JP5281152B2 - Method for producing 2-alkyl-3-aminothiophene derivative - Google Patents

Abstract

A 2-alkyl-3-aminothiophene derivative represented by general formula (4) can be produced by a production process comprising the following steps: oxidizing a compound represented by general formula (1) to produce a compound represented by general formula (3); and reducing the compound represented by general formula (3). Thus, a process for producing a 2-alkyl-3-aminothiophene derivative effectively can be provided. In the formulae, R represents an alkyl group or the like; X represents a hydroxy group, a halogen atom, or a substituent represented by general formula (2); A represents a carbon atom or a sulfur atom; Q represents an alkyl group or the like; n represents 1 or 2; and # represents a binding site.

Description

  The present invention relates to a method for producing 2-alkyl-3-aminothiophene and a production intermediate thereof.

As a method for producing 2-alkyl-3-aminothiophene, a production method by reacting a 3-aminothiophene derivative with various carbonyl compounds to produce a 2-alkenyl-3-aminothiophene derivative and undergoing a reduction step is disclosed. (For example, refer to JP 2008-120710 A).
Further, as a method for producing 2-alkyl-3-nitrothiophene, a production method in which 3-nitrothiophene and a Grignard reagent are reacted and then oxidized is disclosed (for example, TETRAHEDORN Vol. 44 No. 20 (1988). (Year) page 6435).
Further, as a method for producing 3-nitrothiophene, a production method for nitrating thiophene is disclosed (for example, see JUSTUS LIEBIGS ANNALEN DER CHEMIE Vol. 501 (1933) p. 174).

However, in the production method described in Japanese Patent Application Laid-Open No. 2008-120710, it is necessary to use an acyl group, a carbamate group or the like as a protective group for an amino group because 3-aminothiophene derivatives are unstable and difficult to handle. There is room for improvement from the viewpoint of operability and economy, such as requiring a step for attaching and detaching the protecting group.
On the other hand, since it is known that a nitro group can be converted to an amino group by a reduction reaction typified by a catalytic hydrogenation reaction, by reducing a 2-alkyl-3-nitrothiophene derivative, 3-amino-2- It is expected that alkylthiophene derivatives can be produced. However, since the production of 2-alkyl-3-nitrothiophene derivatives is difficult, a method for producing 2-alkyl-3-aminothiophene derivatives by reducing 2-alkyl-3-nitrothiophene derivatives has been reported so far. It has not been.

  Here, in the production method of 2-alkyl-3-nitrothiophene described in TETRAHEDORN Vol. 44 No. 20 (1988), p. 6435, 3-nitrothiophene itself, which is a starting material in the production method, is difficult to produce. There is room for improvement. Further, in the production method described in JUSTUS LIEBIGS ANNALEN DER CHEMIE Vol. 501 (1933), page 174, the product is obtained as a mixture of regioisomers, so the yield is low. In addition, there is room for improvement from the viewpoint of economy and operability, such as requiring a separation step of isomers.

  An object of the present invention is to provide a method for efficiently producing 2-alkyl-3-aminothiophene.

  In order to solve the above-mentioned problems, the present inventor has intensively studied, discovered a method for producing a novel 2-alkyl-3-nitrothiophene derivative, and reduced the efficiency of the 2-alkyl-3-nitrothiophene derivative. As a typical method for producing a 2-alkyl-3-aminothiophene derivative, the present invention has been completed. That is, the present invention is as follows.

<1> The following general formula (1)

[In General Formula (1), R is an alkyl group having 1 to 18 carbon atoms and an alkyl group having 1 to 10 carbon atoms which may be substituted with an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms. A cycloalkyl group having 3 to 10 carbon atoms which may be substituted with a group or a cycloalkyl group having 3 to 10 carbon atoms, or an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms. Represents a bicycloalkyl group having 6 to 12 carbon atoms. X is a hydroxy group, a halogen atom, or the following general formula (2)

(In the formula, A represents a carbon atom or a sulfur atom. When A is a carbon atom, n represents 1. When A represents a sulfur atom, n represents 1 or 2. Q represents an alkyl group having 1 to 10 carbon atoms. Represents an aryl group which may be substituted with a cycloalkyl group having 3 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, a hydrocarbyloxy group having 1 to 10 carbon atoms, or an alkyl group having 1 to 6 carbon atoms. # Represents a bonding position). The compound represented by the following general formula (3)

[In the general formula (3), R is the same as R in the general formula (1)] (A) to obtain a compound represented by:
A step (B) of reducing the compound represented by the general formula (3), and the following general formula (4):

[In general formula (4), R is the same as R in the said General formula (1)] The manufacturing method of the 2-alkyl-3-aminothiophene derivative represented.
<2> R is the following general formula (6)

[In General Formula (6), R ¹ represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. # Represents a bonding position. ] The manufacturing method as described in said <1> which is a substituent represented by.
<3> The production method according to <1> or <2>, wherein R is a 1,3-dimethylbutyl group.
<4> The step (A) is represented by the following general formula (8)

[In General Formula (8), R is the same as R in General Formula (1). The compound represented by the general formula (1a) is reacted with an esterifying agent or a halogenating agent.

[In General Formula (1a), R is the same as R in General Formula (1). Xa represents ^a halogen atom or a substituent represented by the general formula (2). And the step of obtaining the compound represented by the general formula (3) from the compound represented by the general formula (Ia). <1> to <3 The manufacturing method of any one of>.
<5> In the step (A), X is eliminated from the compound represented by the general formula (1), and the following general formula (5)

[In General Formula (5), R is the same as R in General Formula (1). Step (A-1) for obtaining a compound represented by the general formula (5) and a step (A-) for obtaining a compound represented by the general formula (3) by subjecting the compound represented by the general formula (5) to a dehydration reaction . 2) and the manufacturing method according to any one of <1> to <3>.
<6> The following general formula (7)

[In General Formula (7), R is the same as R in General Formula (1), and X ⁷ represents a halogen atom or a substituent represented by General Formula (2). And a compound represented by general formula (8) below, and α-mercaptoacetaldehyde or 1,4-dithian-2,5-diol.

[In General Formula (8), R is the same as R in General Formula (1). The manufacturing method of any one of said <1>-<5> which further includes the process of obtaining the compound represented by this.
<7> The following general formula (9)

[In General Formula (9), R is the same as R in General Formula (1). ] The manufacturing method as described in said <6> which further includes the process of obtaining the compound represented by the said General formula (7) by making the compound represented by an esterifying agent or a halogenating agent react .

[In General Formula (10), R is the same as R in General Formula (1). The method according to claim 7, further comprising a step of reacting the compound represented by formula (II) with nitromethane to obtain the compound represented by the general formula (9).
<9> The following general formula (11)

[In General Formula (11), R is the same as R in General Formula (1). And a compound represented by general formula (8) below, and α-mercaptoacetaldehyde or 1,4-dithian-2,5-diol.

[In General Formula (8), R is the same as R in General Formula (1). ] The manufacturing method of any one of said <1>-<5> which further includes the process of obtaining the compound represented by this.
<10> The following general formula (9)

[In General Formula (9), R is the same as R in General Formula (1). ] The manufacturing method as described in said <9> which further includes the process of dehydrating the compound represented by and obtaining the compound represented by the said General formula (11).
<11> The following general formula (10)

[In General Formula (10), R is the same as R in General Formula (1). ] And a compound represented by is reacted with a nitromethane, producing how according to obtain a compound represented by the general formula (9), to <10>, further comprising.

