Synthesis of 2H- and 13C-substituted dithanes

Details Synthesis of 2H- and 13C-substituted dithanes Synthesis of 2H- and 13C-substituted dithanes

2002-02-13

2003-04-01

Vollano, Jean F. (Department: 1621)

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

Organic compounds

Sulfur containing

C568S038000, C424S001650, C424S001810

Reexamination Certificate

active

06541671

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.
Dithiane has been used in a wide number of reactions to make a large number of such biomolecules and other important synthetic precursors. For example, dithiane, can be used as a nucleophilic synthon. While dithiane could provide a chemically stable and non-volatile carrier for the valuable
13
C and
2
H labels, the preparation of isotopically labeled dithiane has not been previously accomplished. Thus, availability of
2
H- and
13
C-substituted dithianes 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 the labeled compound, [2-
13
C]dithiane wherein the
13
C is directly bonded to exactly one or two deuterium atoms.
The present invention further provides a process of preparing compounds such as [2,2-
2
H
2
, 2-
13
C]dithiane by reacting [
2
H
3
,
13
C]methyl phenyl sulfoxide with sodium acetate to form an intermediate product; and, reacting said intermediate product with HS—(CH
2
)
3
—SH to form [2,2-
2
H
2
, 2-
13
C]dithiane.
The present invention still further provides labeled compounds, of the structure Ar—S—C*D
2−x
H
x
—O—R where Ar is an aryl group, C* is a
13
C labeled carbon atom, D is a
2
H, x is 0 or 1, and R is selected from a C
1
-C
5
lower alkyl group or an acyl group including a C
1
-C
5
lower alkyl group substituent, i.e., the acyl group is (—C(O)R
1
) where R
1
is a C
1
-C
5
lower alkyl. In a preferred embodiment, R is an acyl group wherein R
1
is methyl such that the labeled compounds are [
2
H
1-2
,
13
C]methanol (arylthio)-, acetates wherein said
13
C atom is directly bonded to exactly one or two deuterium atoms.
DETAILED DESCRIPTION
Dithiane is a useful organic reagent that allows for the construction of many useful biochemicals and materials. Isotopically labeled dithiane can be used to introduce a carbon-13 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, phenyl, 1-naphthyl, 2-naphthyl, and derivatives thereof.
As used herein, the term “acyl” means a (—C(O)R
1
group) aryl or aliphatic acyl groups where R
1
is, e.g., a C
1-5
lower alkyl. Examples of acyl include straight chain or branched alkanoyls such as formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, and pentanoyl. Preferably the acyl is acetyl.
In one embodiment of the invention, [2,2-
2
H
2
, 2-
13
C]dithiane can be made from [
2
H
3
,
13
C]methyl phenyl sulfoxide in process as shown below. The [2,2-
2
H
2
, 2-
13
C]dithiane can be used as a non-volatile carrier of the desired carbon and hydrogen labels.
Availability of the [2,2-
2
H
2
, 2-
13
C]dithiane will allow researchers to take advantage of the wealth of chemistry that has been done using unlabeled dithiane.
The present invention provides efficient large scale processes for the preparation of of [2,2-
2
H
2
, 2-
13
C]dithiane from [
2
H
3
,
13
C]methyl phenyl sulfoxide. Dithiane chemically stable and non-volatile carrier for the valuable
13
C and
2
H labels.
In the process of the present invention, [2,2-
2
H
2
, 2-
13
C]dithiane can be prepared in a high yield (>95%) process by first reacting [
2
H
3
,
13
C]methyl phenyl sulfoxide with, e.g., a sodium acylate, preferably sodium acetate, in acetic anhydride to form an intermediate and reacting the intermediate with HS—(CH
2
)
3
—SH in methylene chloride to produce the dithiane. Optionally, the dithiane may be prepared with only a single deuterium atom on the
13
C labeled atom by altering the deuterium substitution on the [
13
C]methyl phenyl sulfoxide.


REFERENCES:
CA:92:21987 abs of J Org. Chem by Lambert et al 44(25) pp 4689-95 1979.*
CA:111:193943 abs of J Am. Chem Soc by Fisher et al 111(19) pp 7379-87 1989.*
CA:93:90890 abs of J Chem Soc Perkin Trans 1 by Battersby et al (1) pp 31-42 1980.*
CA:96:217912 abs of Tetrahedron by Andersen et al 37(23) pp 4069-79 1981.*
CA:101:109832 abs of Helv. Chim. Acta by Gabriel et al 67(4) pp 1070-82 1984.*
Tetrahedron Letters by Cintrat et al vol. 42 pp. 5001-5003 2001.

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