Process for preparation of N-substituted 2-sulfanylimidazoles

Details Process for preparation of N-substituted 2-sulfanylimidazoles Process for preparation of N-substituted 2-sulfanylimidazoles

2003-04-14

2004-05-04

Stockton, Laura L. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06730796

ABSTRACT:

FIELD OF INVENTION
This invention relates to a novel process for preparing N-substituted 2-sulfinylimidazoles compounds.
BACKGROUND
2-Sulfanylimidazoles are important heterocycles that are used in a number of pharmaceutical drugs or drug candidates. For example, both a GPIIB-IIIA antagonist OPC-29030 (
Chem. Pharm. Bull.
43(10), 1724 (1995); CAS RNS: 161190-39-2) and an antiulcer agent T-330 (CSA RNS: 52410-51-2) which are in clinical trials contain an N-aryl 2-sulfanylimidazole substructure. On the other hand, a series of 4,5-unsubstituted 2-sulfanylimidazoles are described as potent inhibitors of the acid secretory enzyme H
+
/K
+
-ATPase (Yamada, M. et al.;
J. Med. Chem
. 39, 596 (1996)). These 2-sulfanylimidazoles are generally prepared from imidazole-2-thiones or imidazoles through alkylation with alkyl halides or activated aryl halides in the presence of bases. Either approach requires stepwise preparation and isolation of the respective intermediates. Furthermore, imidazole-2-thiones are typically synthesized from a thiourea acetal intermediate via an acid-catalyzed cyclization (Hofmann, K. in “
The Chemistry of Heterocyclic Compounds
”, eds. By A. Weissberger, Interscience Publishers Inc., New York, 1953, p86-87; Elslager, E. F. et al.,
J. Heterocyclic Chem
. 17, 129 (1980)). The reactions mentioned above were conducted under either strongly acidic or basic conditions which are incompatible with many functional groups.
SUMMARY OF THE INVENTION
The inventors have developed a convenient one step synthesis of N-substituted 2-sulfanylimidazole compounds without using a base or an acid, thus allowing for functional groups that would otherwise be incompatible with such a reaction.
This invention relates to a process for preparing an N-substituted 2-sulfanylimidazole compound of the formula (I)
by reacting an isothiocyanate of the formula R
1
NCS with an &agr;-aminocarbonyl compound of the formula NH
2
CHR
4
C(OP)
2
R
3
and an alkyl halide or an activated aryl halide of the formula R
2
X in a solvent, alternatively, by reacting an isothiocyanate of the formula R
1
NCS with an &agr;-aminocarbonyl compound of the formula NH
2
CHR
4
C(OP)
2
R
3
before adding an alkyl halide or an activated aryl halide of the formula R
2
X, wherein R
1
and R
2
independently represent alkyl, heterocyclyl, aryl, or heteroaryl groups; R
3
and R
4
independently represent hydrogen, alkyl, heterocyclyl, aryl or heteroaryl or may form a non-aromatic ring; P represents a protecting group of a carbonyl group.
Preferably, R
1
represents aryl or heteroaryl. Preferably, R
2
represents alkyl. Preferably, R
3
represents hydrogen. Preferably, R
4
represents hydrogen. Preferably, said halide is chloride, bromide or iodide. Preferably, the protecting group of the carbonyl group of &agr;-aminocarbonyl is dialkyl or cyclic alkyl acetal.
This invention relates to a convenient one step synthesis of N-substituted 2-sulfanylimidazole from an isothiocyanate, an &agr;-aminocarbonyl compound and an alkyl halide or an activated aryl halide. Reaction of an isothiocyanate with an &agr;-aminocarbonyl compound affords a thiourea acetal intermediate, which without isolation or purification provides the desired N-substituted 2-sulfanylimidazole upon treatment with an alkyl halide.
DETAILED DESCRIPTION OF THE INVENTION
The detailed description of the invention which follows is not intended to be exhaustive or to limit the invention to the precise details or examples disclosed. Details and examples have been chosen to explain the invention to others skilled in the art.
The processes of this invention described herein and in the claims, may be performed in s veral ways. Preferred methodologies are described as follows.
This invention provides a process for preparing an N-substituted 2-sulfanylimidazole compound of the formula (I)