<12 > The following general formula (8)

[In general formula (8), R represents the following general formula (6)

(In General Formula (6), R ¹ represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. # Represents a bonding position) . ] The 3-hydroxy-4-nitrotetrahydrothiophene derivative represented by this .

<13 > The 3-hydroxy-4-nitrotetrahydrothiophene derivative according to < 12 >, wherein R in the general formula (8) is a 1,3-dimethylbutyl group.
< 14 > The following general formula (1)

[In General Formula (1), R represents a substituent represented by General Formula (6) . X is a hydroxy group, a halogen atom, or the following general formula (2)

(In the general formula (2), A represents a carbon atom or a sulfur atom, n represents 1 when A is a carbon atom, and n represents 1 or 2 when A is a sulfur atom. Q represents 1 to 2 carbon atoms. It may be substituted with an alkyl group having 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, a hydrocarbyloxy group having 1 to 10 carbon atoms, or an alkyl group having 1 to 6 carbon atoms. Represents an aryl group, and # represents a bonding position. 3-Nitro tetrahydrothiophene induction member represented by.
< 15 > The 3-nitrotetrahydrothiophene derivative according to < 14 >, wherein R in the general formula (1) is a 1,3-dimethylbutyl group.
< 16 > The following general formula (5)

[In General Formula (5), R is an alkyl group having 1 to 18 carbon atoms which may be substituted with an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms, or an alkyl group having 1 to 10 carbon atoms. A cycloalkyl group having 3 to 10 carbon atoms which may be substituted with a group or a cycloalkyl group having 3 to 10 carbon atoms, or an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms. Represents a bicycloalkyl group having 6 to 12 carbon atoms. ] The 3-nitro-2,5-dihydrothiophene derivative represented by this.
< 17 > R in the general formula (5) is represented by the following general formula (6).

[In General Formula (6), R ¹ represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. # Represents a bonding position. ] The 3-nitro-2,5-dihydrothiophene derivative according to < 16 >, which is a substituent represented by
< 18 > The 3-nitro-2,5-dihydrothiophene derivative according to < 16 >, wherein R in the general formula (5) is a 1,3-dimethylbutyl group.
< 19 > The following general formula (3)

[In General Formula (3), R represents a substituent represented by General Formula (6) . 2-alkyl-3-nitro-thiophene-induced body represented by.

< 20 > The 2-alkyl-3-nitrothiophene derivative according to < 19 >, wherein R in the general formula (3) is a 1,3-dimethylbutyl group.
<21> the <12> to <20> below following general formula according to any one of (12)

[In General Formula (12), Y and Z each independently represent a halogen atom or a hydrogen atom. R represents a substituent represented by the general formula (6) . Pharmaceutical and agrochemical manufacturing intermediates agricultural and horticultural fungicide which is represented by.

< 22 > The intermediate for producing pharmaceutical and agricultural chemicals according to < 21 >, wherein R in the general formula (12) is a 1,3-dimethylbutyl group, Y is a fluorine atom, and Z is a hydrogen atom .

  The method for producing a 2-alkyl-3-aminothiophene derivative represented by the following general formula (4) of the present invention comprises oxidizing the compound represented by the following general formula (1) to obtain the following general formula (3): The process (A) which obtains the compound represented, and the process (B) which reduces the compound represented by the said General formula (3) are included.

In general formula (1), general formula (3), and general formula (4), R is an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms that may be substituted with 1 to 18 carbon atoms. An alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms that may be substituted with an alkyl group having 1 to 10 carbon atoms, or a cycloalkyl group having 3 to 10 carbon atoms, or an alkyl group or carbon having 1 to 10 carbon atoms It represents a C 6-12 bicycloalkyl group that may be substituted with a C 3-10 cycloalkyl group. X represents a hydroxy group, a halogen atom, or a substituent represented by the general formula (2).
A represents a carbon atom or a sulfur atom, n represents 1 when A is a carbon atom, and n represents 1 or 2 when A is a sulfur atom. Q is an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, a hydrocarbyloxy group having 1 to 10 carbon atoms, or an alkyl group having 1 to 6 carbon atoms. Represents an aryl group which may be substituted with # Represents a bonding position.

  In the present invention, the R is preferably a substituent represented by the following general formula (6), and the R is more preferably a 1,3-dimethylbutyl group.

In General Formula (6), R ¹ represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. # Represents a bonding position.

  In addition, the step (A) includes a step of obtaining a compound represented by the following general formula (1a) from a compound represented by the following general formula (8), and a compound represented by the above general formula (Ia). And a step of obtaining a compound represented by the general formula (3).

In general formula (8) and general formula (1a), R is the same as R in the general formula (1). Xa represents ^a halogen atom or a substituent represented by the general formula (2).

  The step (A) is a step (A-1) for obtaining a compound represented by the following general formula (5) from the compound represented by the general formula (1), and the general formula (5). It is also preferable to further include the step (A-2) of obtaining the compound represented by the general formula (3) from the compound to be formed.

  In the general formula (5), R is the same as R in the general formula (1).

  Further, the production method of the present invention comprises reacting a compound represented by the following general formula (7) with α-mercaptoacetaldehyde or 1,4-dithian-2,5-diol, and the following general formula (8): Preferably, the method further includes a step of obtaining the represented compound. Further, it is more preferable to include a step of obtaining the compound represented by the general formula (7) from the compound represented by the following general formula (9). The compound represented by the general formula (9) is represented by the following general formula: More preferably, the method further includes a step obtained by reacting the compound represented by (10) with nitromethane.

In General Formula (7) to General Formula (10), R is the same as R in General Formula (1), and X ⁷ represents a halogen atom or a substituent represented by General Formula (2).

  Further, the production method of the present invention comprises reacting a compound represented by the following general formula (11) with α-mercaptoacetaldehyde or 1,4-dithian-2,5-diol, and the following general formula (8): It is preferable to further include a step of obtaining the represented compound. More preferably, the method further comprises a step of obtaining the compound represented by the general formula (11) by dehydrating the compound represented by the following general formula (9), represented by the general formula (9). It is more preferable to further include a step of obtaining the compound by reacting the compound represented by the following general formula (10) with nitromethane.

  In the general formulas (8) to (11), R is the same as R in the general formula (1).

Hereinafter, the present invention will be described in more detail.
In the present invention, aldehydes represented by general formula (10), hydroxynitroalkanes represented by general formula (9), nitroolefins represented by general formula (11), and general formula (7) Nitroalkanes, 3-hydroxy-4-nitrotetrahydrothiophenes represented by general formula (8), 3-nitro-2,5-dihydrothiophenes represented by general formula (5), In 3-nitrotetrahydrothiophenes represented by 1), 2-alkyl-3-nitrothiophene derivatives represented by general formula (3), and 3-aminoalkylthiophene derivatives represented by general formula (4): An alkyl group having 1 to 10 carbon atoms which may be substituted with an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms represented by R; Substituted with an alkyl group or an optionally substituted cycloalkyl group having 3 to 10 carbon atoms, an cycloalkyl group having 3 to 10 carbon atoms, or an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms Examples of the bicycloalkyl group having 4 to 12 carbon atoms that may be used include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, an isopropyl group, an isobutyl group, a secondary butyl group, and a tertiary butyl group. Group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 1,1-dimethylpropyl group, 2,2-dimethylpropyl group, 1,2-dimethylpropyl group, 1-methylpentyl group, 2-methyl Pentyl group, 3-methylpentyl group, 4-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, , 3-dimethylbutyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylethyl group, cyclopropyl group, cyclobutyl group , Cyclopentyl group, cyclohexyl group, methylcyclohexyl group, cyclohexylcyclohexyl group, hexahydroindan-1-yl group, hexahydroindan-2-yl group, hexahydroindan-4-yl group, hexahydroindan-5-yl group , Decahydronaphthalen-1-yl group, decahydronaphthalen-2-yl group and the like.

