The present invention relates to a process for preparation of an thiopheneacetamide compound represented by the following formula (III):
(Formula Removed)
The present invention further relates to a process for preparation of a 2-ammothiazolecarboxamide derivates represented by the following formula (I);
(Formula Removed) Wherein R1 represents straight-chain or branched C1-5 alkyl, C1-5 haloalkyl, or C3-6 cycloalkyl, and R2 represents C1-3 alkyl or C1-3 haloalkyl.
BACKGROUND ART
The compounds of formula (I) are used as microbicides for treating plant disease caused by Pythiaceae or Peronosporaceace. The compounds of formula (I) were already disclosed in Korean Patent Laid-open publication number 94-19960 and the corresponding foreign Applications, for example, U.S. Patent Application number 08/287,917, JP Patent Application number 192529 and EP Patent Application number 94112652.6 which were filed by the present Applicant.
Further, a process for preparation of 2-aminothiazolecarboxamide derivatives including the compounds of formula (I) using 2-aminothiazole carboxylic acid as an intermediate was described in Korean Patent Laid-open Publication number 97-24120. however, this process has the disadvantage that it is not economic when applied to industrial production due to the many steps for obtaining the intermediate and the low yield.
Accordingly, the present inventors have studied to improve the prior process by solving the above mentioned problems, and as a result, have brought the present invention to completion
DISCLOSURE OF THE INVENTION
The present invention relates to a process for preparation of a 2-aminothiazolecarboxamide derivative represented by the above formula (I) characterized in that an iminothiourea compound represented by the following formula (II):
(Formula Removed) wherein R and R are defined as previously described, and R represents phenyl which may be optionally mono- to penta-substituted independently by chloro, methoxy, ethoxy, phenoxy or nitro, is reacted with a thiopheneacetamide compound represented by the following formula (III):
(Formula Removed) wherein Y represents a leaving group such as chloride, bromide, etc..
BEST MODE FOR CARRYING OUT THE INVENTION
The compound of formula (1) can be prepared by reacting the compound of formula (II) with the compound of formula (III) in a solvent and
in the presence of a base as depicted in the following Reaction Scheme I:
[Reaction Scheme I]
(Scheme Removed)
wherein R1, R2 , R3 and Y are defined as previously described.
Examples of the base used in the above reaction include an organic
base such as triethyiamine, tributylamine, diisopropylethylamine,
N,N-dimethylaniIine, pyridine, 4-dimethylaminopyridine, etc., and an inorganic
base such as sodium hydroxide, potassium hydroxide, potassium carbonate,
sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydride,
potassium hydride, etc. The organic base is preferred, and the alkyl amine
such as triethyiamine, tributylamine, diisopropylethylamine, etc. is more
preferred. The base can be used in an amount of 1 to 5 equivalents,
preferably in an amount of 1 to 2 equivalents
The above reaction can be carried out at the temperature between 20 and 120°C, preferably between 40 and 80°C and the reaction time is suitably about 8 to 12 hours

The solvent includes an alcohol such as methanol, ethanol, isopropyl alcohol, etc.; an aromatic hydrocarbon such as benzene, toluene, xylene, etc.; an ether such as diethylether, dioxane, 1,2-dimethoxyethane, tetrahydrofuran, etc.; a ketone such as acetone, methylethyl ketone, cyclohexanone, etc., a nitrile such as acetonitrile, propionitrile, etc; a halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane, chloroform, etc.; an ester such as methyl acetate, ethyl acetate, etc.; and a polar solvent such as N,N-diethylformarnide, N,N-dimethylacetamide, dimethyl sulfoxide, etc., and the alcohol is preferred.
The compound of formula (II) used as a starting material in the Reaction Scheme (I) is novel and can be prepared in accordance with the following Reaction Scheme (II):
[Reaction Scheme II]
(Scheme Removed)
wherein R1, R2 and R3 are defined as previously described
That is, the compound of formula (II) can be prepared by a process characterized in that
in Step 1, an amide compound represented by the following formula (IV):
(Formula Removed) wherein R and R' are defined as previously described, is reacted with a halogenatinu agent in a solvent in the presence of a base to produce an imidoylchloride compound represented by the following formula (V)
(Formula Removed) wherein R2 and R2 are defined as previously described;
in Step 2, the resulting imidoylchloride compound of formula (V) is reacted with an isothiocyanide compound represented by the following formula (VII):
(Formula Removed) wherein M represents an alkali metal such as sodium, potassium, etc., or NH4, by which the chloride group is replaced with the isothiocyanide group to produce an imidoylisothiocyanate compound represented by the following formula (VI)
(Formula Removed) wherein R' and R' arc defined as previously described,
in Step 3. the resulting iinidoylisothiocvanate compound of formula (VI) is reacted with a primary amine compound represented by the following formula
(Formula Removed)
R'-NH2 (wherein R is defined as previously described, in the presence of a base
In Step 1 for preparing the imidoylchloride compound of formula (V).
