Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-03-15
2004-09-28
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S321500
Reexamination Certificate
active
06797828
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to processes for simply and efficiently preparing 4(5)-aminoimidazole-5-(4)-carboxamido derivatives and intermediates thereof, which are useful as intermediates of agricultural chemicals and medicines.
2. Description of the Prior Art
Among the compounds represented by formula (I):
for example, 1H-4(5)-aminoimidazole-5(4)-carboxamide (wherein R
1
and R
2
represent hydrogen atoms (hereinafter abbreviated as AICA)), and hydrochloric salts thereof are useful intermediates of medicines, and for example, have been known as basic ingredients of anti-cancer drugs such as dacarbazine and temozoromide, and hepatic protectives such as urazamide.
The processes for synthesizing these include the process wherein 4-nitroimidazole-5-carboxamido is contact-reduced, the process wherein phenylazomalonamidine is reduced and cyclized in formic acid, the process wherein &agr;-amino-&agr;-cyanoacetamido is used as a raw material, and the process wherein a compound having a purine core is decomposed. However, these are insufficient in terms of raw materials, manipulation and industry.
Also, there is the process wherein from industrially available diaminomaleonitrile (hereinafter abbreviated as DAMN), 4,5-dicyanoimidazole is synthesized, which is hydrolyzed (Japanese Patent Publication No. 21026/1966) to synthesize 1H-4(5)-cyanoimidazole-5(4)-carboxamide, which is converted to 1H-4(5)-aminoimidazole-5(4)-carbonitrile (hereinafter abbreviated as AICN) using the Hoffman rearrangement reaction (Japanese Patent Publication No. 10889/1971), and subsequently it is hydrolyzed to synthesize AICA. However, it has been problematic in that a yield from the Hoffman rearrangement reaction is low, steps in the process are many and a yield of the objective is low.
Additionally, B. L. Booth et al. (J. Chem. Soc. Perkin Trans. I:1705, 1990) reported that AICN could be synthesized by cyclizing N-(2-amino-1,2-dicyanovinyl) formamidine (hereinafter abbreviated as AMD) but did not describe the synthesis of AICA.
Also, B. L. Booth et al. (J. Chem. Soc. Perkin Trans., I:2120, 1992; J. Chem. Soc. Perkin Trans., 1:669, 1995) reported that 1-substituted-5-aminoimidazole-4-carbonitrile could be synthesized by cyclizing N-(2-amino-1,2-dicyanovinyl)-N′-substituted-formamidine but did not describe the synthesis of 1-substituted-5-aminoimidazole-4-carboxamide which is one of the target substances of the present invention.
Also, B. L. Booth et al. (J. Chem. Soc. Perkin Trans., I:1521, 1987) reported the process for synthesizing 1,2-substituted imidazole as shown by the following formula.
However, it is not suitable for synthesis of N-non-substituents due to the use of a special nitrilium salt, yet it has been problematic in that a yield from cyclization is low and the objective was not obtained with a sufficient yield.
Moreover, it has also been problematic in that in the case of conducting a reaction of alkylation of 1H-4(5)-aminoimidazole-5(4)-carboxamide, both 1- and 3-positions are alkylated and thus its selectivity of position is low.
As the process for synthesis of compounds represented by formula (II) which can be intermediates in synthesis of compounds represented by formula (I), for example, R. F. Shuman et al. (J. Org. Chem., 44:4532, 1979) have reported that N-(2-amino-1,2-dicyanovinyl) formamidine can be synthesized by the method in which DAMN and formamidine acetate are refluxed in ethanol. However, its yield was only 2% and the method is unrealistic as an industrial process for the preparation.