  In addition, in the general formula (2), an alkyl group having 1 to 10 carbon atoms represented by Q, a cycloalkyl group having 3 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, and a hydrocarbyloxy having 1 to 10 carbon atoms Examples of the aryl group which may be substituted with an alkyl group having 1 to 6 carbon atoms include, for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, isopropyl group, isobutyl group, sec-butyl Group, tert-butyl group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 1,1-dimethylpropyl group, 2,2-dimethylpropyl group, 1,2-dimethylpropyl group, 1-methylpentyl Group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-di- Tylbutyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, trifluoromethyl group, 2,2,2 -Trifluoroethyl group, methoxy group, ethoxy group, tert-butyloxy group, benzyloxy group, phenyl group, naphthyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, etc. .

  In addition, aldehydes represented by general formula (10), hydroxynitroalkanes represented by general formula (9), nitroolefins represented by general formula (11), and general formula (7) Nitroalkanes, 3-hydroxy-4-nitrotetrahydrothiophenes represented by general formula (8), 3-nitro-2,5-dihydrothiophenes represented by general formula (5), general formula (1) The 3-nitrotetrahydrothiophenes represented by general formula (2), the 2-alkyl-3-nitrothiophene derivatives represented by general formula (3), and the 2-alkyl-3-aminothiophenes represented by general formula (4) are: In the case where diastereoisomers are present, any one of them, or a mixture of any two or more of them may be used, and the structure is not limited.

In addition, aldehydes represented by general formula (10), hydroxynitroalkanes represented by general formula (9), nitroolefins represented by general formula (11), and general formula (7) Nitroalkanes, 3-hydroxy-4-nitrotetrahydrothiophenes represented by general formula (8), 3-nitro-2,5-dihydrothiophenes represented by general formula (5), general formula (1) 3-nitrotetrahydrothiophenes represented by general formula (3), 2-alkyl-3-nitrothiophene derivatives represented by general formula (3), and 3-aminoalkylthiophenes represented by general formula (4) are enantiomers. When a body is present, any one of the compounds or a mixture of both in any ratio may be used, and the structure is not limited.
Further, the nitroolefin represented by the general formula (11) may be either a cis isomer or a trans isomer, or a mixture of both in any ratio, and the structure is not limited.

  In many cases, the aldehyde represented by the general formula (10) used as a starting compound in the present invention is commercially available and can be easily obtained. In addition, various production methods are known for those which are difficult to obtain, and can be produced, for example, by the method disclosed in JORNAL OF AMERICAN CHEMICAL SOCIETY Vol. 75 No. 20 (1953), p.

According to the novel production method disclosed by the present invention, the hydroxynitroalkane represented by the general formula (9) reacts the aldehyde represented by the general formula (10) with nitromethane in the presence of a base. Is obtained.
No particular limitation is imposed on the equivalents of nitromethane and base used for the aldehydes represented by the general formula (10), but it is preferably 3 equivalents or less from an economical viewpoint.
The base used may be either an inorganic base or an organic base. As the inorganic base, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, ammonia and the like can be used. As the organic base, trialkylamine, pyridines and the like can be used. Specific examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, liquid ammonia, aqueous ammonia solution, triethylamine, triethylamine, Examples include butylamine, pyridine, collidine, 2,6-lutidine, 4-dimethylaminopyridine, and the like. These bases may be used alone or in combination of two or more at any ratio.

  In the method for producing hydroxynitroalkanes represented by the general formula (9) of the present invention, a solvent can be appropriately used, but the solvent to be used is not particularly limited. Examples of the solvent include alkyl halides such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, hydrocarbons such as hexane, heptane and cyclohexane, diethyl ether, diisopropyl ether, 1,2- Ethers such as dimethoxyethane, tetrahydrofuran and dioxane, esters such as ethyl acetate and butyl acetate, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, N, N′-dimethyl Examples include imidazolidinone, acetonitrile, water and the like. Each of these solvents may be used alone, but two or more kinds may be used in combination at any ratio.

The amount of the solvent used in the reaction is not particularly limited, but it is preferably 50 times or less with respect to the weight of the aldehyde represented by the general formula (10) from the economical viewpoint.
Moreover, although there is no restriction | limiting in particular about reaction temperature, it is preferable to set it as more than melting | fusing point and below boiling point of a solvent from a viewpoint of operation efficiency.

Further, according to the novel production method disclosed by the present invention, the nitroolefin represented by the general formula (11) can be obtained by dehydrating the hydroxynitroalkane represented by the general formula (9). .
In the method for producing nitroolefins of the present invention, an acid may be used to assist the reaction. The acid used may be either an inorganic acid or an organic acid, and may be either a Bronsted acid or a Lewis acid.
Specifically, for example, sulfuric acid, fuming sulfuric acid, chlorosulfuric acid, nitric acid, fuming nitric acid, hydrochloric acid, phosphoric acid, hydrogen bromide, acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, fumaric acid, maleic acid, benzoic acid, methanesulfone Examples thereof include acid, benzenesulfonic acid, tosylic acid, trifluoromethanesulfonic acid, aluminum chloride, titanium tetrachloride, and boron trifluoride diethyl ether complex. These acids may be used alone or in combination of two or more at any ratio.

  In the method for producing nitroolefins of the present invention, a base may be used to assist the reaction. The base used may be either an inorganic base or an organic base. As the inorganic base, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, ammonia and the like can be used. As the organic base, trialkylamine, pyridines and the like can be used. Specifically, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, liquid ammonia, aqueous ammonia solution, triethylamine, tributylamine, Examples thereof include pyridine, collidine, 2,6-lutidine, 4-dimethylaminopyridine and the like. These bases may be used alone or in combination of two or more at an arbitrary ratio.

  Furthermore, in the method for producing nitroolefins of the present invention, a known dehydrating agent may be used to assist the reaction. Dehydrating agents used include carboxylic acid halides such as acetyl chloride and benzoyl chloride, carboxylic acid anhydrides such as acetic anhydride and trifluoroacetic anhydride, sulfonic acid halides such as toluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, and chloride. Thionyl, sulfuryl chloride, oxalic chloride, phosgene, diphosgene, triphosgene, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, phosphorus tribromide, phosphorus pentoxide, alkali metal sulfate, alkaline earth metal sulfate, alkaline earth And the like. These dehydrating agents may be used alone or in combination of two or more at any ratio.

In the method for producing nitroolefins of the present invention, a solvent can be appropriately used, but the solvent to be used is not particularly limited. Examples of the solvent include alkyl halides such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, hydrocarbons such as hexane, heptane and cyclohexane, diethyl ether, diisopropyl ether, 1,2- Ethers such as dimethoxyethane, tetrahydrofuran and dioxane, esters such as ethyl acetate and butyl acetate, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, N, N′-dimethyl Examples include imidazolidinone, acetonitrile, water and the like. Each of these solvents may be used alone, but two or more kinds may be used in combination at any ratio.
The amount of the solvent used in the reaction is not particularly limited, but is preferably 50 times or less with respect to the weight of the hydroxynitroalkane represented by the general formula (9) from the economical viewpoint.
The reaction temperature is not particularly limited, but it is preferably from the melting point to the boiling point of the solvent from the viewpoint of operation efficiency.

