NOVEL PROCESS FOR PREPARATION OF 2-AMINOTHIAZOLE CARBOXAMIDE DERIVATIVES
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to a novel process for preparation of 2-aminothiazole carboxamide derivatives represented by the following formula (I). More specifically, the present invention relates to a process for preparing a compound of formula (I), using a certain thiocarbamyl compound (formula II) as a starting material of reaction:
wherein
R1 is C1-5linear or branched alkyl, C1-5 haloalkyl or C3-6 cycloalkyl; and
R2 is C1-3 alkyl orC1-3 haloalkyl.
Description of the Related Art
The compound of formula (I) as described above is a microbicidal substance that is used to control plant diseases caused by any of various fungi of the family Pythiaceae and Peronosporaceae (known as the downy mildew fungi), and is disclosed in Korean Patent Laid-open Publication No. 1995-0005827, entitled "Novel 2-aminothiazole carboxamide derivatives, process for preparing the same and use thereof for controlling phytopathogenic organsims". In addition, Korean Patent Laid-open Publication No. 1999-0000959 discloses a process for preparation of 2-aminothiazole carboxamide derivatives including the above compound of formula (1). This process utilizes 2-aminothiazolecarboxylic acid as an intermediate and suffers from disadvantages in that obtaining of the intermediate involves large numbers of steps upon industrial application, and in particular, productivity of the compound thus obtained is low, thus being economically undesirable.
Therefore, as an attempt to solve such problems, the applicant of the present invention has provided a process for preparing a compound of formula (I) by reacting a thiophene acetamide compound represented by the following formula (III) with an iminothiourea compound represented by the following formula (IV), which is disclosed in Korean Patent Laid-open Publication No. 2000-0021443 and PCT Publication No. WO 00/18766, assigned to the present applicant.
wherein
R1 and R are the same as defined in formula (I);
R7 is phenyl which may be optionally mono- to penta-substituted independently by chloride, methoxy, ethoxy, phenoxy or nitro; and
Y is a leaving group such as chloride and bromide.
More specifically, the synthetic procedure for preparing the compound of formula (I) can be depicted in Reaction Scheme 1 below:
[Reaction Scheme 1 ]

From a point of commercial production, the method of Reaction Scheme 1 is an advanced version for preparing the compound of formula (I), as compared to the initial method using 2-aminotliiazole carboxylic acid as an intermediate compound, which was disclosed in Korean Patent Laid-open Publication No. 1999-0000959.
However, the synthesis method according to Reaction Scheme 1 suffers from a low reaction yield in a range of about 70 to 75% and as a result, there still remains a need in the art for the development of higher-efficiency production process capable of improving such a low yield. Further, the process according to Reaction Scheme 1 leaves much room for improvement such as the possibility of production of byproducts due to side reactions of alcohols resulting from use of alcohol compounds alone as a solvent, and decomposition of reactants and products resulting from use of excessive amounts (1.5 equivalents) of a base.
SUMMARY OF THE INVENTION
As a result of a variety of extensive and intensive studies and experiments, the inventors of the present invention have discovered a novel process for preparing the compound of formula (I) which is totally different from conventional processes in the art, and have confirmed that such a process in accordance with the present invention can easily solve the above-mentioned problems suffered by conventional arts and other technical problems that have been desired to be solved from the past. That is, the process for preparing the compound of formula (I) in accordance with the present invention can prepare a desired compound with a high reaction yield within a short period of time under mild reaction conditions. Further, in accordance with the present invention, it is possible to inhibit side reactions due to no use of an alcohol solvent upon
selection of more favorable solvents, and it is also possible to substantially prevent decomposition of reactants upon use of a small amount of a base. The present invention has been completed based on these findings.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
In accordance with the present invention, the above and other objects can be accomplished by the provision of a process for preparing a compound represented by formula (I):
R1 is C1-5linear or branched alkyl, C1-5haloalkyl or C3-6 cycloalkyl; and R2 is C1-3alkyl or C1-3 haloalkyl;
which comprises reacting a thiocarbamyl compound represented by the following formula (II):
R1 is C1-5 linear or branched alkyl, C1-5 haloalkyl or C3-6 cycloalkyl; R2 is C1-3 alkyl or C1-3 haloalkyl; and
R3 is NH2, NR4R5 wherein R4 and R5are independently C1-3 alkyl, substituted or unsubstituted phenyl, -(CH2)n- or -(CH2)2-X-(CH2)2-, n being 4 or 5 and X being O, NH or S, or OR6 wherein R6is C1-3 alkyl;
with a thiopheneacetamide compound represented by the following formula (III):
wherein Y is a leaving group and may be, for example a halogen such as chloride and bromide, in the presence of a base.
