US20020010340A1 - Process for preparation of 2-aminothiazolecarboxamide derivatives - Google Patents
Process for preparation of 2-aminothiazolecarboxamide derivatives Download PDFInfo
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- US20020010340A1 US20020010340A1 US09/777,706 US77770601A US2002010340A1 US 20020010340 A1 US20020010340 A1 US 20020010340A1 US 77770601 A US77770601 A US 77770601A US 2002010340 A1 US2002010340 A1 US 2002010340A1
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- 0 *C(NC(N*)=S)=N* Chemical compound *C(NC(N*)=S)=N* 0.000 description 6
- RIVUGBHKUDYBNM-UHFFFAOYSA-N C/N=C(\C)NC(=S)NC.II Chemical compound C/N=C(\C)NC(=S)NC.II RIVUGBHKUDYBNM-UHFFFAOYSA-N 0.000 description 3
- XAUFZYSIIDIMJM-UHFFFAOYSA-N N#CC(NC(=O)C[Y])C1=CC=CS1 Chemical compound N#CC(NC(=O)C[Y])C1=CC=CS1 XAUFZYSIIDIMJM-UHFFFAOYSA-N 0.000 description 3
- TXNSHUGNPBQRBL-UHFFFAOYSA-N CNC1=NC(C)=C(C(=O)NC(C#N)C2=CC=CS2)S1 Chemical compound CNC1=NC(C)=C(C(=O)NC(C#N)C2=CC=CS2)S1 TXNSHUGNPBQRBL-UHFFFAOYSA-N 0.000 description 2
- NNJQHPAPVHHYEJ-UHFFFAOYSA-N *.N#CC(N)C1=CC=CS1 Chemical compound *.N#CC(N)C1=CC=CS1 NNJQHPAPVHHYEJ-UHFFFAOYSA-N 0.000 description 1
- SSTVQSHQGIONMZ-CPBOOYLUSA-I C.C/N=C(/C)Cl.C/N=C(\C)N=C=S.C/N=C(\C)NC(=S)NC.CN.CNC(C)=O.II.I[V](I)I.[V].[V]I.[V]I Chemical compound C.C/N=C(/C)Cl.C/N=C(\C)N=C=S.C/N=C(\C)NC(=S)NC.CN.CNC(C)=O.II.I[V](I)I.[V].[V]I.[V]I SSTVQSHQGIONMZ-CPBOOYLUSA-I 0.000 description 1
- AAYNVFUFVRZBJT-UHFFFAOYSA-N C.C/N=C(\C)NC(=S)NC.CN.CNC1=NC(C)=C(C(=O)NC(C#N)C2=CC=CS2)S1.II.N#CC(NC(=O)C[Y])C1=CC=CS1.[Y] Chemical compound C.C/N=C(\C)NC(=S)NC.CN.CNC1=NC(C)=C(C(=O)NC(C#N)C2=CC=CS2)S1.II.N#CC(NC(=O)C[Y])C1=CC=CS1.[Y] AAYNVFUFVRZBJT-UHFFFAOYSA-N 0.000 description 1
- XCTMWNLSAUXAEE-FBZPGIPVSA-N C/N=C(/C)Cl.[V] Chemical compound C/N=C(/C)Cl.[V] XCTMWNLSAUXAEE-FBZPGIPVSA-N 0.000 description 1
- MAPKEHAMYNWDJA-SFKRKKMESA-M C/N=C(\C)N=C=S.[V]I Chemical compound C/N=C(\C)N=C=S.[V]I MAPKEHAMYNWDJA-SFKRKKMESA-M 0.000 description 1
- KRMRLDIVOHKDOX-UHFFFAOYSA-M CNC(C)=O.[V]I Chemical compound CNC(C)=O.[V]I KRMRLDIVOHKDOX-UHFFFAOYSA-M 0.000 description 1
- IGYYEVCZQKXVCL-UHFFFAOYSA-N O=C([Y])C[Y] Chemical compound O=C([Y])C[Y] IGYYEVCZQKXVCL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/04—Derivatives of thiourea
- C07C335/24—Derivatives of thiourea containing any of the groups, X being a hetero atom, Y being any atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Definitions
- the present invention relates to a process for preparation of a 2-aminothiazolecarboxamide derivative represented by the following formula (I)
- R 1 represents straight-chain or branched C 1-5 alkyl, C 1-5 haloalkyl, or C 3-6 cycloalkyl
- R 2 represents C 1-3 alkyl or C 1-3 haloalkyl
- the compounds of formula (I) are used as microbicides for treating plant diseases caused by Pythiaceae or Peronosporaceae.