thionyl chloride(SOCl2), phosgene(COCl2), phosphorus oxychloride(POCh). etc
can be used as the halogenating agent. The halogenating agent is suitably
used in an amount of 1 to 4 equivalents This reaction is carried out at the
temperature between -20°C and 80 °C, preferably between -10°C and 20°C' The reaction time is suitably about 2 to 5 hours As the base, an organic base such as pyridine, 4-dimethylaminopyndine, triethylamine. N,N-dimethyl aniline, tributylamine, etc can be used. A mild base such as pyridine is preferred. The base is suitably used in an amount of 1 to 4 equivalents
As the solvent, an aromatic hydrocarbon such as benzene, toluene, xylene, etc; a halogenated hydrocarbon such as dichloromethane, 1,2-dichioroethane, chloroform, etc.; an ether such as diethylether, dioxane, 1,2-dimethoxyethane, tetrahydrofuran, etc.; a ketone such as acetone, methylethyl ketone, cyclohexanone, etc.; a nitrile such as acetonitrile, propionitrile. etc.; an ester such as methyl acetate, ethyl acetate, etc.; or a polar solvent such as N,N-dimethylforrnamide, N,N-dimethylacetamide, dimethyl sulfoxide, etc., preferably a halogenated hydrocarbon such as dichloroethane, chloroform, etc can be used In addition, N,N-dimethylformamide can be used as a catalyst
In Step 2. the imidoylisothiocyanate compound of formula (VI) is
prepared by reacting the imidoylchloride compound of formula (V) prepared in
step 1 with the lsotmocyanide compound of formula (VII) The thiocyanatye
compound of formula (VII) is suitably used in an amount of 1 to 2 equivalent The reaction temperature can be between -20V. and 50V, preferably between 0 V and 20V. and the reaction time ranges suitably from 2 to 5 hours

In Step 3, the iminothiourea compound of formula (II) is prepared from the imidoylisothiocyanate compound of formula (VI) In this step, the carbon atom of isothiocyanate is attacked by the amine compound of formula (VIII) in the presence of a base, by which the thiourea derivative of formula (II) is produced. The amine compound of formula (VIII) can be used in an amount of 1 to 4 equivalents, preferably 2 to 3 equivalents This reaction can be carried out at the temperature between -20 ( and 80''(.', preferably between O°C, and 30"C. The reaction time is suitably from 2 to 4 hours
The above processes according to the present invention will be more specifically explained through the following examples As typical examples of the compounds of formula (II) according to the present invention, those described in the following table (I) can be mentioned
[Table I] (Table Removed)
The compound of formula (III) used as a starting material in the Reaction Scheme (I) is also a novel compound, and can be prepared in accordance with the following Reaction Scheme (III)
[Reaction Scheme III]
(Scheme Removed)
wherein Y is defined as previously described.
That is, the compound of formula (III) can be prepared by a process characterized in that
in Step 1, an aldehyde compound represented by the following formula (IX):
(Formula Removed)
is converted into an aminonitrile compound represented by the following formula (X):
(Formula Removed)
through the known Streeker Synthesis,
in Step 2, the resulting aminonitrile compound of formula (X) is reacted with a compound represented by the following formula (XI):
(Formula Removed)
Wherein Y is defined as previously described, in the presence of a base.
In step 1 of the above reaction, the aldehyde compound of formula (IX) can be readily converted into the aminonitrile compound of formula (X) through the known Strecker Synthesis as stated above.
In step 2, the thiopheneacetamide compouind of formula (III) can be prepared by recating the aminonitrile compound of formula (X) with 1 to 3 equivalents, preferably 1 to 1.5 equivalents of chloroacetyl chloride or bromoacetyl bromide of formula (XI) in the presence of a base. This reaction can be carried out at the temperature between -20° C and 80° C, preferably between 0° C and 20° C. The reaction time is suitably from 30 minutes to 2 hours.
As the base, an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine, N,N-dimethyl aniline, tributylamine, diisopropylethylamine, etc., preferably pyridine or 4-diemthylamino pyridine can be used. The base can be suitably used in an amount of 1 or 3 equivalents.
As the solvent, a halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane,, chloroform etc,; an aromatic hydrocarbon such as bezene, toluene, xylene etc;, an ether such as diethylether, dioxane, 1, 2-dimethoxy ethane, tetrahydrofuran, etc,; a ketone such as acetone, methylethyl ketone, cyclohexanone, etc,; a nitrile such as acetonitrile, propionitrile, etc,; an ester such as methyl acetate, ethyl acetate, etc,; or a polar solvent such as N,N-dimethylformamide, N,N-diemthylacetamide, dimethyl sulfoxide, etc,; preferably a halogenated hydrocarbon or an aromatic hydrocarbon can be used.