The iminothiourea compound of formula (IV), which was used as a starting material in above-mentioned conventional method, contains a primary amine consisting of substituted or unsubstituted phenyl as a leaving group of the reaction, whereas the compound of formula (II), which was used as a starting material in the preparation method of the present invention, is characterized in that it contains ammonia, a secondary amine and an alcohol as the leaving group of the reaction.
In accordance with the process of the present invention, a desired compound, i.e., the compound of formula (I) can be prepared by reacting the compound of formula
(II) with the compound of formula (III) in the presence of a base in a solvent, as depicted in the following Reaction Scheme 2:
Examples of the solvent used in the process of the present invention include alcohol compounds such as methanol, ethanol and isopropyl alcohol; aromatic hydrocarbon compounds such as benzene, toluene and xylene; ether compounds such as diethylether, dioxane, 1,2-dimethoxyethane and tetrahydrofuran; ketone compounds such as acetone, methylethyl ketone and cyclohexanone; nitrile compounds such as acetonitrile and propionitrile; halogenated hydrocarbon compounds such as dichloromethane, 1,2-dichloroethane and chloroform; ester compounds such as methyl acetate and ethyl acetate; and polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide and dimethylsulfoxide. Among those compounds, particularly preferred is the aromatic hydrocarbon compound, toluene.
Examples of the base that can be used in the present invention include organic bases such as triethylamine, tributylamine, diisopropylethylamine, N,N-dimethylaniline, pyridine and 4-dimethylaminopyridine, and inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydride and potassium hydride. More preferred is the organic base. Particularly preferred examples of the organic base may include alkyl amines such as triethylamine, tributylamine and diisopropylethylamine. In addition, the base may be used in an amount of 0.2 to 5 equivalents, preferably in an amount of 0.2 to 1 equivalent.
The reaction can be carried out at a temperature of 20 to 120, particularly preferably a temperature of 30 to 50. The reaction time is suitably in a range of 3 to 6 hours.
The present invention uses the thiocarbamyl compound of formula (II) as a starting material for preparing the compound of formula (I) and therefore provides a variety of advantages as follows, as compared to conventional methods:
First, the present invention provides a very high reaction yield of 90 to 95%, thus resulting in achievement of a high-efficiency process.
Second, the reaction can be carried out at a relatively low temperature and the reaction time can be significantly reduced. Therefore, it is possible to prepare a desired compound within a short period of time under mild conditions.
In addition, where the aromatic hydrocarbon compound such as toluene is used as a preferred reaction solvent, it is possible to inhibit side reactions which occur upon using alcohols as the solvent, as shown in conventional arts.
Finally, where the base is used in a small amount of less than 1.0 equivalent, it is also possible to substantially prevent decomposition of reactants and/or products which results from use of excessive amounts of the base.
Hereinafter, respective exemplary methods for preparing the thiocarbamyl compounds of formula (II) will be illustrated depending upon kinds of substituents of R3 (NH2, NR4R5 and OR6).