  In addition, according to the novel production method disclosed by the present invention, the nitroalkane represented by the general formula (7) is converted from the hydroxynitroalkane represented by the general formula (9) by a known esterifying agent or halogen. It is obtained by reacting with an agent.

  In the method for producing a nitroalkane represented by the general formula (7) of the present invention, a base may be used for assisting the reaction. The base used may be either an inorganic base or an organic base. As the inorganic base, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, ammonia and the like can be used. As the organic base, trialkylamine, pyridines and the like can be used. Specifically, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, liquid ammonia, aqueous ammonia solution, triethylamine, tributylamine, pyridine , Collidine, 2,6-lutidine, 4-dimethylaminopyridine and the like. These bases may be used alone or in combination of two or more at an arbitrary ratio.

  Examples of the esterifying agent or halogenating agent used in the method for producing a nitroalkane represented by the general formula (7) of the present invention include carboxylic acid halides such as acetyl chloride and benzoyl chloride, acetic anhydride, trifluoroacetic anhydride, and the like. Carboxylic anhydride, sulfonyl halides such as toluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, thionyl chloride, sulfuryl chloride, oxalic chloride, phosgene, diphosgene, triphosgene, phosphorus pentachloride, phosphorus trichloride, oxy Examples include phosphorus chloride and phosphorus tribromide. These esterifying agents or halogenating agents may be used alone or in combination of two or more at any ratio.

  In the method for producing nitroalkanes represented by the general formula (7) of the present invention, a solvent can be appropriately used, but the solvent to be used is not particularly limited. Examples of the solvent include alkyl halides such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, hydrocarbons such as hexane, heptane and cyclohexane, diethyl ether, diisopropyl ether, 1,2- Ethers such as dimethoxyethane, tetrahydrofuran and dioxane, esters such as ethyl acetate and butyl acetate, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, N, N′-dimethyl Examples include imidazolidinone, acetonitrile, water and the like. Each of these solvents may be used alone, but two or more kinds may be used in combination at any ratio.

The amount of the solvent used in the reaction is not particularly limited, but is preferably 50 times or less with respect to the weight of the hydroxynitroalkane represented by the general formula (9) from the economical viewpoint.
The reaction temperature is not particularly limited, but it is preferably from the melting point to the boiling point of the solvent from the viewpoint of operation efficiency.

  Further, according to the novel production method disclosed by the present invention, the 3-hydroxy-4-nitrotetrahydrothiophene represented by the general formula (8) is a nitroolefin represented by the general formula (11) or It can be obtained by reacting the nitroalkane represented by the formula (7) with α-mercaptoacetaldehyde or 1,4-dithian-2,5-diol.

  In the reaction, the equivalent of α-mercaptoacetaldehyde and 1,4-dithian-2,5-diol used for the nitroolefin represented by the general formula (11) or the nitroalkane represented by the general formula (7) Is not particularly limited, but it is preferably 3 equivalents or less (in terms of α-mercaptoaldehyde) from an economical viewpoint. Although α-mercaptoacetaldehyde itself can be used as a monomer, 1,4-dithian-2,5-diol, which is a commercially available dimer, is more preferably used.

  In the method for producing 3-hydroxy-4-nitrotetrahydrothiophenes represented by the general formula (8) of the present invention, a base may be used for assisting the reaction. The base used may be either an inorganic base or an organic base. As the inorganic base, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, ammonia and the like can be used. As the organic base, trialkylamine, pyridines and the like can be used. Specific examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, liquid ammonia, aqueous ammonia solution, triethylamine, triethylamine, Examples include butylamine, pyridine, collidine, 2,6-lutidine, 4-dimethylaminopyridine, and the like. These bases may be used alone or in combination of two or more at any ratio.

  In the method for producing 3-hydroxy-4-nitrotetrahydrothiophenes represented by the general formula (8) of the present invention, a solvent can be appropriately used, but the solvent to be used is not particularly limited. Examples of the solvent include alkyl halides such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, hydrocarbons such as hexane, heptane and cyclohexane, diethyl ether, diisopropyl ether, 1,2- Ethers such as dimethoxyethane, tetrahydrofuran and dioxane, esters such as ethyl acetate and butyl acetate, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, N, N′-dimethyl Examples include imidazolidinone, acetonitrile, water and the like. Each of these solvents may be used alone, but two or more kinds may be used in combination at any ratio.

The amount of the solvent used for the reaction is not particularly limited, but is 50% based on the weight of the nitroolefin represented by the general formula (11) or the nitroalkane represented by the general formula (7) from the economical viewpoint. It is preferable to set it to a double amount or less.
The reaction temperature is not particularly limited, but it is preferably from the melting point to the boiling point of the solvent from the viewpoint of operation efficiency.

  In addition, according to the novel production method disclosed by the present invention, 3-nitro-2,5-dihydrothiophene represented by the general formula (5) is a 3-hydroxy represented by the general formula (8). It can be obtained by dehydrating -4-nitrotetrahydrothiophenes.

  In the method for producing 3-nitro-2,5-dihydrothiophenes of the present invention, an acid may be used to assist the reaction. The acid used may be either an inorganic acid or an organic acid, and may be either a Bronsted acid or a Lewis acid. Examples of acids include sulfuric acid, fuming sulfuric acid, chlorosulfuric acid, nitric acid, fuming nitric acid, hydrochloric acid, phosphoric acid, hydrogen bromide, acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, fumaric acid, maleic acid, benzoic acid, methanesulfone. Examples thereof include acid, benzenesulfonic acid, tosylic acid, trifluoromethanesulfonic acid, aluminum chloride, titanium tetrachloride, and boron trifluoride diethyl ether complex. These acids may be used alone or in combination of two or more at any ratio.

  In the method for producing 3-nitro-2,5-dihydrothiophenes of the present invention, a base may be used to assist the reaction. The base used may be either an inorganic base or an organic base. As the inorganic base, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, ammonia and the like can be used. As the organic base, trialkylamine, pyridines and the like can be used. Specifically, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, liquid ammonia, aqueous ammonia solution, triethylamine, tributylamine, Examples thereof include pyridine, collidine, 2,6-lutidine, 4-dimethylaminopyridine and the like. These bases may be used alone or in combination of two or more at any ratio.

  In the method for producing 3-nitro-2,5-dihydrothiophenes represented by the general formula (5) of the present invention, a known dehydrating agent may be used for assisting the reaction. Dehydrating agents used include carboxylic acid halides such as acetyl chloride and benzoyl chloride, carboxylic acid anhydrides such as acetic anhydride and trifluoroacetic anhydride, sulfonic acid halides such as toluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, and chloride. Thionyl, sulfuryl chloride, oxalic chloride, phosgene, diphosgene, triphosgene, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, phosphorus tribromide, phosphorus pentoxide, alkali metal sulfate, alkaline earth metal sulfate, alkaline earth And the like. These dehydrating agents may be used alone or in combination of two or more at any ratio.

  In the method for producing 3-nitro-2,5-dihydrothiophenes represented by the general formula (5) of the present invention, a solvent can be appropriately used, but the solvent to be used is not particularly limited. Examples of the solvent include alkyl halides such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, hydrocarbons such as hexane, heptane and cyclohexane, diethyl ether, diisopropyl ether, 1,2- Ethers such as dimethoxyethane, tetrahydrofuran and dioxane, esters such as ethyl acetate and butyl acetate, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, N, N′-dimethyl Examples include imidazolidinone, acetonitrile, water and the like. Each of these solvents may be used alone, but two or more kinds may be used in combination at any ratio.