- the compounds of formula (I) were already disclosed in Korean Patent Laid-open Publication No. 94-19960 and the corresponding foreign applications, for example, U.S. patent application Ser. No 08/287,917, JP Patent Application No. 192529 and EP Patent Application No 94112652.6 which were filed by the present applicant.
- the present invention relates to a process for preparation of a 2-arninothiazolecarboxamide derivative represented by the above formula (I) characterized in that an iminothiourea compound represented by the following formula (II):
- R 1 and R 2 are defined as previously described, and R 3 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):
- Y represents a leaving group such as chloride, bromide, etc.
- the compound of formula (I) 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 1.
- R 1 , R 2 , R 3 and Y are defined as previously described.
- Examples of the base used in the above reaction include an organic base such as triethylamine, tributylamine, diisopropylethylamine, N,N-dimethylaniline, 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 triethylamine, 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-diethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, etc., and the alcohol is preferred
- R 1 , R 2 and R 3 are defined as previously described.
- the compound of formula (II) can be prepared by a process characterized in that
- Step 2 the resulting imidoylchloride compound of formula (V) is reacted with an isothiocyanide compound represented by the following formula (VII):
- M represents an alkali metal such as sodium, potassium, etc., or NH 4 , by which the chloride group is replaced with the isothiocyanide group to produce an imidoylisothiocyanate compound represented by the following formula (VI).
- Step 3 the resulting imidoylisothiocyanate compound of formula (VI) is reacted with a primary amine compound represented by the following formula (VIII)
- Step 1 for preparing the imidoylchloride compound of formula (V), thionyl chloride (SOCl 2 ), phosgene (COCl 2 ), phosphorus oxychloride (POCl 3 ), 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.
- an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine, N,N-dimethyl aniline, tributylamine, etc.
- a mild base such as pyridine is preferred.
- the base is suitably used in an amount of 1 to 4 equivalents.
- an aromatic hydrocarbon such as benzene, toluene, xylene, etc.
- a halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane, 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-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, etc., preferably a halogenated hydrocarbon such as dichloroethane, chloroform, etc.
- the imidoylisothiocyanate compound of formula (VI) is prepared by reacting the imidoylchloride compound of formula (V) prepared in step 1 with the isothiocyanide compound of formula (VII).
- the isothiocyanide compound of formula (VII) is suitably used in an amount of 1 to 2 equivalent.
- the reaction temperature can be between ⁇ 20° C. and 50°C., preferably between 0° C. and 20° C., and the reaction time ranges suitably from 2 to 5 hours.
- step 3 the iminothiourea compound of formula (II) is prepared from the imidoylisothiocyanate compound of formula (VI).
- 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° C. and 80° C., preferably between 0° C., and 30° C.
- the reaction time is suitably from 2 to 4 hours.
- 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).
- the compound of formula (III) can be prepared by a process characterized in that
- Step 2 the resulting aminonitrile compound of formula (X) is reacted with a compound represented by the following formula (XI).
- the thiopheneacetamide compound of formula (III) can be prepared by reacting 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.
- an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine, N,N-dimethyl aniline, tributylamine, diisopropylethylamine, etc., preferably pyridine or 4-dimethylamino pyridine can be used.
- the base can be suitably used in an amount of 1 to 3 equivalents.
- 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-dimethylacetamide, dimethyl sulfoxide, etc., preferably a halogenated hydrocarbon or an aromatic hydrocarbon can be used.
- a halogenated hydrocarbon such as dichloromethane, 1,2-
- N-phenylpropionamide (149.2 g, 1.0 mol) and pyridine (261.0 g, 3.3 mol) were dissolved in dichloromethane (300 g), and the mixture was cooled to 0° C.