First, a thiocarbamyl amidine compound represented by the following formula (V) wherein R3 in the formula (II) is NR4R5 can be prepared by a process comprising the steps of:
reacting an amide compound represented by the following formula (VI):


wherein R1, R2, R4 and R5are the same as defined in formulae 1 and 2, with a halogenating agent in a solvent, thus converting the amide compound of the formula (VI) into a Vilsmeyer intermediate represented by the following formula (VII) (hereinafter, referred to as Step 1):wherein R , R and R are the same as defined in formulae 1 and 2;
reacting the resulting Vilsmeyer intermediate of the formula (VII) with ammonia to substitute chloride, thus converting the compound of the fonnula (VII) into an amidine compound represented by the following formula (VIII) (hereinafter, referred to as Step 2):
wherein R2, R4 and R5 are the same as defined in formulae I and 2; and
reacting the resulting amidine compound of the formula (VIII) with an isothiocyanate compound represented by the following fonnula(IX):
R'NCS (IX)
wherein R1 is the same as defined in formulae 1 and 2, in the presence of a base to produce a compound represented by the following formula(V) (hereinafter, referred to as Step 3):
wherein R , R , R and R are the same as defined in formulae 1 and 2.
The above reaction process can be depicted as in Reaction Scheme 3 below:

In Reaction Scheme 3, the halogenating agent that can be used in the reaction of Step 1 for preparing the Vilsmeyer intermediate of the formula (VII) includes for example, thionyl chloride (SOCl2), phosgene (COCl2) and phosphorus oxychloride
(FOCl3)). A suitable amount of the halogenating agent used herein is in a range of 1 to 4 equivalents. The reaction can be carried out at a temperature of -20 to 8O, preferably a temperature of -5 to 40. The reaction time is suitably 2 to 6 hours. Examples of the reaction solvent used herein include aromatic hydrocarbon compounds such as benzene, toluene and xylene; halogenated hydrocarbon compounds such as dichloromethane, 1,2-dichloroethane and chloroform; ether compounds such as diethylether, dioxane, 1,2-dimethoxyethane and tetrahydrofuran; and ketone compounds such as acetone, methylethylketone and cyclohexanone. Inter alia, more preferred are halogenated hydrocarbon compounds such as dichloromethane, 1,2-dichloroethane and chloroform. If necessary, N,N-dimethylformamide may be used as a catalyst.
A suitable amount of ammonia used in the reaction of Step 2 is in a range of 2 to 8 equivalents. The reaction is suitably carried out at a temperature of -15 to 30 for 3 to 6 hours.
The base that can be used in the reaction of Step 3 includes organic bases such as triethylamine, tributylamine, diisopropylethylamine, N,N-dimethylaniline, pyridine and 4-dimethylaminopyridine, and inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydride and potassium hydride. Preferably, the inorganic base is used. Particularly preferred is sodium hydroxide. The base may be used in an amount of 1.0 to 4 equivalents, preferably in an amount of 1.0 to 2.0 equivalents.
The suitable amount of the isothiocyanate compound of formula (IX) used in Step 3 is in a range of 1 to 2 equivalents. The reaction may be carried out at a temperature of 0 to 5O, more preferably a temperature of 10 to 30. The reaction time is suitably in a range of 4 to 7 hours.
A thiocarbamyl imidate compound represented by the following formula (XIII) wherein R3 in the formula (II) is OR6 can be prepared by a process comprising the steps of:
reacting a nitrile compound represented by the following formula (X):
R2CN (X)
wherein R2 is the same as defined in formulae 1 and 2, with an alcohol compound represented by the following formula (XI):
wherein R6 is the same as defined in formulae 1 and 2, in the presence of hydrochloric gas, thus converting the nitrile compound of the formula (X) into a imidate compound represented by the following formula (XII) (hereinafter, referred to as Step 1):
wherein R2 andR6 are the same as defined in formulae 1 and 2; and
reacting the resulting imidate compound of formula (XII) with the isothiocyanate compound of formula (IX) in the presence of a base, thus preparing a compound represented by the following formula (XIII) (hereinafter, referred to as Step 2):
wherein R1, R and R6 are the same as defined in formulae 1 and 2.