The amount of the solvent used in the reaction is not particularly limited, but it should be 50 times or less with respect to the weight of the 3-hydroxy-4-nitrotetrahydrothiophene represented by the general formula (8) from the economical viewpoint. Is preferred.
The reaction temperature is not particularly limited, but it is preferably from the melting point to the boiling point of the solvent from the viewpoint of operation efficiency.

  In addition, according to the novel production method disclosed by the present invention, 3-nitrotetrahydrothiophenes represented by the general formula (1a) are represented by 3-hydroxy-4-nitrotetrahydro represented by the general formula (8). It can be obtained by reacting thiophenes with a known esterifying agent or halogenating agent.

  In the method for producing 3-nitrotetrahydrothiophenes represented by the general formula (1a) of the present invention, a base may be used for assisting the reaction. The base used may be either an inorganic base or an organic base. As the inorganic base, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, ammonia and the like can be used. As the organic base, trialkylamine, pyridines and the like can be used. Specifically, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, liquid ammonia, aqueous ammonia solution, triethylamine, tributylamine, pyridine , Collidine, 2,6-lutidine, 4-dimethylaminopyridine and the like. These bases may be used alone or in combination of two or more at an arbitrary ratio.

  Examples of the esterifying agent or halogenating agent used in the method for producing 3-nitrotetrahydrothiophene represented by the general formula (1a) of the present invention include carboxylic acid halides such as acetyl chloride and benzoyl chloride, acetic anhydride, Carboxylic anhydrides such as fluoroacetic acid, sulfonic acid halides such as toluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, thionyl chloride, sulfuryl chloride, oxalic chloride, phosgene, diphosgene, triphosgene, phosphorus pentachloride, trichloride Examples thereof include phosphorus, phosphorus oxychloride, and phosphorus tribromide. These esterifying agents or halogenating agents may be used alone or in combination of two or more at any ratio.

  In the method for producing 3-nitrotetrahydrothiophenes represented by the general formula (1a) of the present invention, a solvent can be appropriately used, but the solvent to be used is not particularly limited. Examples of the solvent include alkyl halides such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, hydrocarbons such as hexane, heptane and cyclohexane, diethyl ether, diisopropyl ether, 1,2- Ethers such as dimethoxyethane, tetrahydrofuran and dioxane, esters such as ethyl acetate and butyl acetate, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, N, N′-dimethyl Examples include imidazolidinone, acetonitrile, water and the like. Each of these solvents may be used alone, but two or more kinds may be used in combination at any ratio.

The amount of the solvent used in the reaction is not particularly limited, but it should be 50 times or less with respect to the weight of the 3-hydroxy-4-nitrotetrahydrothiophene represented by the general formula (8) from the economical viewpoint. Is preferred.
The reaction temperature is not particularly limited, but it is preferably from the melting point to the boiling point of the solvent from the viewpoint of operation efficiency.

  Further, according to the novel production method disclosed by the present invention, the 2-alkyl-3-nitrothiophene derivative represented by the general formula (3) is a 3-nitro-2,5 represented by the general formula (5). -Obtained by oxidizing dihydrothiophenes or 3-nitrotetrahydrothiophenes represented by the general formula (1a) using an oxidizing agent.

  In the method for producing a 2-alkyl-3-nitrothiophene derivative represented by the general formula (3) of the present invention, as the oxidizing agent used, manganese compounds, chromic acids, lead tetrachloride, osmium tetrachloride, tetrachloride Ruthenium, chlorine, bromine, iodine, hypochlorous acid or its salt, chloric acid or its salt, bromic acid or its salt, oxygen, ozone, hydrogen peroxide, organic peroxide, organic peracid, sulfuryl chloride, thionyl chloride Oxalic chloride, phosgene, diphosgene, triphosgene and the like, and chlorine and sulfuryl chloride are preferably used.

  In the method for producing a 2-alkyl-3-nitrothiophene derivative represented by the general formula (3) of the present invention, a base may be used for assisting the reaction. The base used may be either an inorganic base or an organic base. As the inorganic base, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, ammonia and the like can be used. As the organic base, trialkylamine, pyridines and the like can be used. Specifically, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, liquid ammonia, aqueous ammonia solution, triethylamine, tributylamine, Examples thereof include pyridine, collidine, 2,6-lutidine, 4-dimethylaminopyridine and the like. These bases may be used alone or in combination of two or more at any ratio.

  In the method for producing a 2-alkyl-3-nitrothiophene derivative of the present invention, a solvent can be appropriately used, but the solvent to be used is not particularly limited. Examples of the solvent include alkyl halides such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, hydrocarbons such as hexane, heptane and cyclohexane, diethyl ether, diisopropyl ether, 1,2- Ethers such as dimethoxyethane, tetrahydrofuran and dioxane, esters such as ethyl acetate and butyl acetate, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, N, N′-dimethyl Examples include imidazolidinone, acetonitrile, water and the like. Each of these solvents may be used alone, but two or more kinds may be used in combination at any ratio.

The amount of the solvent used in the reaction is not particularly limited, but 3-nitro-2,5-dihydrothiophenes represented by the general formula (5) or 3 represented by the general formula (1a) from the economical viewpoint. -It is preferable to make it 50 times or less with respect to the weight of nitrotetrahydrothiophenes.
The reaction temperature is not particularly limited, but it is preferably from the melting point to the boiling point of the solvent from the viewpoint of operation efficiency.

  Further, according to the novel production method disclosed by the present invention, the 2-alkyl-3-aminothiophene derivative represented by the general formula (4) is a 2-alkyl-3-nitro represented by the general formula (3). It can be obtained by reducing a thiophene derivative.

  Examples of the reduction method used in the method for producing a 2-alkyl-3-aminothiophene derivative of the present invention include a catalytic hydrogenation method, a method using an alkali metal in liquid ammonia, and a metal such as iron, zinc, aluminum, and tin. Reduction method using metal salt such as tin (II) chloride, reduction method using metal hydride complex such as sodium borohydride, lithium aluminum hydride, etc. A reduction method and a reduction method with tin (II) chloride are preferably used.

  In the method for producing a 2-alkyl-3-aminothiophene derivative of the present invention, a solvent can be appropriately used, but the solvent to be used is not particularly limited. Examples of the solvent include alkyl halides such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, hydrocarbons such as hexane, heptane and cyclohexane, diethyl ether, diisopropyl ether, 1,2- Ethers such as dimethoxyethane, tetrahydrofuran and dioxane, esters such as ethyl acetate and butyl acetate, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, N, N′-dimethyl Examples include imidazolidinone, acetonitrile, water and the like. Each of these solvents may be used alone, but two or more kinds may be used in combination at any ratio.

The amount of the solvent used for the reaction is not particularly limited, but may be 50 times or less with respect to the weight of the 2-alkyl-3-nitrothiophene derivative represented by the general formula (3) from the economical viewpoint. preferable.
The reaction temperature is not particularly limited, but it is preferably from the melting point to the boiling point of the solvent from the viewpoint of operation efficiency.

  The 2-alkyl-3-aminothiophene obtained by the method for producing 2-alkyl-3-aminothiophene of the present invention comprises an agricultural and horticultural fungicide production intermediate, an agricultural and horticultural insecticide production intermediate, and an agricultural and horticultural herbicide It can be used as a production intermediate or a pharmaceutical production intermediate. For example, it is useful as an intermediate for agricultural and horticultural fungicides described in JP-A 09-235282.