- Phosphorus oxychloride (168.7 g, 1.1 mol) 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
- the reactant was slowly added dropwise to the reaction vessel containing the mixture of potassium isothiocyanide (145.8 g, 1.5 mol) and sodium carbonate (318.0 g, 3.0 mol) in acetone (1,000 ml) at the temperature of 10° C. or less for 2 hours and then the mixture was stirred for 1 hour to produce N-phenylpropionimidoyl isothiocyanate.
- Ethylamine (128.8 g, 2.0 mol) was added dropwise thereto maintaining the temperature of 10° C. or less for 2 hours, and then the mixture was stirred for 1 hour.
- N-(2,6-dichlorobenzene)propionamide (21.8 g, 0.1 mol) and pyridine (27.7 g, 0.35 mol) were dissolved in dichloromethane (30 g), and the mixture was cooled to 0° C.
- Phosphorus oxychloride (16.9 g, 0.11 mol) was added dropwise thereto for 2 hours, and then the mixture was stirred at room temperature (20° C.) for 2 hours to produce N-(2,6-dichloro benzene)propionimidoylchloride.
- the reactant was slowly added dropwise to the reaction vessel containing the mixture of potassium isothiocyanide (14.6 g, 0.15 mol) and sodium carbonate (31.8 g, 0.3 mol) in acetone (100 ml) at the temperature of 10° C. or less for 2 hours, and then the mixture was stirred for 1 hour to produce N-(2,6-dichlorobenzene)propionimidoyl isothiocyanate.
- Ethylamine (12.9 g, 0.2 mol) was added dropwise thereto maintaining the temperature of 10° C. or less for 2 hours, and then the mixture was stirred for 1 hour.
- N-phenylpropionamide (7.46 g, 0.05 mol) and pyridine (13.8 g, 0.18 mol) were dissolved in dichloromethane (300 g), and the mixture was cooled to 0° C. And then phosphorus oxychloride (8.43 g, 0.05 mol) 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.
- the reactant was slowly added dropwise to the reaction vessel containing the mixture of potassium isothiocyanide (7.3 g, 0.08 mol) and sodium carbonate (15.9 g, 0.15 mol) in acetone (50 ml) at the temperature of 10° C. or less for 2 hours, and then the mixture was stirred for 1 hour to produce N-phenylpropionimidoyl isothiocyanate.
- isopropylamine (5.9 g, 0.1 mol) was added dropwise thereto maintaining the temperature of 10° C. or less for 2 hours, and then the mixture was stirred for 1 hour.
- N-ethyl- N ′-(1-phenyliminopropyl)thiourea (23.5 g, 0.1 mol) and 2-chloro-N-( ⁇ -cyano-2-thenyl)acetamide (21.4 g, 0.1 mol) were dissolved in methaniol (200 ml). And then triethylamine (15.2 g, 0.15 mol) was introduced therein, and the mixture was refluxed for 8 hours.
- N-(1-(2,6-dichlorophenyl)iminopropyl)- N ′-ethylthiourea (3.1 g, 0.1 mol) and 2-chloro- N -( ⁇ -cyano-2-thenyl)acetamide (21.4 g, 0.1 mol) were dissolved in methanol (200 mg). And then triethylamine (15.2 g, 0.15 mol) was introduced therein, and the mixture was refluxed for 8 hours.
- N -ethyl- N ′-(1-phenyliminopropyl)thiourea (22.1 g, 0.1 mol) and 2-chloro-N-( ⁇ -cyano-2-thenyl)acetamide(21.4 g, 0.1 mol) were dissolved in ethanol (200 mg). And then diisopropylethylamine (15.5 g, 0.12 mol) was introduced therein, and the mixture was stirred at the temperature of 60° C. for 10 hours.
- N -isopropyl- N ′-(1-phenyliminopropyl)thiourea (2.5 g, 0.01 mol) and 2-bromo- N -( ⁇ -cyano-2-thenyl)acetamide (2.6 g, 0.01 mol) were dissolved in methanol (20 ml). And then triethylamine (1.5 g, 0.02 mol) was introduced therein, and the mixture was stirred at the temperature of 60° C. for 7 hours
- 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.
Abstract
Description
-
- 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.
