Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2002-09-17
2003-05-27
Ford, John M. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
active
06570015
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for producing a 2-substituted thiopyrimidine-4-carboxylate which is useful as a synthetic starting materials for medicine, agricultural chemicals, etc.
2. Prior Art
As a process for producing 2-substituted thiopyrimidine-4-carboxylate (carboxylic acid ester), there has been disclosed a method in which methyl isothiourea is reacted with a sodium salt of diethyl oxalacetate to prepare 6-hydroxy-2-methylthiopyrimidine-4-carboxylic acid, then, methanol is reacted therewith under acidic conditions to prepare methyl 6-hydroxy-2-methylthiopyrimidine-4-carboxylate, and then, phosphorus oxychloride is reacted therewith to prepare methyl 6-chloro-2-methylthiopyrimidine-4-carboxylate, and further, the resulting compound is subjected to hydrogen reduction in the presence of palladium black to synthesize methyl 2-methylthiopyrimidine-4-carboxylate (Japanese Provisional Patent Publication No. 57-112391, J. Org. Chem., vol. 26, 2755 (1961)).
Also, there has been disclosed a method of synthesizing ethyl 2-methylthiopyrimidine-4-carboxylate by preparing 4-iodo-2-methylpyrimidine by reacting hydriodic acid with 4-chloro-2-methylthiopyrimidine, and then, isopropyl magnesium chloride (Grignard reagent) is reacted to the resulting compound, and ethyl cyanoformate is reacted thereto (Tetrahedron, vol. 56, 265 (2000), ibid., vol. 45, 993 (1989)).
However, in either of the above-mentioned methods, there are problems that a number of the steps is so many and a yield of the resulting compound is low and the like.
SUMMARY OF THE INVENTION
An object of the present invention is to overcome the above-mentioned problems and to provide an industrially useful process for producing a 2-substituted thiopyrimidine-4-carboxylate by a simple and easy method with single step to produce a 2-substituted thiopyrimidine-4-carboxylate with a high yield.
The above object of the present invention can be accomplished by a process for producing a 2-substituted thiopyrimidine-4-carboxylate represented by the formula (3):
wherein R
2
represents a substituted or unsubstituted hydrocarbon group and R
3
represents a hydrocarbon group,
which comprises reacting an &agr;-keto ester compound represented by the formula (1):
R
1
OCH═CHCOCO
2
R
2
(1)
wherein R
1
represents a substituted or unsubstituted hydrocarbon group, and R
2
has the same meaning as defined above,
with an isothiourea compound represented by the formula (2):
wherein R
3
has the same meaning as defined above.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The &agr;-keto ester compound to be used in the reaction of the present invention is represented by the above-mentioned formula (1). In the formula (1), R
1
and R
2
each represent a substituted or unsubstituted hydrocarbon group, and for example, there may be mentioned an alkyl group preferably having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, a butyl group, etc.; an aralkyl group preferably having 7 to 12 carbon atoms such as a benzyl group, a phenethyl group, a phenylpropyl group, etc.; an aryl group preferably having 6 to 14 carbon atoms such as a phenyl group, a naphthyl group, an anthryl group, etc. Incidentally, these groups may include various kinds of isomers.
As the above-mentioned substituent, there may be mentioned, for example, an alkoxy group preferably having 1 to 6 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group, etc. (these groups include various kinds of isomers); a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc. Incidentally, a number of the substituents or a position thereof is not specifically limited.