The disclosure of Japanese application 2009-100197 is incorporated herein in its entirety.
All documents, patent applications, and technical standards mentioned in this specification are to the same extent as if each individual document, patent application, and technical standard were specifically and individually described to be incorporated by reference, Incorporated herein by reference.

  Hereinafter, examples will be described for specific description, but the present invention is not limited to these examples.

[Example 1-1]

  After dissolving 7.0 g of sodium hydroxide in 50 ml of water and 50 ml of ethanol at 4 ° C., 10.7 g of nitromethane and 10.0 g of 2-methylpentanal were added, and the mixture was returned to room temperature and stirred for 2 hours. Ethanol was concentrated under reduced pressure, and neutralized with 1 mol / l hydrochloric acid so that the pH of the solution was around 7. Ethyl acetate was added to the solution, washed with a saturated saline solution, the organic layer was dried over magnesium sulfate, concentrated, purified by silica gel chromatography (hexane / ethyl acetate = 8/1), and 3-methyl-1-nitro- 13.3 g (yield: 94.2%) of 2-hexanol was obtained.

¹ H-NMR (CDCl ₃ ): δ = 0.90-0.96 (6H, m), 1.18-1.47 (4H, m), 1.62 (1H, m), 4.15 ( 1H, m), 4.39 (2H, m)

[Example 1-2]

  After dissolving 5.0 g of sodium hydroxide in 25 ml of water and 25 ml of ethanol at 4 ° C., 7.7 g of nitromethane and 7.2 g of 2,4-dimethylpentanal were added, and the mixture was returned to room temperature and stirred for 1 hour. Ethanol was concentrated under reduced pressure, and neutralized with 1 mol / l hydrochloric acid so that the pH of the solution was around 7. Ethyl acetate was added to the solution, washed with a saturated aqueous sodium chloride solution, the organic layer was dried over magnesium sulfate, concentrated, purified by silica gel chromatography (hexane / ethyl acetate = 8/1), and 3,5-dimethyl-1- 9.0 g (yield: 81.4%) of nitro-2-hexanol was obtained.

¹ H-NMR (CDCl ₃ ): δ = 0.85-0.95 (9H, m), 1.12-1.28 (2H, m), 1.64-1.69 (2H, m), 4.22-4.24 (1H, m), 4.44-4.46 (2H, m)

[Example 2-1]

  After dissolving 15.0 g of 3-methyl-1-nitro-2-hexanol in 100 ml of dichloromethane and subsequently slowly dropping 11.7 g of mesyl chloride and 18.8 g of triethylamine at 4 ° C., the solution is returned to room temperature. Stir for 1 hour. The reaction was quenched with water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, concentrated, and purified by silica gel chromatography (hexane / ethyl acetate = 10/1) to give 9.0 g of 3-methyl-1-nitrohex-1-ene (yield: 81.4%). )

¹ H-NMR (CDCl ₃ ): δ = 0.90-0.93 (3H, t, 7.2), 1.11-1.13 (3H, d, 6.8), 1.26-1 .46 (4H, m), 2.41-4.45 (1H, m), 6.93-6.96 (1H, d, J = 13.2), 7.16-7.22 (1H, dd, J = 13.8, 5.6)

[Example 2-2]

  After dissolving 9.0 g of 3,5-dimethyl-1-nitro-2-hexanol in 100 ml of dichloromethane and subsequently slowly dropping 6.5 g of mesyl chloride and 10.4 g of triethylamine at 4 ° C., the solution was brought to room temperature. The mixture was returned and stirred for 1.5 hours. The reaction was quenched with water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, concentrated and purified by silica gel chromatography (hexane / ethyl acetate = 10/1) to give 6.8 g of 3,5-dimethyl-1-nitrohex-1-ene (yield: 83. 9%).

¹ H-NMR (CDCl ₃ ): δ = 0.89-0.95 (6H, m), 1.10-1.12 (3H, d, J = 6.8), 1.25-1.43 (2H, m), 1.56-1.62 (1H, m), 2.49-2.53 (1H, m), 6.95-6.99 (1H, d, J = 13.8) , 7.14-7.20 (1H, dd, J = 13.8, 8.3)

[Example 2-3]

7.8 g of 3,5-dimethyl-1-nitrohexane-2-ol was dissolved in 30 ml of pyridine, 10 ml of acetic anhydride was added, and the mixture was stirred at room temperature for 2.5 hours. Ethyl acetate was added to the solution, washed with 1 mol / l hydrochloric acid aqueous solution and saturated brine solution, and the organic layer was dried over magnesium sulfate and concentrated. Purification by silica gel chromatography (hexane / ethyl acetate = 10/1) gave 8.4 g (87.3%) of 3,5-dimethyl-1-nitrohexane-2-yl acetate.
¹ H-NMR (CDCl ₃ ): δ = 0.85-0.95 (9H, m), 1.12-1.28 (2H, m), 1.64-1.67 (2H, m), 2.23 (3H, s), 4.22-4.24 (2H, m), 4.45 (1H, m)

[Example 2-4]

  2.0 g of 3,5-dimethyl-1-nitro-2-hexanol was dissolved in 15 ml of toluene, 4.1 g of thionyl chloride and 2 drops of N, N-dimethylformamide were added, and the mixture was stirred at 80 ° C. for 2.5 hours. After cooling to room temperature, the mixture was concentrated and purified by silica gel chromatography (hexane / ethyl acetate = 8/1) to give 1.5 g of 2-chloro-3,5-dimethyl-1-nitrohexane (yield: 72.4). %).

¹ H-NMR (CDCl ₃ ): δ = 0.86-1.36 (9H, m), 1.14-1.17 (2H, m), 1.64-1.68 (2H, m), 4.40-4.42 (1H, m), 4.59-4.61 (2H, m)

[Example 3-1]

  After dissolving 0.30 g of 3-methyl-1-nitrohex-1-ene in 6 ml of ethanol and subsequently adding 0.32 g of triethylamine and 0.16 g of 1,4-dithian-2,5-diol, The mixture was heated to ° C and stirred for 1 hour. After returning to room temperature, the mixture was diluted with ethyl acetate, washed with 1 mol / l aqueous hydrochloric acid and saturated aqueous sodium chloride, and the organic layer was dried over magnesium sulfate and concentrated. Silica gel chromatography (hexane / ethyl acetate = 8 / Purification by 1) gave 0.18 g (yield: 42.6%) of 4-nitro-5- (pentan-2-yl) tetrahydrothiophen-3-ol.

¹ H-NMR (CDCl ₃ ): δ = 0.87-1.03 (6H, m), 1.22-1.32 (4H, m), 1.64-1.69 (1H, m), 2.85-2.91 (1H, m), 3.08-3.11 (1H, m), 3.30 (1H, Brs), 3.79-3.85 (1H, m), 4. 70-4.76 (2H, m)

[Example 3-2]

  6.8 g of 3,5-dimethyl-1-nitrohex-1-ene was dissolved in 40 ml of dichloromethane, and then 6.7 g of triethylamine and 3.6 g of 1,4-dithian-2,5-diol were added. Stir for 5 hours. Diluted with ethyl acetate, washed with 1 mol / l aqueous hydrochloric acid solution and saturated aqueous sodium chloride solution, the organic layer was dried over magnesium sulfate, concentrated and purified by silica gel chromatography (hexane / ethyl acetate = 8/1), 10.9 g (yield: 93.5%) of 5- (4-methylpentan-2-yl) -4-nitrotetrahydrothiophen-3-ol was obtained.