- The compounds of formula (I) are used as microbicides for treating plant diseases caused by Pythiaceae or Peronosporaceae. The compounds of formula (I) were already disclosed in Korean Patent Laid-open Publication No. 94-19960 and the corresponding foreign applications, for example, U.S. patent application Ser. No 08/287,917, JP Patent Application No. 192529 and EP Patent Application No 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 No 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.
-
-
- wherein Y represents a leaving group such as chloride, bromide, etc.
-
- 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 triethylamine, tributylamine, diisopropylethylamine, N,N-dimethylaniline, 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 triethylamine, 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-diethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, etc., and the alcohol is preferred
-
- 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
-
-
- wherein R2 and R3 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):
- MSCN (VII)
-
- wherein R2 and R3 are defined as previously described,
- in Step 3, the resulting imidoylisothiocyanate compound of formula (VI) is reacted with a primary amine compound represented by the following formula (VIII)
- R1—NH2 (VIII)
- wherein R1 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 (POCl3), 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-dimethylaminopyridine, 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-dichloroethane, 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-dimethylformamide, 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 isothiocyanide compound of formula (VII). The isothiocyanide compound of formula (VII) is suitably used in an amount of 1 to 2 equivalent. The reaction temperature can be between −20° C. and 50°C., preferably between 0° C. and 20° C., 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° C. and 80° C., preferably between 0° 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 1 COM. NO. R1 R2 R3 1 ethyl methyl phenyl 2 ethyl ethyl phenyl 3 ethyl ethyl 2,6-dichlorophenyl 4 ethyl ethyl 4-methoxyphenyl 5 ethyl ethyl 4-phenoxyphenyl 6 ethyl ethyl 4-nitrophenyl 7 n-butyl methyl phenyl 8 n-butyl ethyl phenyl 9 isopropyl ethyl phenyl 10 isopropyl methyl phenyl -
- wherein Y is defined as previously described.
- That is, the compound of formula (III) can be prepared by a process characterized in that
-
-
- through the known Strecker Synthesis,
-
- 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 compound of formula (III) can be prepared by reacting 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-dimethylamino pyridine can be used. The base can be suitably used in an amount of 1 to 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-dimethylacetamide, 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.
- Into a reaction vessel were placed aniline (279.4 g, 3.0 mol) and dichloromethane (2400 g), the reaction vessel was cooled to 0° C., and sodium hydroxide (132.0 g, 3.3 mol) dissolved in water (660 g) was slowly added dropwise thereto.
- It was confirmed that the temperature of the reaction vessel was 0° C. and then propionyl chloride (291.5 g, 3.2 mol) 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 (434.7 g, 2.9 mol) in a yield of 97%.
-
- N-phenylpropionamide (149.2 g, 1.0 mol) and pyridine (261.0 g, 3.3 mol) were dissolved in dichloromethane (300 g), and the mixture was cooled to 0° C. Phosphorus oxychloride (168.7 g, 1.1 mol) 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 slowly added dropwise to the reaction vessel containing the mixture of potassium isothiocyanide (145.8 g, 1.5 mol) and sodium carbonate (318.0 g, 3.0 mol) in acetone (1,000 ml) at the temperature of 10° C. or less for 2 hours and then the mixture was stirred for 1 hour to produce N-phenylpropionimidoyl isothiocyanate. Ethylamine (128.8 g, 2.0 mol) was added dropwise thereto maintaining the temperature of 10° C. or less for 2 hours, and then the mixture was stirred for 1 hour.
- After the reaction was completed, the solvent was removed by 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 (157.2 g, 0.7 mol) in a yield of 67%.
-
- N-(2,6-dichlorobenzene)propionamide (21.8 g, 0.1 mol) and pyridine (27.7 g, 0.35 mol) were dissolved in dichloromethane (30 g), and the mixture was cooled to 0° C. Phosphorus oxychloride (16.9 g, 0.11 mol) was added dropwise thereto for 2 hours, and then the mixture was stirred at room temperature (20° C.) for 2 hours to produce N-(2,6-dichloro benzene)propionimidoylchloride.
