JP2010143826A - Method for producing 3-aminothiophene derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for industrially producing a 3-aminothiophene derivative useful as an intermediate for agrochemicals, at a low cost. <P>SOLUTION: The method of producing the 3-aminothiophene derivative represented by formula (4) includes a process of hydrolyzing a 3-aminothiophene-2-carboxylic acid ester derivative represented by formula (1) under a basic condition to produce a 3-aminothiophene-2-carboxylic acid salt represented by formula (2), a process of subjecting the resulting compound represented by formula (2) to a decarboxylation reaction under an acidic condition to produce a 3-aminothiophene salt represented by formula (3), and a subsequent neutralization process, which method is capable of enhancing the yield by preventing the intermediate and the product present in each of the processes from decomposing. In the formula, R represents a 1-12C alkyl group or a phenyl group, M represents an alkali metal or alkaline earth metal, and HX represents an acid. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a method for producing a 3-aminothiophene derivative useful as an agricultural or horticultural fungicide or an intermediate thereof.

  Japanese Laid-Open Patent Publication No. 9-235282 (European Patent Publication No. 0737682A1) describes certain 2-alkyl-3-aminothiophene derivatives having a powerful control effect against various plant diseases and a method for producing the same. Yes.

  Various methods are known as a production method of 3-aminothiophene which is a useful intermediate of the above compound. For example, Japanese Examined Patent Publication No. 44-12895 discloses synthesis of 3- (hydroxyimino) tetrahydrothiophene by reacting tetrahydrothiophen-3-one with hydroxylamine, aromatization by acid treatment, and 3-aminothiophene. Is described (Chemical Formula 1).

  Further, Journal of Heterocyclic Chemistry, 10 (6), 1067-1068 (1973) describes a method for synthesizing 3-aminothiophene by a rearrangement reaction of 3-thiophenecarboxamide (Chemical Formula 2).

However, in the methods described in these documents, it is difficult to ensure chemical engineering safety from the viewpoint of physicochemical properties of raw materials and intermediates and reaction control, and there is a problem in industrialization.
Japanese Patent Application Laid-Open No. 1-128980 discloses a method for producing 3-aminothiophene by deprotecting 3-bromothiophene into 3-phthalimide (Chemical Formula 3).

However, even in the method described in this document, a large amount of waste and copper waste resulting from phthalimide are produced, which is not desirable for industrialization.
In Synthetic Communications, 25 (23), 3729-3734 (1995), a 3-aminothiophene-2-carboxylic acid ester derivative, which is industrially available at a low price, is used as a starting material to produce 3-amino After conversion to a thiophene-2-carboxylic acid derivative, a decarboxylation reaction was performed with oxalic anhydride to obtain a 3-aminothiophene derivative (Chemical Formula 4).

[Wherein R represents an optionally substituted alkyl group]
Although this method is a production method applicable industrially, the yield of 3-aminothiophene is around 60%, which is not satisfactory from the viewpoint of economy. In addition, 3-aminothiophene-2-carboxylic acid, which is an intermediate, easily undergoes a decarboxylation reaction to produce 3-aminothiophene. The product, 3-aminothiophene, is known to be an unstable substance that readily decomposes without care in handling. Thus, in this method, since unstable intermediates and products are handled, yields are likely to decrease or vary, and there is a problem in industrial stable production.

  Similarly to the above, a method for producing 3-aminothiophene using a 3-aminothiophene-2-carboxylic acid ester derivative as a raw material is disclosed in WO2005-040110, US6492383, Tetrahedron Letters, 46, 109-112 (2005). Although described, the yield of 3-aminothiophene is 29-56%, which is not satisfactory. Bioorganic & Medicinal Chemistry Letters, 14, 21-24 (2004) describe that 3-aminothiophene can be obtained in 85% yield from Scheme 2 using methyl 3-aminothiophene-2-carboxylate as a raw material. However, a detailed experimental method is not described, and US Pat. No. 6,492,383, which is cited as a reference, describes a yield of 40%.

