Synthesis of [2H1, 13C], [2H2, 13C] and...

Details Synthesis of [2H1, 13C], [2H2, 13C] and... Synthesis of [2H1, 13C], [2H2, 13C] and...

2003-01-14

2004-03-30

Vollano, Jean F. (Department: 1621)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

C568S038000

Reexamination Certificate

active

06713044

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to labeled compounds and more particularly to compounds labeled with carbon-13 and hydrogen-2.
BACKGROUND OF THE INVENTION
Stable isotope labeled amino acids and nucleotides are required for structural and mechanistic studies of proteins and oligonucleotides. In addition, isotopically labeled biologically active compounds are required for many phases of drug discovery and development including elucidation of biosynthetic pathways, pharmacokinetics, and drug metabolism. For many applications, site-specific
13
C or combined
13
C and
2
H labeling are required. While a number of stable isotope labeled compounds are available from companies such as Sigma-Aldrich Chemicals, a need remains for other labeled synthetic precursors.
Methyl aryl sulfides such as methyl phenyl sulfide have been used in a wide number of reactions to make a large number of such biomolecules and other important synthetic precursors. For example, methyl phenyl sulfide can be used as a nucleophilic synthon and is easily converted into an electrophilic synthon. While methyl phenyl sulfide could provide a chemically stable and non-volatile carrier for the valuable
13
C and
2
H labels, the preparation of few isotopically labeled methyl phenyl sulfides has been previously accomplished. One example of an isotopically labeled methyl phenyl sulfide labeled at the methyl group is shown by Chaudhary et al., J. Labelled Cpd. Radiopharm., 43, 683-691 (2000), although that sulfide wasn't described or suggested as a synthetic reagent for synthesis of labeled compounds. Availability of other significant [
2
H
1
,
13
C], [
2
H
2
,
13
C] and [
2
H
3
,
13
C]methyl phenyl sulfides would allow researchers to take advantage of the wealth of chemistry that has been done using unlabeled methyl phenyl sulfide.
As carbon-13 is separated from its lighter isotope by cyrogenic distillation of carbon monoxide (CO), all labeled carbons are derived ultimately from CO. The highly efficient conversion of CO to useful chemical precursors is perhaps the most unique aspect of stable isotope labeling technology. Any inefficiencies in the early synthetic steps add greatly to the overall expense of isotope labeling. Thus, considerable efforts have been directed to the development of methods for the preparation of useful synthetic precursors or synthons. This effort has given rise to efficient large-scale methods for the synthesis of methane, methanol, methyl iodide, sodium formate, potassium cyanide and carbon dioxide. These methods are the foundation of all labeling chemistry. The most useful of the electrophilic one-carbon precursors, methyl iodide and carbon dioxide, are difficult to store and use efficiently due to their high volatility.
As spectroscopic instrumentation and techniques continue to improve, there is a drive to study ever more complicated bio-systems. This has lead to demands for more complex labeling patterns in biomolecules. In the past, the simple introduction of a labeled atom site-specifically without stereospecificity was the major thrust for stable isotope labeling and the first generation of labeled synthons served this effort well. Increasingly, in today's labeling climate, in addition to site-specific labeling, the requirement for stereospecificity has been added. This includes both the ability to stereospecific label chiral compounds as well as the ability to differentiate between prochiral centers with deuterium or carbon. Additional synthons as starting materials will address those growing demands.
It is an object of the present invention to provide labeled compounds.
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, [
2
H
1
,
13
C], [
2
H
2
,
13
C] and [
2
H
3
,
13
C]methyl aryl sulfides wherein the
13
C methyl group attached to the sulfur of the sulfide includes exactly one, two or three deuterium atoms and the aryl group is selected from the group consisting of 1-naphthyl, substituted 1-naphthyl, 2-naphthyl, substituted 2-naphthyl, and phenyl groups with the structure
wherein R
1
, R
2
, R
3
, R
4
and R
5
are each independently, hydrogen, a C
1
-C
4
lower alkyl, a halogen, an amino group from the group consisting of NH
2
, NHR and NRR′ where R and R′ are each a C
1
-C
4
lower alkyl, a phenyl, or an alkoxy group.
The present invention further provides a process of preparing a [
2
H
1
,
13
C], [
2
H
2
,
13
C] and [
2
H
3
,
13
C]methyl aryl sulfide wherein the
13
C methyl group attached to the sulfur of the sulfide includes exactly one, two or three deuterium atoms and the aryl group is selected from the group consisting of 1-naphthyl, substituted 1-naphthyl, 2-naphthyl, substituted 2-naphthyl, and phenyl groups with the structure
wherein R
1
, R
2
, R
3
, R
4
and R
5
are each independently, hydrogen, a C
1
-C
4
lower alkyl, a halogen, an amino group from the group consisting of NH
2
, NHR and NRR′ where R and R′ are each a C
1
-C
4
lower alkyl, a phenyl, or an alkoxy group, the process including reacting [
13
C]methanol with hydriodic acid to form a product mixture including volatile [
13
C]methyl iodide, passing said volatile [
13
C]methyl iodide directly into a biphasic mixture including aqueous sodium hydroxide, benzene, and an arylthiol having the structure
wherein R
1
, R
2
, R
3
, R
4
and R
5
are each independently a C
1
-C
4
lower alkyl, a halogen, an amino group from the group consisting of NH
2
, NHR or NRR′ where R and R′ are each a C
1
-C
4
lower alkyl, a phenyl or an alkoxy group and maintaining said biphasic mixture for time sufficient to form the, [
2
H
1
,
13
C], [
2
H
2
,
13
C] and [
2
H
3
,
13
C]methyl aryl sulfide
DETAILED DESCRIPTION
Methyl aryl sulfides are useful organic reagents that allows for the construction of many useful biochemicals and materials. Isotopically labeled methyl aryl sulfide can be used to introduce a carbon-13 [
13
C] and a hydrogen-2 or deuterium label [
2
H] into such biochemicals and materials.
As used herein, 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
1
, R
2
, R
3
, R
4
and R
5
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.
As used herein, the term “[
2
H
1
,
13
C]” means exactly one deuterium atom, the term “[
2
H
2
,
13
C]” means exactly two deuterium atoms, and the term “[
2
H
3
,
13
C]” means exactly three deuterium atoms within the respective compound.
[
2
H
1
,
13
C], [
2
H
2
,
13
C] and [
2
H
3
,
13
C]Methyl aryl sulfides can be made from [
2
H
1
,
13
C], [
2
H
2
,
13
C] and [
2
H
3
,
13
C]methyl alcohol in a one step process as shown below. The [
2
H
1
,
13
C], [
2
H
2
,
13
C] and [
2
H
3
,
13
C]methyl aryl sulfides can be used as a non-volatile carrier of the desired labels, i.e., carbon and hydrogen label

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