¹ H-NMR (CDCl ₃ ): δ = 0.87-1.01 (6H, m), 1.14-1.28 (5H, m), 1.64-1.72 (2H, m), 2.85-3.12 (3H, m), 4.11-4.31 (1H, m), 4.70-4.83 (2H, m)

[Example 3-3]

  After dissolving 1.20 g of 3,5-dimethyl-1-nitrohexane-2-yl acetate in 7.0 ml of toluene, 0.80 g of triethylamine and 0.60 g of 1,4-dithian-2,5-diol were added. It was. After stirring at room temperature for 30 minutes, insoluble components were filtered off. The filtrate was concentrated and purified by silica gel chromatography (hexane / ethyl acetate = 8/1) to give 1.26 g of 5- (4-methylpentan-2-yl) -4-nitrotetrahydrothiophen-3-ol. 99.0%).

[Example 3-4]

  After 1.5 g of 2-chloro-3,5-dimethyl-1-nitrohexane was dissolved in 10 ml of toluene, 0.9 g of triethylamine and 0.9 g of 1,4-dihydroxydithiane were added at 4 ° C. After stirring at room temperature for 4.5 hours, the solid was filtered and the solution was concentrated. Purification by silica gel chromatography (hexane / ethyl acetate = 8/1) gave 0.7 g of 5- (4-methylpentan-2-yl) -4-nitrotetrathiophen-3-ol (yield: 39.3%). )

[Example 4-1]

  In 4 ml of dichloromethane, 150 mg of 4-nitro-5- (pentan-2-yl) tetrahydrothiophen-3-ol was dissolved. Subsequently, 86 mg of mesyl chloride and 138 mg of triethylamine were each slowly added dropwise at 4 ° C. The mixture was returned and stirred for 3.5 hours. The reaction was quenched with water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, concentrated and purified by silica gel chromatography (hexane / ethyl acetate = 10/1) to give 78 mg of 3-nitro-2- (pentan-2-yl) -2,5-dihydrothiophene ( Yield: 57.3%).

¹ H-NMR (CDCl ₃ ): δ = 0.84-0.98 (6H, m), 1.17-1.40 (4H, m), 2.10-2.25 (1H, m), 3.76-3.80 (2H, m), 4.60-4.75 (1H, m), 7.22-7.24 (1H, m)

[Example 4-2]

  Dissolve 0.50 g of 5- (4-methylpentan-2-yl) -4-nitrotetrahydrothiophen-3-ol in 4 ml of dichloromethane, and then slowly add 0.27 g of mesyl chloride and 0.33 g of triethylamine at 4 ° C. Then, the solution was returned to room temperature and stirred for 7.5 hours. The reaction was quenched with water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, concentrated and purified by silica gel chromatography (hexane / ethyl acetate = 10/1) to give 2- (4-methylpentan-2-yl) -3-nitro-2,5-dihydro 0.22 g (yield: 47.7%) of thiophene was obtained.

¹ H-NMR (CDCl ₃ ): δ = 0.87-1.00 (6H, m), 1.15-1.30 (5H, m), 1.64-1.72 (2H, m), 3.75-3.79 (2H, m), 4.60-4.74 (1H, m), 7.21-7.24 (1H, m)

[Example 4-3]

  Dissolve 1.00 g of 5- (4-methylpentan-2-yl) -4-nitrotetrahydrothiophen-3-ol in 10 ml of toluene and stir at room temperature for 2 hours with 0.7 g of pyridine and 1.4 g of acetic anhydride. did. The reaction was stopped with water, washed with 1 mol / l aqueous hydrochloric acid and saturated aqueous sodium chloride, and the organic layer was dried over magnesium sulfate and concentrated. Purification by silica gel chromatography (hexane / ethyl acetate = 9/1) gave 1.10 g (94.8%) of 5- (4-methylpentan-2-yl) -4-nitrotetrahydrothiophen-3-yl-acetate. Got.

¹ H-NMR (CDCl ₃ ): δ = 0.87-1.01 (6H, m), 1.14-1.28 (5H, m), 1.64-1.72 (2H, m), 2.41 (3H, s), 2.85-3.12 (3H, m), 4.11-4.31 (1H, m), 4.70-4.83 (2H, m)

[Example 5-1]

  78 mg of 3-nitro-2- (pentan-2-yl) -2,5-dihydrothiophene was dissolved in 2 ml of dichloromethane, and a solution of 78 mg of sulfuryl chloride in 2 ml of dichloromethane was added and stirred at room temperature for 2.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with dichloromethane and further washed with saturated brine. The organic layer was dried over magnesium sulfate, concentrated and purified by NH-silica gel chromatography (hexane / ethyl acetate = 10/1) to give 69 mg of 3-nitro-2- (pentan-2-yl) thiophene (yield: 88 .7%).

¹ H-NMR (CDCl ₃ ): δ = 0.90-0.93 (3H, m), 1.30-1.42 (5H, m), 1.60-1.70 (2H, m), 4.01-4.07 (1H, m), 7.01-7.10 (1H, d, J = 5.9 Hz), 7.53-7.55 (1H, d, J = 5.4 Hz)

[Example 5-2]

  2.8 g of 2- (4-methylpentan-2-yl) -3-nitro-2,5-dihydrothiophene was dissolved in 40 ml of dichloromethane, and a solution of 2.6 g of sulfuryl chloride in 5 ml of dichloromethane was added to the solution at room temperature for 1. Stir for 5 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with dichloromethane and further washed with saturated brine. The organic layer was dried over magnesium sulfate, concentrated, purified by NH-silica gel chromatography (hexane / ethyl acetate = 10/1), and 2.0 g of 2- (4-methylpentan-2-yl) -3-nitrothiophene. (Yield: 70.1%) was obtained.

¹ H-NMR (CDCl ₃ ): δ = 0.80-0.96 (6H, m), 1.30-1.34 (3H, m), 1.44-1.64 (2H, m), 3.06-3.08 (1H, m), 4.12-4.14 (1H, m), 7.09-7.10 (1H, d, J = 5.4 Hz), 7.53-7 .54 (1H, d, J = 5.9 Hz)

[Example 5-3]

  After dissolving 1.10 g of 5- (4-methylpentan-2-yl) -4-nitrotetrahydrothiophen-3-yl-acetate in 7 ml of toluene, the reaction solution was cooled to 4 ° C. Thereafter, 0.80 g of sulfuryl chloride dissolved in 2 ml of toluene was added, and the mixture was returned to room temperature and stirred for 2 hours. The reaction was stopped with water and washed with 1 mol / l aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, concentrated and purified by silica gel chromatography (hexane / ethyl acetate = 10/1) to give 0.80 g (85 of 2- (4-methylpentan-2-yl) -3-nitrothiophene. 0.0%).

[Example 6]

  After dissolving 0.33 g of 2- (4-methylpentan-2-yl) -3-nitrothiophene in 6 ml of ethanol and adding 0.88 g of tin (II) chloride and 0.97 g of concentrated hydrochloric acid, the reaction solution was dissolved. The mixture was heated to 70 ° C. and stirred for 1 hour. After cooling the solution to room temperature, 1 mol / l sodium hydroxide aqueous solution was added and stirred for 5 minutes. The mixture was filtered over celite, and the solution was extracted with ethyl acetate, and further washed with 1 mol / l aqueous sodium hydroxide solution and saturated brine. The organic layer was dried over magnesium sulfate, concentrated and purified by silica gel chromatography (hexane / ethyl acetate = 8/1) to give 0.11 g of 2- (4-methylpentan-2-yl) -3-aminothiophene ( Yield: 39.0%).