The above reaction process can be depicted as in Reaction Scheme 4 below:
In the reaction of Step 1, hydrochloric gas is suitably used in an amount of 1 to 5 equivalents, the reaction temperature is suitably in a range of -10 to 30 and the reaction time is suitably in a range of 5 to 15 hours. In fact, the alcohol compound of formula (XI) also serves as a solvent.
Examples of the solvent that can be used in the reaction of Step 2 include aromatic hydrocarbon compounds such as benzene, toluene and xylene; halogenated hydrocarbon compounds such as dichloromethane, 1,2-dichloroethane and chloroform; ether compounds such as diethylether, dioxane, 1,2-dimethoxyethane and tetrahydrofuran; ketone compounds such as acetone, methyl ethyl ketone and cyclohexanone; and ester compounds such as methyl acetate and ethyl acetate. Particularly preferred is toluene. The base that can be used in the reaction of Step 2 includes organic bases such as triethylamine, tributylamine, diisopropylethylamine, N,N-dimethylaniline, pyridine and 4-dimethylaminopyridine, and inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide,
potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydride and potassium hydride. More preferred is the organic base. The base can be used in an amount of 1.0 to 4 equivalents. A suitable amount of the isothiocyanate compound of formula (IX) used herein is in a range of 1 to 2 equivalents. The reaction may be carried out at a temperature of 10 to 120. The reaction time is suitably in a range of 2 to 5 hours.
A thiocarbamyl amidine compound represented by formula (XV) wherein R3 in the formula (II) is NH2 can be prepared by a process comprising the steps of:
reacting the imidate compound of formula (XII) with ammonia gas, thus converting the imidate compound of formula (XII) into an amidine compound represented by the following formula (XIV) (hereinafter, referred to as Step 1):
wherein R is the same as defined in formulae 1 and 2; and
reacting the resulting amidine compound of formula (XIV) with the isothiocyanate compound of formula (IX) in the presence of a base in a solvent, thus preparing a compound represented by the following formula (XV) (hereinafter, referred to as Step 2):

wherein R1 and R2 are the same as defined in formulae 1 and 2.
The above reaction process can be depicted as in Reaction Scheme 5 below:

In the reaction of Step 1, a suitable amount of ammonia used is in a range of 3 to 7 equivalents. The reaction temperature is suitably in a range of-15 to 25 and the reaction time is suitably in a range of 1 to 5 hours.
In the reaction of Step 2, the usable base includes, for example aromatic hydrocarbon compounds such as benzene, toluene and xylene; halogenated hydrocarbon compounds such as dichloromethane, 1,2-dichloroethane and chloroform; ether compounds such as diethylether, dioxane, 1,2-dimethoxyethane and tetrahydrofuran; ketone compounds such as acetone, methylethyl ketone and cyclohexanone; nitrile compounds such as acetonitrile and propionitrile; and ester compounds such as methyl acetate and ethyl acetate. Particularly preferred is the nitrile compound. The base that can be used in the reaction of Step 2 includes organic bases such as triethylamine,
tributylamine, diisopropylethylamine, N,N-dimethylaniline, pyridine and 4-dimethylaminopyridine, and inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydride and potassium hydride. More preferred is the inorganic base. The base can be used in an amount of 1.0 to 4 equivalents, preferably an amount of 1.0 to 2.0 equivalents. A suitable amount of the isothiocyanate compound of formula (IX) used herein is in a range of 1 to 2 equivalents. The reaction may be carried out at a temperature of 10 to 120 . The reaction time is suitably in a range of 2 to 5 hours.
The above-illustrated synthetic methods will be more specifically described in Preparative Examples which will be followed hereinafter, and the representative ones of compounds of formula (II) in accordance with the present invention thus prepared are given in Table 1 below.
Meanwhile, regarding the thiophene amide compound of formula (III) which was used as another starting material in Reaction Scheme 2, the preparation thereof was known from Korean Patent Laid-open Publication No. 2000-0021443 and PCT

Publication WO 00/18766, the disclosures of which are incorporated by reference herein in their entirety, and therefore details thereof will be omitted herein.