Also, B. L. Booth et al. (J. Chem. Soc. Perkin Trans., I:1705, 1990) have reported that DAMN and triethylorthoformate are reacted in dioxane to synthesize ethyl N-(2-amino-1-,2-@ diaminovinyl) formimidate, which is further reacted with ammonia in chloroform at a low temperature of −20° C. or below using aniline hydrochloride as a catalyst resulting in being capable of synthesizing N- (2-amino-1,2-dicyanovinyl) formamidine. However, in this method there are many problems such as the vexatious complication of reaction manipulation, reaction at a low temperature, many solvents being required, potential environmental pollution by halide solvents and the like, and it was insufficient as an industrial process for the preparation.
SUMMARY OF THE INVENTION
As mentioned above, no simple and efficient process has been known for preparing 4(5)-aminoimidazole-5(4)-carboxamide derivatives and intermediates thereof, which are useful as intermediates of agricultural chemicals and medicines, and the present invention is aimed to provide processes for the preparation thereof.
That is, the present invention relates to;
a process for the preparation characterized in that a compound represented by formula (II):
(wherein R
1
and R
2
each independently represent a hydrogen atom, an alkyl group of C1 to C10 which may have substituents, a hydrocarbon group of C3 to C14 having alicyclic skeletons, an alkynyl group which may have substituents, an aryl group which may have substituents, an aralkyl group which may have substituents, a heterocyclic group which may have substituents, a heterocyclic alkyl group which may have substituents, an N-unsubstituted or substituted carbamoyl group, or an alkoxycarbonyl group) and/or a salt thereof are cyclized and hydrolyzed in an aqueous basic solution in a process for preparing a compound represented by formula (I):
(wherein R
1
and R
2
represent the same as defined above) [Constitution 1];
a process for the preparation characterized in that a compound represented by formula (II):
(wherein R
1
represents a hydrogen atom, an alkyl group of C1 to C10 which may have substituents, a hydrocarbon group of C3 to C14 having alicyclic skeletons, an alkynyl group which may have substituents, an aryl group which may have substituents, an aralkyl group which may have substituents, a heterocyclic group which may have substituents, a heterocyclic alkyl group which may have substituents, an N-unsubstituted or substituted carbamoyl group, or an alkoxycarbonyl group; and R
2
represents a hydrogen atom) and/or a salt thereof are cyclized/ hydrolyzed in an aqueous basic solution followed by adjusting the pH to the isoelectric point to precipitate crystal in a process for preparing a compound represented by formula (I):
(wherein R
1
and R
2
represent the same as defined above) [Constitution 2];
a process for the preparation characterized in that a compound represented by formula (II):
(wherein R
1
represents a hydrogen atom, an alkyl group of C1 to C10 which may have substituents, a hydrocarbon group of C3 to C14 having alicyclic skeletons, an alkynyl group which may have substituents, an aryl group which may have substituents, an aralkyl group which may have substituents, a heterocyclic group which may have substituents, a heterocyclic alkyl group which may have substituents, an N-unsubstituted or substituted carbamoyl group, or an alkoxycarbonyl group and R
2
represents a hydrogen atom) and/or a salt thereof are cyclized/ hydrolyzed in an aqueous basic solution followed by adjusting the pH to 9 to 13 to precipitate crystal in a process for preparing a compound represented by formula (I):
(wherein R
1
and R
2
represent the same as defined above). [Constitution 3];
the process for the preparation according to [Constitution 3] characterized in that the pH is adjusted to a range of 11 to 12 [Constitution 4];
the process for the preparation according to any of [Constitution 1] through [Constitution 4] characterized in that a basic compound is sodium hydroxide or potassium hydroxide [Constitution 5];
a process for the preparation characterized in that a compound represented by formula (III):
(wherein R
1
represents the same as defined above and R
3
represents an alkyl group of C1 to C6) is reacted with ammonia in alcohol of C1 to C5 in a process for preparing a compound represented by formula (II):
(wherein R
1
represents the same as
Ishii Yutaka
Nagasaki Fumihiko
Oohata Kimihiko
Shibasaki Hiroaki
Takase Mitsuru
LaPointe Dennis G.
Mason Law, P.A.
McKane Joseph K.
Nippon Soda Co. Ltd.
Wright Sonya
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