, [2-
13
C]acetic acid, (dimethylamino)oxo-, ethyl ester, and [1,2-
13
C
2
]acetic acid, (dimethylamino)oxo-, ethyl ester.
Each of these labeled compounds can be synthesized from similar starting materials, e.g., methyl phenyl sulfide.
In an exemplary process of the present invention, C*O
2
where C* is
12
C or
13
C is reacted with a [
12
C or
13
C]methyl phenyl sulfide to form an addition product, a chlorination reaction is conducted with the addition product to form an acid chloride-containing intermediate, an exchange reaction is conducted between dimethyl amine and the acid chloride-containing intermediate, and reaction with thionyl chloride is conducted followed by reaction with an ethanol-water mixture to yield the labeled compound.
Unlike labeled diethyl oxalate, the reactivity of the labeled acetic acid, (dimethylamino)oxo-, ethyl esters can be tailored to produce a variety of labeled biochemicals and pharmaceuticals with predictable regioselectivity. For example, a general reaction for the production of isotopically labeled glycerol using such a reagent can be as follows.
Lithium methyl phenyl sulfide can be reacted with any one of the described labeled acetic acid, (dimethylamino)oxo-, ethyl esters in THF to form an intermediate product. Such an intermediate product can then be reacted with diisobutylaluminum hydride (DIBAL) followed by reaction with acetic anhydride and sodium acetate and followed by reaction with lithium borohydrate to form differently labeled glycerols. In the case of [1-
13
C]acetic acid, (dimethylamino)oxo-, ethyl ester as a starting material, the product will be [1,3-
13
C
2
]glycerol. In the case of [2-
13
C]acetic acid, (dimethylamino)oxo-, ethyl ester as a starting material, the product will be [1,2-
13
C
2
]glycerol. In the case of [1,2-
13
C
2
]acetic acid, (dimethylamino)oxo-, ethyl ester as a starting material, the product will be [U-
13
C
3
]glycerol.
The present invention is more particularly described in the following examples which are intended as illustrative only, since numerous modifications and variations will be apparent to those skilled in the art.


REFERENCES:
Wilmes et al, Journal of Labeled Compounds and Radiopharmaceuticals, Preparation of Mono-15N-Cyanogen and Mono-13C-Cyanogen, 1992, 31(12), pp. 1037-1040.

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