- Subsequently, the reactant was slowly added dropwise to the reaction vessel containing the mixture of potassium isothiocyanide (14.6 g, 0.15 mol) and sodium carbonate (31.8 g, 0.3 mol) in acetone (100 ml) at the temperature of 10° C. or less for 2 hours, and then the mixture was stirred for 1 hour to produce N-(2,6-dichlorobenzene)propionimidoyl isothiocyanate. Ethylamine (12.9 g, 0.2 mol) was added dropwise thereto maintaining the temperature of 10° C. or less for 2 hours, and then the mixture was stirred for 1 hour.
- After the reaction was completed, the title compound (21.9 g, 72 mmol) was obtained in a yield of 72% according to the same procedure as Example 1.
-
- N-phenylpropionamide (7.46 g, 0.05 mol) and pyridine (13.8 g, 0.18 mol) were dissolved in dichloromethane (300 g), and the mixture was cooled to 0° C. And then phosphorus oxychloride (8.43 g, 0.05 mol) 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 slowly added dropwise to the reaction vessel containing the mixture of potassium isothiocyanide (7.3 g, 0.08 mol) and sodium carbonate (15.9 g, 0.15 mol) in acetone (50 ml) at the temperature of 10° C. or less for 2 hours, and then the mixture was stirred for 1 hour to produce N-phenylpropionimidoyl isothiocyanate. And isopropylamine (5.9 g, 0.1 mol) was added dropwise thereto maintaining the temperature of 10° C. or less for 2 hours, and then the mixture was stirred for 1 hour.
- After the reaction was completed, the title compound (8.1 g, 0.03 mol) was obtained in a yield of 65% according to the same procedure as Example 1.
-
- Amino-thiophen-2-yl-acetonitrile hydrochloride(17.5 g, 0.1 mol) was dissolved in dichloromethane (100 ml), and then pyridine (16.6 g, 0.21 mol) was dropwise thereto. The mixture was cooled to 10° C., and then chloroacetyl chloride (12.4 g, 0.11 mol) was added dropwise thereto for 1 hour.
- After the reaction was completed, the mixture was washed three times with each time water (60 ml), the solvent was removed by distillation under reduced pressure, and the residue was recrystallized from toluene to give the title compound (19.8 g, 0.09 mol) in a yield of 92%.
-
- Amino-thiophen-2-yl-acetonitrile hydrochloride (8.8 g, 0.05 mol) was dissolved in dichloromethane (50 ml), and then pyridine (8.7 g, 0.11 mol) was dropwise thereto. The mixture was cooled to 0° C., and then bromoacetyl bromide (10.1 g, 0.05 mol) was added dropwise thereto for 1 hour.
- After the reaction was completed, the title compound (11.4 g, 0.04 mol) was obtained in a yield of 88% according to the same procedure as Example 4.
-
- Method 1)
- N-ethyl-N′-(1-phenyliminopropyl)thiourea (23.5 g, 0.1 mol) and 2-chloro-N-(α-cyano-2-thenyl)acetamide (21.4 g, 0.1 mol) were dissolved in methaniol (200 ml). And then triethylamine (15.2 g, 0.15 mol) was introduced therein, and the mixture was refluxed for 8 hours.
- After the reaction was completed, the mixture was cooled and filtered. The residue was washed with cool methanol, and dried to give the title compound (24.0 g, 0.08 mol) in a yield of 75%.
- Method 2)
- N-(1-(2,6-dichlorophenyl)iminopropyl)-N′-ethylthiourea (3.1 g, 0.1 mol) and 2-chloro-N-(α-cyano-2-thenyl)acetamide (21.4 g, 0.1 mol) were dissolved in methanol (200 mg). And then triethylamine (15.2 g, 0.15 mol) was introduced therein, and the mixture was refluxed for 8 hours.
- After the reaction was completed, the mixture was cooled by using cool methanol, and dried to give the title compound (24.0 g, 0.08 mol) in a yield of 75%.
-
-
- 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 toluene and water (v/v=10/1) to give the title compound (22.1 g, 0.07 mol) in a yield of 72%.
-
-
- 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=1/1) to give the title compound (2.0 g, 0.01 mol) in a yield of 60%.
-
- 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.