That is, in a method for producing 3-aminothiophene by the hydrolysis reaction of ester and subsequent decarboxylation reaction using 3-aminothiophene-2-carboxylic acid ester derivative as a raw material so far, from the viewpoint of industrial production, the yield is high. There is no known method that can be stably manufactured.
JP-A-9-235282 (European Patent Publication No. 0737682A1) Japanese Examined Patent Publication No. 44-12895 Japanese Patent Laid-Open No. 1-128980 WO2005-040110 US6492383 Journal of Heterocyclic Chemistry, 10 (6), 1067-1068 (1973) Synthetic Communications, 25 (23), 3729-3734 (1995) Tetrahedron Letters, 46, 109-112 (2005) Bioorganic & Medicinal Chemistry Letters, 14, 21-24 (2004)

  The present invention provides a method for industrially inexpensively and stably producing a 3-aminothiophene derivative useful as an agrochemical intermediate using a commercially available 3-aminothiophene-2-carboxylic acid ester derivative as a raw material. The purpose is to provide.

  In order to solve the above-mentioned problems, the present inventors diligently studied a method for producing a 3-aminothiophene derivative using a 3-aminothiophene-2-carboxylic acid ester derivative as a raw material, and 3-aminothiophene as an intermediate. -2-carboxylic acid and its salts, and a method capable of inhibiting the decomposition of 3-aminothiophene and its salt, which are products, is found and can be applied to the production method to be industrially useful as an agrochemical intermediate The present invention was completed as an inexpensive method for producing a 3-aminothiophene derivative.

That is, the present invention relates to the following [1] to [8].
[1] General formula (1)

[Wherein R represents an alkyl group having 1 to 12 carbon atoms or a phenyl group], by hydrolysis of a 3-aminothiophene-2-carboxylic acid ester derivative represented by the general formula (2) (Formula 6)

[Wherein M represents an alkali metal or an alkaline earth metal] A metal salt of 3-aminothiophene-2-carboxylic acid represented by the following formula is produced, a decarboxylation reaction is performed under acidic conditions, and a general formula ( 3) (Chemical formula 7)

[Wherein HX represents an acid] A salt formed from 3-aminothiophene and an acid represented by the formula (4)

  In the method for producing 3-aminothiophene of the formula (5) (formula 9) obtained by neutralizing a metal salt of 3-aminothiophene-2-carboxylic acid represented by the general formula (2) or neutralization

  A method for producing 3-aminothiophene represented by the general formula (4), wherein the decarboxylation reaction is carried out without isolating 3-aminothiophene-2-carboxylic acid.

  [2] A method of neutralizing a salt formed from 3-aminothiophene represented by general formula (3) and an acid is a method of neutralizing a salt formed from 3-aminothiophene represented by general formula (3) and an acid. The method according to [1], wherein the 3-aminothiophene represented by the general formula (4) is produced by adding an aqueous solution to a two-phase solution of an alkaline aqueous solution and an organic solvent.

[3] When performing the decarboxylation reaction of the metal salt of 3-aminothiophene-2-carboxylic acid represented by the general formula (2), the 3-aminothiophene-2-carboxylic acid represented by the general formula (2) An aqueous solution of an acid metal salt is added to a two-phase solution of an acidic aqueous solution and an organic solvent to produce a salt formed from 3-aminothiophene represented by the general formula (3) and an acid [ [1] or [2].
[4] The method according to any one of [1] to [3], wherein in general formula (1), R is an alkyl group having 1 to 12 carbon atoms.
[5] The method according to [4], wherein in general formula (1), R is a methyl group or an ethyl group.
[6] The method according to any one of [1] to [5], wherein in general formula (2), M is an alkali metal.
[7] The method according to [6], wherein in the general formula (2), M is sodium (Na).
[8] The method according to any one of [1] to [7], wherein in the general formula (3), HX is hydrogen chloride (HCl).

  The present invention finds a method capable of suppressing decomposition of an intermediate and a product and applies it to a production method, so that an industrially available 3-aminothiophene-2-carboxylic acid ester derivative is used as a raw material. The 3-aminothiophene derivative useful as a product can be produced inexpensively and stably by an industrially applicable method.

