Process for producing imidazole derivatives

Details Process for producing imidazole derivatives Process for producing imidazole derivatives

1999-06-10

2000-05-02

McKane, Joseph

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

5483235, 5483241, C07D40100

Patent

active

060574488

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to a process for producing imidazole derivatives.


BACKGROUND ART

Various imidazole derivatives have been researched to apply them to medicines, and the present inventors found that the imidazole derivatives having an arylthio group at 5-position were efficient as an antiviral agent or an anti-HIV agent.
It is known, as a process for producing imidazole derivatives having a substituted thio group, that halogenated imidazole derivatives are reacted with mercaptane/NaH/DMF after formation of an imidazole ring (HETEROCYCLES, Vol 33, No 1, 21-26, (1992)). It is also known that imidazole derivatives are reacted with disulfide in the presence of a base after halogenation of --CH of the imidazole ring (J. Chem. Perkin Trans. I 1139-1145 (1989) and WO 96/10019). These methods are, however, inappropriate to the reaction on an industrial scale because they require halogenation of --CH of the imidazole ring and a strong base such as NaH or the like. As mentioned above, a process for producing imidazole derivatives having a substituted thio group, which is appropriate to convenient, economical, large-scaled production, has not been known heretofore.


DISCLOSURE OF INVENTION

The present inventors have intensively studied to develop convenient, economical, large-scaled production of substituted thio imidazole derivatives such as 5-arylthio imidazole derivatives, and succeeded in the reaction of imidazole derivatives of the following formula (I) with thiohalide of the formula (II) in the presence of a base to give imidazole derivatives having a substituted thio group of the formula (III). Thus, the present invention has been accomplished.
Accordingly, the present invention provides a process for producing a compound of the formula (III): ##STR3## wherein R.sup.1 and R.sup.3 are independently hydrogen or an organic group; R.sup.2 is an organic group; and R.sup.4 is an optionally substituted aryl, which comprises reacting a compound of the formula (I): ##STR4## wherein R.sup.1, R.sup.2, and R.sup.3 are as defined above, with a compound of the formula (II): a base.


BEST MODE FOR CARRYING OUT THE INVENTION

A preferable embodiment of the present invention includes the process wherein the organic groups in the formula (I) are an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted aryl, an optionally substituted thioaryl, an optionally substituted heteroaryl, an optionally substituted heteroarylalkyl, an optionally substituted aralkyl, an optionally substituted acyl, an optionally substituted carbamoyl, an optionally substituted alkoxycarbonyl, --CH.dbd.NOH, --CH.dbd.NNH.sub.2, or --A--X wherein A is --CH.sub.2 OCH.sub.2 -- or --CH.sub.2 O-- and X is an optionally substituted aryl or --COR.sup.5 wherein R.sup.5 is an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted aryl, or an optionally substituted amino.
The more preferable embodiment of the present invention is (l) the process wherein R.sup.1 is hydrogen or an optionally substituted heteroarylalkyl; R.sup.2 is --A--X wherein A is --CH.sub.2 OCH.sub.2 -- or --CH.sub.2 O-- and X is an optionally substituted aryl or --COR.sup.5 wherein R.sup.5 is an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted aryl, or an optionally substituted amino; and R.sup.3 is an optionally substituted alkyl. In particular, the process for producing the compound wherein R.sup.1 is optionally substituted pyridylmethyl (esp. pyridin-4-ylmethyl) is preferred. Especially, the process for the compound wherein R.sup.2 is benzyloxymethyl, acetyloxymethyl, benzoyloxymethyl, methoxycarbonyloxymethyl, and carbamoyloxymethyl is preferred.
A preferable compound of the formula (II) is (2) 3,5-dichlorobenzenesulfenyl chloride.
A preferable base is (3) triethylamine or N-methylmorphorine.
The terms used in the present specification are defined below.
The term "organic group" refers to an optionally substituted alkyl, an optionally substituted a

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