EXAMPLES
Now, the present invention will be described in more detail with reference to the following examples. These examples are provided only for illustrating the present invention and should not be construed as limiting the scope and spirit of the present invention.
Preparative Example 1: Synthesis of l-ethylthiocarbamyl-2-ethyl-3.3-diethyl amidine (Compound 2 in Table 1)
12.92 g (0.1 mol) of diethylpropionamide was dissolved in 50 mL of dichloromethane and the resulting solution was cooled to 10. Then, 23 g (0.15 mol) of phosphorus oxychloride was added dropwise thereto over 1 hour. The mixture was stirred at a temperature of about 30D for 4 hours and cooled to -10D, and 13.6 g (0.8 mol) of ammonia was added dropwise thereto over 4 hours while maintaining the temperature below 20D. The resulting white solids were filtered and washed with 1.5 L of dichloromethane. An aqueous sodium hydroxide solution (0.1 mol) was added to the thus-obtained dichloromethane solution, to which 8.71 g (0.1 mol) of ethylisothiocyanate was then added dropwise over 1 hour while maintaining the temperature below 10, followed by stirring at room temperature for 5 hours. After the reaction was complete, the layers were separated and washed with water, and dichloromethane was removed by distillation in vacuo. The residue was recrystallized
from toluene/hexane and filtered at 10D . After drying, 18.31 g (85.0 mmol) of the title compound as light yellow solids was afforded in a yield of 85%.
'H NMR (DMSO-d6): d 8.40(0.6H, s), 8.33(0.4H, s), 3.41 (1.2H, qd), 3.36-3.26(4H, m), 3.04(0.8H, qd), 2.83(0.8H, q), 2.60(1.2H, q), 1.1-0.97(12H, m)
Preparative Example 2: Synthesis of l-ethylthiocarbamyl-2-ethvl-3-methyl-3-phenyl amidine (Compound 3 in Table 1)
3.26 g (20 mmol) of N-methyl-N-phenylpropionamide was dissolved in 10 mL of dichloromethane and the resulting solution was cooled to 10. Then, 4.6 g (30 mmol) of phosphorus oxychloride was added dropwise thereto over 1 hour. The mixture was stirred at a temperature of about 30 for 4 hours and cooled to -10, and 2.72 g (0.16 mol) of ammonia was added dropwise thereto over 4 hours while maintaining the temperature below 20. The resulting white solids were filtered and washed with 0.3 L of dichloromethane. An aqueous sodium hydroxide solution (20 mmol) was added to the thus-obtained dichloromethane solution, to which 1.74 g (20 mmol) of ethylisothiocyanate was then added dropwise over 1 hour while maintaining the temperature below 10, followed by stirring at room temperature for 5 hours. After the reaction was complete, the layers were separated and washed with water, and dichloromethane was removed by distillation in vacuo. The residue thus obtained was separated by column chromatography to afford 1.45 g (6.7 mmol) of the title compound with a yield of 34%.
Among the thiocarbamyl amidine compounds of formula (V), thiocarbamyl amidine compounds of Compounds 1, 4 and 5 exemplified in Table 1 are synthesized analogously to Preparative Example 1.
Preparative Example 3: Synthesis of l-ethylthiocarbamyl-2-ethyl-3-ethyl-imidate (Compound 7 in Table 1)
1.1 g (20 mmol) of propionitrile was dissolved in 20 mL of ethanol and 2.92 g (80 mmol) of hydrochloric gas was introduced thereto at 0°C over 1 hour, and the resulting solution was stirred for 10 hours to prepare imidate-hydrochloride. Thereafter, the ethanol was removed by distillation in vacuo, and 20 mL of toluene, 6.1 g (60 mmol) of triethylamine and 1.92 g (22 mmol) of ethylisothiocyanate were added thereto. The resulting mixture was elevated and refluxed for 3 hours. Toluene was removed by distillation in vacuo and the residue thus obtained was separated by column chromatography to afford 2.83 g (15.0 mmol) of the title compound with a yield of 75%.