The present invention is described in detail below.
In the method for producing 3-aminothiophene in the present invention, a 3-aminothiophene-2-carboxylic acid ester derivative represented by the general formula (1) is hydrolyzed to produce a 3-aminothiophene represented by the general formula (2). After deriving into a metal salt of 2-carboxylic acid, a decarboxylation reaction is performed under acidic conditions, and neutralization of the obtained salt of 3-aminothiophene represented by the general formula (3) yields a formula (4) When producing 3-aminothiophene represented, the metal salt of 3-aminothiophene-2-carboxylic acid represented by the general formula (2), or 3 represented by the formula (5) obtained by neutralization -A method for producing 3-aminothiophene, wherein a decarboxylation reaction is carried out without isolating aminothiophene-2-carboxylic acid. (Chemical Formula 10)

[R represents an alkyl group having 1 to 12 carbon atoms and a phenyl group, M represents an alkali metal and an alkaline earth metal, and HX represents an acid].
In the compound represented by the general formula (1), although not limited to the following, typical examples of R include the following.

  That is, examples of the alkyl group having 1 to 12 carbon atoms include methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, isopropyl group, isobutyl group, sec-butyl group, tert. -A butyl group, a neopentyl group, etc. can be illustrated.

  The alkyl group having 1 to 12 carbon atoms and the phenyl group represented by R may be substituted. In this case, the alkyl group having 1 to 12 carbon atoms and the substituent of the phenyl group include a methyl group, an ethyl group, Alkyl groups such as isopropyl group or isobutyl group, alkenyl groups such as vinyl group or propenyl group, alkynyl groups such as ethynyl group or propynyl group, halogenated alkyl groups such as trifluoromethyl group, alkoxy groups such as methoxy group or ethoxy group Halogen substituted alkoxy groups such as trifluoromethoxy group or difluoromethoxy group, alkylthio groups such as methylthio group or ethylthio group, phenyl group, naphthyl group, furan, thiophene, oxazole, pyrrole, 1H-pyrazole, 3H-pyrazole, imidazole, Thiazole, oxazole, isocyanate Tetrazole can isothiazole, tetrahydrofuran, heterocyclic such as pyridine, a fluorine atom, a chlorine atom, may be respectively exemplified halogen atom such as a bromine atom or an iodine atom.

  Examples of the metal represented by M in the compound represented by the general formula (2) will be given. Although not limited to the following, examples of the alkali metal include lithium, sodium, potassium, and the like, and examples of the alkaline earth metal include magnesium, calcium, barium, and the like.

  Examples of the acid represented by HX in the compound represented by the general formula (3) or HX used in the decarboxylation reaction will be given. Although not limited to the following, as representative examples, hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids, acetic acid, trifluoroacetic acid, cyanoacetic acid, benzoic acid, citric acid, oxalic acid, Examples thereof include organic acids such as methanesulfonic acid, p-toluenesulfonic acid, and benzenesulfonic acid.

  Although it does not limit to the following about the hydrolysis reaction of the compound represented by General formula (1), an example is given and demonstrated.

  The base used in the reaction is not limited to the following, but alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide, and alkali metal carbonates such as sodium carbonate and potassium carbonate. Examples include salts, alkali metal alkoxides such as sodium methoxide and sodium ethoxide, and alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide and barium hydroxide, and mixtures of these bases can also be used. is there. The amount of the base used in the reaction is not limited as long as the target reaction proceeds, but usually 1.0 to 20.0 equivalents relative to the compound represented by the general formula (1) It is.

  Examples of the solvent used for the reaction include, but are not limited to, alcohols such as water, methanol, and ethanol, ethers such as tetrahydrofuran, and aprotic polar solvents such as dimethylformamide. It can be used alone or in combination. Although the usage-amount of a solvent is not specifically limited, Usually, the weight of 1 times or more and 40 times or less is preferable with respect to the weight of the compound represented by General formula (1).

  The reaction temperature and reaction time for the above reaction can be varied over a wide range. Generally, the reaction temperature is not particularly limited as long as the target reaction proceeds and the raw materials, intermediates, and products are not decomposed, but 0-100 ° C. is preferable, and the reaction time is the target. The reaction is not particularly limited as long as the reaction proceeds, but it is preferably 0.1 to 50 hours.