Claims (10)
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US09/777,706 US6388096B2 (en) | 1998-09-29 | 2001-02-07 | Process for preparation of 2-aminothiazolecarboxamide derivatives |
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KR1998-40539 | 1998-09-29 | ||
KR1019980040539A KR20000021443A (en) | 1998-09-29 | 1998-09-29 | Method for preparing 2-aminothiazole carboxamide derivatives |
KR98-40539 | 1998-09-29 | ||
US09/554,020 US6277995B1 (en) | 1998-09-29 | 1999-09-10 | Process for preparation of 2-aminothiazolecarboxamide derivatives |
US09/777,706 US6388096B2 (en) | 1998-09-29 | 2001-02-07 | Process for preparation of 2-aminothiazolecarboxamide derivatives |
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US09/777,706 Expired - Lifetime US6388096B2 (en) | 1998-09-29 | 2001-02-07 | Process for preparation of 2-aminothiazolecarboxamide derivatives |
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EP (1) | EP1045848B1 (en) |
JP (1) | JP3350035B2 (en) |
KR (1) | KR20000021443A (en) |
CN (1) | CN1137121C (en) |
AR (1) | AR023331A1 (en) |
AT (1) | ATE210133T1 (en) |
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BR (1) | BR9913012B1 (en) |
DE (1) | DE69900543T2 (en) |
ES (1) | ES2167118T3 (en) |
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US7652146B2 (en) * | 2004-02-06 | 2010-01-26 | Bristol-Myers Squibb Company | Process for preparing 2-aminothiazole-5-carboxamides useful as kinase inhibitors |
KR101142283B1 (en) * | 2005-03-11 | 2012-05-07 | 스미또모 가가꾸 가부시끼가이샤 | Novel Process For Preparation Of 2-Aminothiazole Carboxamide Derivatives |
CN111004208B (en) * | 2019-12-25 | 2020-11-24 | 西华大学 | 2-cyano-3-thiophene substituted valeramide derivative and application thereof |
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CA1224471A (en) * | 1980-06-20 | 1987-07-21 | Shell Canada Limited | Phenylamino (imino) - acetonitrile plant growth regulating agents |
US4399075A (en) | 1981-06-25 | 1983-08-16 | Asahi Chemical Company, Limited | Process for producing chlorinated phenoxytoluene derivatives |
DE3851004T2 (en) | 1987-05-26 | 1995-01-26 | Sumitomo Chemical Co | Amide derivatives, their manufacture and agricultural fungicides containing them. |
US4980363A (en) | 1987-10-23 | 1990-12-25 | Mitsui Toatsu Chemicals, Inc. | Novel amide derivatives, processes for production thereof, and agricultural-horticultural fungicide containing them |
EP0434620A3 (en) | 1989-12-21 | 1992-01-08 | Ciba-Geigy Ag | Pesticides |
US5514643A (en) | 1993-08-16 | 1996-05-07 | Lucky Ltd. | 2-aminothiazolecarboxamide derivatives, processes for preparing the same and use thereof for controlling phytopathogenic organisms |
KR100212635B1 (en) | 1997-06-11 | 1999-08-02 | 성재갑 | Process for preparation of 2-aminothiazolecarboxamide derivatives |
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JP3350035B2 (en) | 2002-11-25 |
ES2167118T3 (en) | 2002-05-01 |
PL195975B1 (en) | 2007-11-30 |
AU5534299A (en) | 2000-04-17 |
EP1045848B1 (en) | 2001-12-05 |
RU2193034C2 (en) | 2002-11-20 |
DE69900543D1 (en) | 2002-01-17 |
US6388096B2 (en) | 2002-05-14 |
BR9913012B1 (en) | 2010-03-23 |
DE69900543T2 (en) | 2002-07-25 |
CN1277610A (en) | 2000-12-20 |
KR20000021443A (en) | 2000-04-25 |
AR023331A1 (en) | 2002-09-04 |
US6277995B1 (en) | 2001-08-21 |
EP1045848A1 (en) | 2000-10-25 |
PT1045848E (en) | 2002-04-29 |
PL340733A1 (en) | 2001-02-26 |
JP2002525372A (en) | 2002-08-13 |
BR9913012A (en) | 2001-03-27 |
CN1137121C (en) | 2004-02-04 |
WO2000018766A1 (en) | 2000-04-06 |
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