Preparative Example 4: Synthesis of l-ethylthiocarbamyl-2-elhyl amidine (Compound 6 in Table 1)
1.1 g (20 mmol) of propionitrile was dissolved in 20 mL of ethanol and 2.92 g (80 mmol) of hydrochloric gas was introduced thereto at 0°C over 1 hour, and the resulting mixture was stirred for 10 hours to prepare imidate-hydrochloride.
The resulting imidate-hydrochloride was cooled to -10D, and 2.04 g (120 mmol) of ammonia was added thereto over 1 hour while being maintained at a temperature below 20D, thereby converting the imidate-hydrochloride into an amidine compound. Ethanol was removed by distillation in vacuo, and 30 mL of acetonitrile, 4.24 g (40 mmol) of sodium carbonate and 1.92 g (22 mmol) of ethylisothiocyanate were added thereto. The resulting mixture was elevated and refluxed for 3 hours.
Acetonitrile was removed by distillation in vacuo and the residue thus obtained was separated by column chromatography to afford 0.86 g (5.4 mmol) of the title compound with a yield of 27%.
Starting from compounds given in Table 1, synthesis of 4-ethyl 2-ethylamino-thiazole-5-carboxylic acid (cyano-thiophen-2-yl-methyl)-amide was carried as in the following examples.
Example 1: Synthesis of 4-ethyl 2-ethylamino-thiazole-5-carboxylic acid (cyano-thiophen-2-yl-methyl)-amide (using 1 -ethvlthiocarbamyl-2-ethyl-3,3-diethyl amidine. Compound 2 in Table 1)
21.54 g (0.1 mol) of l-ethylthiocarbamyl-2-ethyl-3,3-diethyl amidine, 21.47 g (0.1 mol) of 2-chloro-N-(cyano-thiophen-2-yl-methyl)-acetamide and 2.02 g (0.02 mol) of triethylamine were sequentially introduced into 200 mL of toluene, and the mixture was stirred at room temperature for 4 hours to completion of the reaction. Toluene was removed by distillation in vacuo, and then the mixture was recrystallized from acetone and water and dried to afford 30.12 g (94.0 mmol) of the title compound with a yield of 94%.
'H NMR (CDC13): 8 7.38(1H, d), 7.33(1H, d), 7.04(1H, t), 6.43(1H, d), 5.94(1H, d, br), 5.59(1H, s, br), 3.26(2H, q), 2.93(2H, q), 1.26(6H, m)
Example 2: Synthesis of 4-ethyl 2-ethylamino-thiazole-5-carboxylic acid (cyano-thiophen-2-yl-methvl)-amide (using 1 -ethylthiocarbaniyl-2-ethy1-3-methyl-3-phenyl amidine, Compound 3 in Table 1)
2.49 g (10 mmol) of l-ethylthiocarbamyl-2-ethyl-3-methyl-3-phenyl amidine, 2.15 g (10 mmol) of 2-chloro-N-(cyano-thiophen-2-yl-methyl)-acetamide and 1.11 g (11 mmol) of triethylamine were sequentially introduced into 20 mL of acetonitrile, and the mixture was stirred at room temperature for 5 hours to completion of the reaction. Acetonitrile was removed by distillation in vacuo, and then the mixture was recrystallized from methanol and water and dried to afford 2.88 g (9 mmol) of the title compound with a yield of 90%.