  Various conditions in the above hydrolysis reaction, that is, the types of base and the amount used, the type and amount of solvent, the reaction temperature, and the reaction time can be appropriately selected and combined with each other.

  As described above, in the conventional technique, after completion of the hydrolysis reaction, the product 3-aminothiophene-2-carboxylic acid represented by the formula (5) is isolated, and the decarboxylation reaction of the next operation is performed. Generally, 3-aminothiophene-2-carboxylic acid is known to easily cause decarboxylation, and the product 3-aminothiophene represented by the formula (4) is an unstable substance. For this reason, yield reduction and variation in the isolation operation are likely to occur, which is not preferable.

  On the other hand, as a result of the stability test of the 3-aminothiophene-2-carboxylic acid derivative, it was found that these compounds are stable in a salt state. The 3-aminothiophene-2-carboxylic acid obtained by the hydrolysis reaction of the 3-aminothiophene-2-carboxylic acid ester derivative represented by the general formula (1) is represented by the general formula (2) in the reaction solution. Therefore, the reaction solution is acidified to a pH at which decarboxylation can occur without neutralizing the reaction solution and isolating the carboxylic acid represented by formula (5). It was possible to avoid a decrease in yield due to the isolation of the carboxylic acid represented by the formula (5) by carrying out the decarboxylation reaction, and an improvement in the yield was achieved.

  About the method using the reaction liquid obtained by the said hydrolysis reaction about the decarboxylation reaction of 3-aminothiophene-2-carboxylic acid or its metal salt represented by Formula (5) or General formula (2) below, Although not limited, it demonstrates by giving an example.

  Acids used in the reaction are not limited to the following, but include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, cyanoacetic acid, benzoic acid, citric acid, and the like. Organic acids such as acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, and benzenesulfonic acid can be used, and a mixture of these acids can also be used. The amount of the acid used in the reaction is not limited as long as the target reaction proceeds and the raw materials, intermediates, and products are not decomposed, but usually the formula (5) or the general formula (2) It is 1.0-20.0 equivalent with respect to 3-aminothiophene-2-carboxylic acid or its metal salt represented by these.

  Examples of the solvent used in the reaction include, but are not limited to, the following. Since this reaction uses the reaction solution of the previous hydrolysis reaction as a raw material, the solvent used is water, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, non-dimethylformamide and the like used in the hydrolysis reaction. Protic polar solvents and the like, and mixed solvents thereof are used. Further, ketone solvents such as MIBK (4-methyl-2-pentanone), aromatic solvents such as toluene and xylene, halogen solvents such as dichloromethane, etc. Can be added and mixed. The amount of the solvent used is not particularly limited, but is usually based on the weight of 3-aminothiophene-2-carboxylic acid represented by formula (5) or general formula (2) or a metal salt thereof. A weight of 1 to 40 times is preferable.

  As a result of the stability test of 3-aminothiophene under the reaction conditions, it was found that this compound has the lowest stability in the weakly acidic region near pH 4, and is stable in the strongly acidic and alkaline regions. When handling 3-aminothiophene, it is important to avoid a weakly acidic state where the present compound is unstable as much as possible, and to handle with strong acidity or alkalinity in order to suppress a decrease in yield and variation in reaction results.

  Since the decarboxylation reaction starts at a weak acidity of about pH 5, when an acid is added to the metal salt of 3-aminothiophene-2-carboxylic acid generated by hydrolysis that is strongly alkaline, There is a high risk that 3-aminothiophene is present in an unstable weakly acidic state, and 3-aminothiophene produced when a reaction is performed by adding a hydrolysis reaction solution to an acidic solution is present at an unstable pH. The present inventors have found that it is possible to avoid the danger and thus contribute to the improvement of the reaction yield. Specifically, when the decarboxylation reaction of the metal salt of 3-aminothiophene-2-carboxylic acid represented by the general formula (2) is performed, 3-aminothiophene-2 represented by the general formula (2) -An aqueous solution of a metal salt of a carboxylic acid is added to a two-phase solution of an acidic aqueous solution and an organic solvent to produce a salt formed from 3-aminothiophene represented by the general formula (3) and an acid.