by reacting an isothiocyanate of the formula R
1
NCS with an &agr;-aminocarbonyl compound of the formula NH
2
CHR
4
C(OP)
2
R
3
and an alkyl halide or an activated aryl halide of the formula R
2
X in a solvent, alternatively, by reacting an isothiocyanate of the formula R
1
NCS with an &agr;-aminocarbonyl compound of the formula NH
2
CHR
4
C(OP)
2
R
3
before adding an alkyl halide of the formula R
2
X, wherein R
1
and R
2
independently represent alkyl, heterocyclyl, aryl, or heteroaryl groups; R
3
and R
4
independently represent hydrogen, alkyl, heterocyclyl, aryl or heteroaryl or may form a non-aromatic ring; P represents a protecting group of a carbonyl group.
Preferably, R
1
represents aryl or heteroaryl. Preferably, R
2
represents alkyl. Preferably, R
3
represents hydrogen. Preferably, R
4
represents hydrogen. Preferably, said halide is chloride, bromide or iodide. Preferably, the protecting group of the carbonyl group of &agr;-aminocarbonyl is dialkyl or cyclic alkyl acetal.
The reaction is performed by mixing all reactants, i.e., an isothiocyanate of the formula R
1
NCS, an &agr;-aminocarbonyl compound of the formula NH
2
CHR
4
C(OP)
2
R
3
and an alkyl halide of the formula R
2
X in a solvent. Alternatively, an isothiocyanate of the formula R
1
NCS is reacted with a protected &agr;-aminocarbonyl compound of the formula NH
2
CHR
4
C(OP)
2
R
3
in a solvent to provide a thiourea intermediate. There is no restriction on the solvent used in this reaction. The reaction can be conducted in either organic or inorganic solvents. Preferably, the solvents used in the invention are organic solvents. More preferably, the reaction is conducted in an organic solvent, such as toluene or ethanol. Subsequently, the thiourea intermediate is reacted with an alkyl halide to provide the desired N-substituted 2-sulfanylimidazole compound. Preferably, the reaction is conducted under sealed condition. Preferably, alcohol solvent is added along with an alkyl halide or an activated aryl halide. Preferably, the reaction is conducted at elevated temperature aftermixing all reactants. More preferably, the reaction is heated to 60-80° C. from room temperature. The reaction is useful for a large scale production of N-substituted 2-sulfanylimidazoles. This invention is useful for preparing important pharmaceutical agents such as drugs or drug candidates which contain N-substituted 2-sulfanylimidazoles.
DEFINITION
As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
“Activated aryl halide”, as used herein, means an aryl halide that is substituted by some type of substituents that activate the aryl halide so that it can be reacted with thiourea intermediate to form the desired N-substituted 2-sulfanylimidazole. Substituents used for activation of an aryl halide are electron-withdrawing groups.
“Alkyl”, as used herein, means a cyclic, branched, or straight chain chemical group containing only carbon and hydrogen, such as methyl, pentyl, and adamantyl. Alkyl groups can either be unsubstituted or substituted with one or more substituents, e.g., halogen, alkoxy, acyloxy, amino, cyano, nitro, hydroxyl, mercapto, carboxy, benzyloxy, aryl, heteroaryl, or other functionality that may be suitably blocked, if necessary for purposes of the invention, with a protecting group. Alkyl groups can be saturated or unsaturated (e.g., containing —C═C— or —C
═
C— subunits), at one or several positions. Typically, alkyl groups will comprise 1 to 12 carbon atoms, preferably 1 to 10, and more preferably 1 to 8 carbon atoms.
“Aryl”, as used herein, means a monovalent unsaturated aromatic carbocyclic group having a single-ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl), which can be optionally unsubstituted or substituted with amino, cyano, hydroxyl, lower alkyl, haloalkyl, alkoxy, nitro, halo, mercapto, and other substituents.
“Electron-withdrawing group”, as used herein, means a specific group that makes the electron density of the parent molecule unevenly distributed when it is attached to the parent molecule. An electron-withdrawing group pulls the electron from the paren

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