Example 3: Synthesis of 4-ethyl 2-ethylamino-thiazole-5-carboxylic acid (cyano-thiophen-2-yl-methyl)-amide (using l-ethylthiocarbamyl-2-ethyl amidine. Compound 6 in Table 1)
1.59 g (10 mmol) of l-ethylthiocarbamyl-2-ethyl amidine, 2.15 g (10 mmol) of 2-chloro-N-(cyano-thiophen-2-yl-methyl)-acetamide and 1.11 g (11 mmol) of triethylamine were sequentially introduced into 20 mL of methanol, and the mixture was elevated to 60 °C and stirred at that temperature for 5 hours. Methanol was removed by distillation in vacuo, and then the mixture was recrystallized from methanol and water and dried to afford 1.09 g (3.4 mmol) of the title compound with a yield of 34%.
Example 4: Synthesis of 4-ethyl 2-ethylamino-thiazole-5-carboxylic acid (cyano-thiophen-2-vl-methy])-amide (using 1 -ethylthiocarbamyl-2-ethyl-3-ethyl imidate, Compound 7 in Table 1)
1.88 g (10 mmol) of l-ethylthiocarbamyl-2-ethyl-3-ethyl imidate, 2.15 g (10 mmol) of 2-chloro-N-(cyano-thiophen-2-yl-methyl)-acetamide and 1.11 g (11 mmol) of
triethylamine were sequentially introduced into 20 mL of toluene, and the mixture was elevated to 70 °C and stirred at that temperature for 6 hours. Toluene was removed by distillation in vacuo, and then the mixture was recrystallized from methanol and water and dried to afford 17.7 g (55.2 mmol) of the title compound with a yield of 55.2%.
Further, using Compounds 1, 4 and 5 given in Table 1, 4-ethyl 2-ethylamino-thiazole-5-carboxylic acid (cyano-thiophen-2-yl-methyl)-amide was prepared in the same manner as in the above-mentioned Examples.
As apparent from the above description, in accordance with the preparation method of the present invention, it is possible to prepare compounds of formula (I) with a high reaction yield within a short period of time under mild reaction conditions, using a thiocarbamyl compound (a compound of formula II) as a starting material. Further, in accordance with the present invention, it is possible to inhibit side reactions by selection of preferred solvents, and it is also possible to substantially prevent decomposition of products by a preferred amount of a base.
Although the preferred embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims.

WHAT IS CLAIMED IS:
1. A process for preparing a 2-aminothiazole carboxamide derivative represented by formula (I):
wherein
R1 is C1-5 linear or branched alkyl, C1-5 haloalkyl or C3-6, cycloalkyl; and
R is C1-3 alkyl orC1-3 haloalkyl;
which comprises reacting a thiocarbamyl compound represented by formula
R1 is C1-5 linear or branched alkyl, C1-5 haloalkyl or C3-6 cycloalkyl;
R2 is C1-3 alkyl orC1-3 haloalkyl; and
R3 is NH2, NR4R5 wherein R4 and R5are independently C1-3 alkyl, substituted or unsubstituted phenyl, -(CH2)n- or -(CH2)2-X-(CH2)2-, n being 4 or 5 and X being O, NH or S, or OR6 wherein R6 is CM alkyl,
with a thiophene acetamide compound represented by formula (III):

(III) wherein Y is a leaving group, in the presence of a base.
2. The process according to claim 1, wherein the reaction is carried out in a
solvent selected from the group consisting of an alcohol compound, an aromatic
hydrocarbon compound, an ether compound, a ketone compound, a nitrile compound, a
halogenated hydrocarbon compound, an ester compound and a polar solvent.
3. The process according to claim 2, wherein the solvent of the aromatic
hydrocarbon compound is toluene.
4. The process according to claim 1, wherein the base is an organic base or an
inorganic base.
5. The process according to claim 4, wherein the base is the organic base.
6. The process according to claim 5, wherein the organic base is an alkyl
amine.
7. The process according to claim 1, wherein the base is used in an amount of
0.2 to 5 equivalents.
8. The process according to claim 7, wherein the base is used in an amount of
0.2 to 1 equivalent.
9. The process according to claim 1, wherein the reaction is carried out at a
temperature of 20 to 120D for 3 to 6 hours.
10. The process according to claim 9, wherein the reaction temperature is in a
range of 30 to 5O.