  The reaction temperature and reaction time of the decarboxylation reaction can be varied over a wide range. Generally, the reaction temperature is not particularly limited as long as the intended reaction proceeds and the raw materials, intermediates and products are not decomposed, but it is preferably −10 to 100 ° C., preferably 0 to 30 ° C. Is more preferable. The reaction time is not particularly limited as long as the intended reaction proceeds, but it is preferably 0.1 to 50 hours.

  Moreover, 3-aminothiophene produced | generated by a decarboxylation reaction exists in the state of a salt in a reaction liquid. The resulting aqueous solution of the salt formed by the 3-aminothiophene represented by the general formula (3) and the acid is adjusted to an alkaline pH and extracted into the organic solvent as the 3-aminothiophene represented by the formula (4). To do. Compared with the case of adjusting the pH by adding an alkaline aqueous solution to a reaction solution containing a salt formed from a strongly acidic 3-aminothiophene and an acid during the pH adjustment, the alkaline aqueous solution and the organic solvent Risk of 3-aminothiophene staying at unstable pH when pH adjustment is performed by adding a reaction solution containing a strongly acidic 3-aminothiophene salt to a mixed solvent system (two-phase solvent) It has been found that can contribute to the improvement of the reaction yield.

  Although the base used for pH adjustment is not limited to the following, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc. are mentioned, The mixture of these bases can also be used. The temperature during pH adjustment is not particularly limited as long as the product does not decompose, but is preferably −10 to 30 ° C.

  Examples of the solvent used include, but are not limited to, ketone solvents such as MIBK, aromatic solvents such as toluene and xylene, and halogen solvents such as dichloromethane. The amount of the solvent used is not particularly limited, but is usually 1 to 40 times the weight of the salt formed by 3-aminothiophene represented by the general formula (3) and the acid. Weight is preferred.

  Various conditions in the above decarboxylation reaction and post-treatment, that is, the type of acid used in the reaction and the amount thereof used, the type and amount of alkali used in the post-treatment, the type and amount of solvent used, the reaction temperature, Each condition such as reaction time can be appropriately selected and combined with each other.

  The obtained 3-aminothiophene solution can be used as it is for another reaction by appropriately selecting a solvent, but can also be isolated as a stable form by a salt with an acid.

  The acid used for isolation as a salt is not limited to the following, but representative examples include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, cyano Acetic acid, benzoic acid, 4-cyanobenzoic acid, 2-chlorobenzoic acid, 2-nitrobenzoic acid, citric acid, fumaric acid, malonic acid, oxalic acid, maleic acid, phenoxyacetic acid, methanesulfonic acid, p-toluenesulfonic acid , Organic acids such as benzenesulfonic acid and p-toluenesulfinic acid. Although there is no restriction | limiting in particular about the usage-amount of the acid at the time of forming a salt with 3-aminothiophene, about monovalent acid, it is 1.0 with respect to the 3-aminothiophene derivative represented by General formula (4). The molar equivalent or more is preferable, and the polyvalent acid is preferably the theoretical equivalent or more that forms a salt with the 3-aminothiophene derivative represented by the general formula (4). The temperature for forming the salt is preferably -20 to 100 ° C, more preferably -10 to 30 ° C.

  Hereinafter, the present invention will be described in more detail with reference to examples and test examples, but the present invention is not limited to these examples.

[Example 1] Synthesis method of 3-aminothiophene using methyl 3-aminothiophene-2-carboxylate as a raw material