The present invention is more specifically explained by the following preparation and examples. However, it should be understood that the present invention is not limited to these examples in any manner.
In accordance with the present invention it relates to an thiopheneacetamide compound characterized by the following formula (III):
(Formula Removed)
wherein Y represents a leaving group
Preparation 1 : Synthesis of N-phenyl-propionamidc
Into a reaction vessel were placed aniline(279.4g, 3.0mol) and dichloromethane(2400g), the reaction vessel was cooled to 0°C, and sodium hydroxide(132.0g, 3.3mol) dissolved in water(660g) was slowly added dropwise thereto.
It was confirmed that the temperature of the reaction vessel was 0°C, and then propionyl chloride(291.5g, 3.2mol; was added dropwise thereto for 2 hours. And then the mixture was stirred at room temperature(20'C) for 2 hours, and the reaction was completed. After the reaction was completed, the layers were separated, and dichloromethane was removed by distillation under the reduced pressure to produce a brown solid. The solid was recrystallized from toluene to give the title compound(434.7g, 2.9mol) in a yield of 97%.
1H NMR (CDC13) : δ7.750H, s, br), 7.52(2H, d), 7.29(2H, d), 7.08(1H, t), 2.37(2H, q), 1.22(3H, t)
Example 1 : Synthesis of N-ethyI-N'-(l-phenyliminopropyl)-thiourea
N-phenylpropionarnide(149.2g, l.0mol) and pyridine(261.0g, 3.3mo!) were dissolved in dichloromethane(300g), and the mixture was cooled to O'C. Phosphorus oxychloride(168.7g, l.lmol) was added dropwise thereto for 2 hours, and then the mixture was stirred at room temperature (20 °C) for 2 hours to produce N-phenylpropionimidoylchloride
Subsequently, the reactant was slowlv added dropwise to the reaction vessel containing the mixture oi potassium (145.8g, 1.5mol) and sodium carbonate(3!8.0g, 3.0mol) in acetone( l,()00mℓ) at the temperature of 10 Xl or less for 2 hours, and then the mixture was stirred for 1 hour to produce N-phenylpropronimidoyl isothiocyanaic Ethvlamine( 128 8g. 20mo!) was added dropwise 'hereto maintaining the temperature of 10°C or less for 2 hours, and
hen the mixture was stirred for 1 hour
After the reaction was completed the solvent was removed bv
distillation under reduced pressure. And the product was extracted by toluene
and washed with sodium hydroxide solution And then the toluene was
removed by distillation under reduced pressure, and the residue was recrystallized from isopropyl alcohol to give the title compound(157.2g, 0.7mol) in a yield of 67%
1H NMR (CDC13) : -
'H NMR (CDC13) : δ 7.36(1 H, d). 7.30(1 H, d), 7.04(1H, t), 6.10(1H, d), 5.99(1H, s, br). 3.28(211, q), 2.53(311 s). 1.30(311, t)
Example 8 : Synthesis of N-( α -cyano-2-thenyl)-4-ethyl-2-(isopropylamino)-5-thiazolecarboxamide
N-isopropvl-N'-( 1 -phenyliminopropyl)(thiourea(2.5g, 0.0lmol) and
2-bromo-N-(α-cyano-2-thenyl)acetamide(2.6g. 0.0lmol) were dissolved in methanol(20mℓ) And then triethylamine( 1 5g, 0.02mol) was introduced therein, and the mixture was stirred at the temperature of 60°C, for 7 hours.
After the reaction was completed, the solvent was removed by distillation under reduced pressure to produce a brown solid. The solid was recrystallized from the mixture solution of ethanol and water (v/v=l/l) to give the title compound(2.0g, ℓ0.0lmol) in a yield of 60%.
1H NMR (CDC13) : δ 7.38(1H. d). 7.30(1H, d), 7.01(1H, t), 6.44(1H, d), 6.00(1H, d), 5.49(1H, s, br), 3.61(1H, m). 2.91 (2H, q), 1.27(9H, m)
As described above, a 2-aminothiazolecarboxamide derivative of formula (I) can be prepared by using the intermediates of formulae (II) and (III) in the high yield, according to the process of the present invention. And the present process is more economic than the conventional process because of the high yield from the industrial viewpoint

WE CLAIM:
1. A thiopheneacetamide compound of formula (III):
(Formula Removed)
wherein Y represents a leaving group.
2. A compound as claimed in claim 1 wherein Y represents chloride or
bromide.
3. A thiopheneacetamide compound of formula (III) substantially as herein
described with reference to the foregoing description and the accompanying
drawings.