The above-mentioned &agr;-keto ester compound can be easily synthesized by the method as disclosed in, for example, Synthesis (1988) 274, and more specifically, there may be mentioned, for example, methyl 4-methoxy-2-oxo-3-butenoate, methyl 4-ethoxy-2-oxo-3-butenoate, methyl 4-n-propoxy-2-oxo-3-butenoate, methyl 4-n-butoxy-2-oxo-3-butenoate, ethyl 4-methoxy-2-oxo-3-butenoate, ethyl 4-ethoxy-2-oxo-3-butenoate, ethyl 4-n-propoxy-2-oxo-3-butenoate, ethyl 4-n-butoxy-2-oxo-3-butenoate, n-propyl 4-methoxy-2-oxo-3-butenoate, n-propyl 4-ethoxy-2-oxo-3-butenoate, n-propyl 4-n-propoxy-2-oxo-3-butenoate, n-propyl 4-n-butoxy-2-oxo-3-butenoate, n-butyl 4-methoxy-2-oxo-3-butenoate, n-butyl 4-ethoxy-2-oxo-3-butenoate, n-butyl 4-n-propoxy-2-oxo-3-butenoate, n-butyl 4-n-butoxy-2-oxo-3-butenoate, phenyl 4-methoxy-2-oxo-3-butenoate, phenyl 4-ethoxy-2-oxo-3-butenoate, phenyl 4-n-propoxy-2-oxo-3-butenoate, phenyl 4-n-butoxy-2-oxo-3-butenoate, etc.
The isothiourea compound to be used in the reaction of the present invention is represented by the above-mentioned formula (2). In the formula (2), R
3
represents a hydrocarbon group, and there may be mentioned, for example, an alkyl group preferably having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, a butyl group, etc.; an aryl group preferably having 6 to 14 carbon atoms such as a phenyl group, a naphthyl group, an anthryl group, etc. Incidentally, these groups may include various kinds of isomers.
The above-mentioned isothiourea compound may specifically include, for example, an alkyl isothiourea such as methyl isothiourea, ethyl isothiourea, propyl isothiourea, butyl isothiourea, etc.; an aryl isothiourea such as phenyl isothiourea, naphthyl isothiourea, anthryl isothiourea, etc., and preferably an alkyl isothiourea is used. These isothiourea compounds can be used not only as a free isothiourea compound (including a hydrate), but also as an acidic salt such as a hydrochloride, sulfate, nitrate, phosphate, etc., and an aqueous solution thereof may be also used.
An amount of the above-mentioned isothiourea compound to be used is preferably 0.1 to 20 mol, more preferably 0.3 to 10 mol, particularly preferably 0.5 to 5 mol based on 1 mol of the &agr;-keto ester compound.
The reaction of the present invention is preferably carried out in the presence of a base. As the base to be used, there may be mentioned, for example, amines such as triethylamine, diisopropylamine, pyridine, etc.; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, etc., preferably amines, more preferably triethylamine. Incidentally, these bases may be used alone or in combination of two or more.
An amount of the base to be used is preferably 0.05 to 60 mol, more preferably 0.1 to 30 mol based on 1 mol of the &agr;-keto ester compound.
The reaction of the present invention is carried out in the presence or absence of a solvent. As the solvent to be used, it is not particularly limited so long as it does not pertain the reaction, and there may be mentioned, for example, water; alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, t-butyl alcohol, etc.; amides such as N,N-di-methylformamide, N,N-dimethylacetamide, N,N′-dimethyl-2-imidazolidone, etc.; nitriles such as acetonitrile, propionitrile, benzonitrile, etc.; carboxylic acid esters such as methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, n-butyl propionate, methyl butyrate, ethyl butyrate, n-propyl butyrate, n-butyl butyrate, etc., preferably amides or nitriles are used. Incidentally, these solvents may be used alone or in combination of two or more.
An amount of the solvent to be used may be optionally adjusted depending on uniformity or stirrability of the solution, and it is preferably 1 to 500 ml, more preferably 2 to 100 ml based on 1 g of the &agr;-keto ester compound.
The reaction of the present invention is carried out, for example, by mixing the &agr;-keto ester compound, isothiourea compound, base and solvent in an atmosphere of an inert gas, and stirring the mixture or the like. A reaction temperature at the time is preferably 0 to 200° C., more preferably 10 to 150° C. and s reaction pressure is not specifically limited. A reaction t
Matsushita Akio
Nakamura Taku
Oue Masayoshi
Yamada Shuji
Yoshii Kiyotaka
Ford John M.
Frishauf Holtz Goodman & Chick P.C.
Ube Industries Ltd.
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