  A 48% aqueous sodium hydroxide solution (16.48 g, 0.20 mol) was diluted with water (51.90 g) and then methyl 3-aminothiophene-2-carboxylate (98.70%, 30.00 g, 0) at room temperature. .19 mol) was added and reacted at 60 ° C. for 3 hours. After the reaction solution was cooled to 25 ° C., insoluble matters derived from the raw material contaminants were filtered and washed with water (9.77 g). Toluene (148.05 g) was added to the obtained filtrate. 36% hydrochloric acid (44.83 g, 0.44 mol) was added dropwise while maintaining the reaction solution temperature at 25 ° C. under a nitrogen stream. After completion of dropping, the reaction solution was in an acidic state and reacted at 25 ° C. for 3 hours. The reaction solution was cooled to 5 ° C. or lower and separated under a nitrogen atmosphere. 25% sodium hydroxide (40.69 g, 0.25 mol) cooled to −5 ° C. was added to the organic layer, and the aqueous layer was added dropwise to the resulting bilayer solution with stirring to make it alkaline. After separation of the organic layer, toluene (148.05 g) was added to the aqueous layer for extraction, and the resulting organic layer and the previous organic layer were mixed, and the desired toluene solution of 3-aminothiophene (301.62 g, 3-aminothiophene concentration: 6.03 wt%, content: 18.19 g, yield: 96.56%).

[Example 2] Synthesis of 3-aminothiophene using methyl 3-aminothiophene-2-carboxylate as a raw material

  A 32% aqueous sodium hydroxide solution (64.13 g, 0.51 mol) was diluted with water (204.50 g) and then methyl 3-aminothiophene-2-carboxylate (94.87%, 68.00 g, 0) at room temperature. .41 mol) was added and reacted at 70 ° C. for 3 hours. After the reaction was cooled to 25 ° C., MIBK (267.08 g) was added. 35% hydrochloric acid (98.09 g, 0.94 mol) was added dropwise while maintaining the reaction solution temperature at 25 ° C. under a nitrogen stream. After completion of the dropping, the reaction solution became acidic and reacted at 25 ° C. for 5 hours. The reaction solution was cooled to 5 ° C. or lower and made alkaline by adding a 32% aqueous sodium hydroxide solution (68.74 g, 0.55 mol) under a nitrogen atmosphere. After separating the organic layer, MIBK (267.12 g) is added to the aqueous layer, extraction is performed under a nitrogen stream, the obtained organic layer and the previous organic layer are mixed, and the target 3-aminothiophene MIBK solution is obtained. (556.40 g, 3-aminothiophene concentration: 6.73 wt%, content: 37.47 g, yield: 92.15%).

[Example 3] Synthesis method of 3-aminothiophene using methyl 3-aminothiophene-2-carboxylate as a raw material

  After diluting a 32% aqueous sodium hydroxide solution (77.50 g, 0.62 mol) with water (246.14 g), methyl 3-aminothiophene-2-carboxylate (97.06%, 80.00 g, 0) at room temperature. .49 mol) was added and reacted at 70 ° C. for 3 hours. After the reaction was cooled to 25 ° C., MIBK (321.46 g) was added. 36% hydrochloric acid (118.07 g, 1.17 mol) was added dropwise while maintaining the reaction solution temperature at 25 ° C. under a nitrogen stream. After completion of the dropping, the reaction solution became acidic and reacted at 25 ° C. for 5 hours. The reaction solution was cooled to −5 ° C. or lower and separated under a nitrogen atmosphere. 25% sodium hydroxide (105.91 g, 0.66 mol) cooled to −25 ° C. was added to the organic layer, and the aqueous layer was added dropwise to the resulting bilayer solution with stirring to make it alkaline. After separating the organic layer, MIBK (321.46 g) was added to the aqueous layer, and extraction was performed at −5 ° C. under a nitrogen stream. The obtained organic layer and the previous organic layer were mixed to obtain the desired 3-amino MIBK solution of thiophene (705.74 g, 3-aminothiophene concentration: 6.62 wt%, content: 46.72 g, yield: 96.16%).