¹ H-NMR (CDCl ₃ ): δ = 0.83-0.98 (6H, m), 1.19-1.60 (5H, m), 2.93-2.95 (1H, m), 3.38 (1H, Brs), 6.41-6.55 (1H, dd, J = 4.9 Hz, 5.4 Hz), 6.93-7.04 (1H, dd, J = 4.9 Hz, 5.4Hz)

  According to the present invention, it has become possible to efficiently provide a 2-alkyl-3-aminothiophene derivative that is an effective production intermediate in the field of medicine and agrochemicals. Furthermore, since the present invention can be advantageously produced industrially, the industrial utility value is high.

Claims (22)

The following general formula (1)

[In General Formula (1), R is an alkyl group having 1 to 18 carbon atoms and an alkyl group having 1 to 10 carbon atoms which may be substituted with an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms. A cycloalkyl group having 3 to 10 carbon atoms which may be substituted with a group or a cycloalkyl group having 3 to 10 carbon atoms, or an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms. Represents a bicycloalkyl group having 6 to 12 carbon atoms. X is a hydroxy group, a halogen atom, or the following general formula (2)

(In the formula, A represents a carbon atom or a sulfur atom. When A is a carbon atom, n represents 1. When A represents a sulfur atom, n represents 1 or 2. Q represents an alkyl group having 1 to 10 carbon atoms. Represents an aryl group which may be substituted with a cycloalkyl group having 3 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, a hydrocarbyloxy group having 1 to 10 carbon atoms, or an alkyl group having 1 to 6 carbon atoms. # Represents a bonding position). The compound represented by the following general formula (3)

[In the general formula (3), R is the same as R in the general formula (1)] (A) to obtain a compound represented by:
A step (B) of reducing the compound represented by the general formula (3), and the following general formula (4):

[In general formula (4), R is the same as R in the said General formula (1)] The manufacturing method of the 2-alkyl-3-aminothiophene derivative represented. R is the following general formula (6)

[In General Formula (6), R ¹ represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. # Represents a bonding position. The manufacturing method of Claim 1 which is a substituent represented by this.   The production method according to claim 1, wherein R is a 1,3-dimethylbutyl group. In the step (A), the following general formula (8)

[In General Formula (8), R is the same as R in General Formula (1). The compound represented by the general formula (1a) is reacted with an esterifying agent or a halogenating agent.

[In General Formula (1a), R is the same as R in General Formula (8). Xa represents ^a halogen atom or a substituent represented by the general formula (2). A step of obtaining a compound represented by:
Obtaining a compound represented by the general formula (3) from the compound represented by the general formula (Ia);
The manufacturing method according to any one of claims 1 to 3, further comprising: The step (A)
X is eliminated from the compound represented by the general formula (1), and the following general formula (5)

[In General Formula (5), R is the same as R in General Formula (1). A step of obtaining a compound represented by formula (A-1);
A step of dehydrating the compound represented by the general formula (5) to obtain a compound represented by the general formula (3) (A-2);
The manufacturing method according to any one of claims 1 to 3, further comprising: The following general formula (7)

[In General Formula (7), R is the same as R in General Formula (1), and X ⁷ represents a halogen atom or a substituent represented by General Formula (2). And a compound represented by general formula (8) below, and α-mercaptoacetaldehyde or 1,4-dithian-2,5-diol.

[In General Formula (8), R is the same as R in General Formula (1). The manufacturing method of any one of Claims 1-5 which further includes the process of obtaining the compound represented by this. The following general formula (9)

[In General Formula (9), R is the same as R in General Formula (1). ] The manufacturing method of Claim 6 which further includes the process of obtaining the compound represented by the said General formula (7) by making the compound represented by an esterifying agent or a halogenating agent react . The following general formula (10)

[In General Formula (10), R is the same as R in General Formula (1). The method according to claim 7, further comprising a step of reacting the compound represented by formula (II) with nitromethane to obtain the compound represented by the general formula (9). The following general formula (11)

[In General Formula (11), R is the same as R in General Formula (1). And a compound represented by general formula (8) below, and α-mercaptoacetaldehyde or 1,4-dithian-2,5-diol.

[In General Formula (8), R is the same as R in General Formula (1). The manufacturing method of any one of Claims 1-5 which further includes the process of obtaining the compound represented by this. The following general formula (9)

[In General Formula (9), R is the same as R in General Formula (1). The production method according to claim 9, further comprising a step of dehydrating the compound represented by formula (II) to obtain the compound represented by the general formula (11). The following general formula (10)

[In General Formula (10), R is the same as R in General Formula (1). The process of Claim 10 which further includes the process of obtaining the compound represented by the said General formula (9) by making the compound represented by this, and nitromethane react. The following general formula (8)

[In general formula (8), R represents the following general formula (6)

(In General Formula (6), R ¹ represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. # Represents a bonding position) . ] The 3-hydroxy-4-nitrotetrahydrothiophene derivative represented by this. The 3-hydroxy-4-nitrotetrahydrothiophene derivative according to claim 12 , wherein R in the general formula (8) is a 1,3-dimethylbutyl group. The following general formula (1)

[In general formula (1), R represents the following general formula (6)

(In General Formula (6), R ¹ represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. # Represents a bonding position) . X is a hydroxy group, a halogen atom, or the following general formula (2)

(In the general formula (2), A represents a carbon atom or a sulfur atom, n represents 1 when A is a carbon atom, and n represents 1 or 2 when A is a sulfur atom. Q represents 1 to 2 carbon atoms. It may be substituted with an alkyl group having 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, a hydrocarbyloxy group having 1 to 10 carbon atoms, or an alkyl group having 1 to 6 carbon atoms. Represents an aryl group, and # represents a bonding position. ] The 3-nitrotetrahydrothiophene derivative represented by this. The 3-nitrotetrahydrothiophene derivative according to claim 14 , wherein R in the general formula (1) is a 1,3-dimethylbutyl group. The following general formula (5)

[In General Formula (5), R is an alkyl group having 1 to 18 carbon atoms which may be substituted with an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms, or an alkyl group having 1 to 10 carbon atoms. A cycloalkyl group having 3 to 10 carbon atoms which may be substituted with a group or a cycloalkyl group having 3 to 10 carbon atoms, or an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms. Represents a bicycloalkyl group having 6 to 12 carbon atoms. ] The 3-nitro-2,5-dihydrothiophene derivative represented by this. R in the general formula (5) is the following general formula (6)

[In General Formula (6), R ¹ represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. # Represents a bonding position. The 3-nitro-2,5-dihydrothiophene derivative according to claim 16 , which is a substituent represented by the formula: The 3-nitro-2,5-dihydrothiophene derivative according to claim 16 , wherein R in the general formula (5) is a 1,3-dimethylbutyl group. The following general formula (3)

[In general formula (3), R represents the following general formula (6)

(In General Formula (6), R ¹ represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. # Represents a bonding position) . ] The 2-alkyl-3-nitrothiophene derivative represented by this. The 2-alkyl-3-nitrothiophene derivative according to claim 19 , wherein R in the general formula (3) is a 1,3-dimethylbutyl group. The following general formula (12) according to any one of claims 12 to 20

[In General Formula (12), Y and Z each independently represent a halogen atom or a hydrogen atom. R is the following general formula (6)

(In General Formula (6), R ¹ represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. # Represents a bonding position). ] An intermediate for producing agricultural and horticultural fungicides represented by The intermediate for producing pharmaceutical and agrochemical according to claim 21 , wherein R in the general formula (12) is a 1,3-dimethylbutyl group, Y is a fluorine atom, and Z is a hydrogen atom.