[Example 4] Synthesis of 3-aminothiophene using methyl 3-aminothiophene-2-carboxylate as a raw material

  After diluting a 32% aqueous sodium hydroxide solution (73.75 g, 0.59 mol) with water (85.23 g), methyl 3-aminothiophene-2-carboxylate (97.01%, 78.00 g, 0 at room temperature). .48 mol) was added and reacted at 60 ° C. for 3 hours. After cooling the reaction solution to 25 ° C., insoluble matters were removed by filtration and washed with water (25.11 g). The obtained filtrate was added dropwise at 25 ° C. to a two-layer solution of MIBK (328.73 g) and 36% aqueous hydrochloric acid (108.36 g, 1.07 mol) under a nitrogen stream. After completion of dropping, the reaction solution was in an acidic state and reacted at 25 ° C. for 2 hours. The reaction solution was cooled to 5 ° C. or lower and made alkaline by adding a 32% aqueous sodium hydroxide solution (81.25 g, 0.65 mol) under a nitrogen atmosphere. After separating the organic layer, MIBK (321.12 g) was added to the aqueous layer, extraction was performed under a nitrogen stream, the obtained organic layer and the previous organic layer were mixed, and the target 3-aminothiophene MIBK solution was obtained. (652.98 g, 3-aminothiophene concentration: 6.87 wt%, content: 44.86 g, yield: 94.25%).

[Example 5] Synthesis of 3-aminothiophene using methyl 3-aminothiophene-2-carboxylate as a raw material

  A 32% aqueous sodium hydroxide solution (77.14 g, 0.62 mol) was diluted with water (86.92 g), and then methyl 3-aminothiophene-2-carboxylate (97.01%, 80.00 g, 0) at room temperature. .49 mol) was added and reacted at 60 ° C. for 3 hours. After the reaction solution was cooled to 25 ° C., insoluble matters were removed by filtration and washed with water (25.61 g). The obtained filtrate was added dropwise at 25 ° C. to a two-layer solution of MIBK (310.43 g) and 36% aqueous hydrochloric acid (110.01 g, 1.09 mol) under a nitrogen stream. After completion of dropping, the reaction solution was in an acidic state and reacted at 25 ° C. for 2 hours. The reaction solution was cooled to −5 ° C. or lower and separated under a nitrogen atmosphere. 25% sodium hydroxide (106.64 g, 0.67 mol) cooled to −25 ° C. was added to the organic layer, and the aqueous layer was added dropwise to the resulting bilayer solution with stirring to make it alkaline. After separating the organic layer, MIBK (310.43 g) was added to the aqueous layer, followed by extraction at −5 ° C. under a nitrogen stream. The obtained organic layer and the previous organic layer were mixed, and the target 3-amino MIBK solution of thiophene (671.99 g, 3-aminothiophene concentration: 7.04 wt%, content: 47.30 g, yield: 97.35%).

[Example 6] Synthesis of 3-aminothiophenebenzenesulfonate

  After replacing the nitrogen solution of 3-aminothiophene obtained in the same manner as in Example 5 (300.00 g, 3-aminothiophene concentration: 6.80 wt%, content: 20.10 g, 202.72 mmol) with nitrogen, 60 Dehydrated under reduced pressure at 60 ° C. and 60 mmHg. The obtained MIBK solution was cooled to 0 ° C., benzenesulfonic acid monohydrate (98%, 40.09 g, 222.99 mmol) was gradually added with stirring, and the mixture was stirred at 0 ° C. for 1 hour. The precipitated crystals were filtered, washed with MIBK (40.20 g), and dried under reduced pressure to obtain the desired 3-aminothiophenebenzenesulfonate as light yellow crystals (51.38 g, yield 97). .60%).

Claims (8)

General formula (1)

[Wherein R represents an alkyl group having 1 to 12 carbon atoms or a phenyl group], and hydrolysis of a 3-aminothiophene-2-carboxylic acid ester derivative represented by the general formula (2) (Chemical Formula 2)

[Wherein M represents an alkali metal or an alkaline earth metal] A metal salt of 3-aminothiophene-2-carboxylic acid represented by the following formula is produced, a decarboxylation reaction is performed under acidic conditions, and a general formula ( 3) (Chemical formula 3)

[Wherein HX represents an acid] A salt formed from 3-aminothiophene and an acid represented by the formula (4)

Of 3-aminothiophene-2-carboxylic acid represented by the general formula (2), or a compound obtained by neutralization (5)

A method for producing 3-aminothiophene represented by the general formula (4), wherein the decarboxylation reaction is carried out without isolating 3-aminothiophene-2-carboxylic acid.   The neutralization method of the salt formed from 3-aminothiophene represented by the general formula (3) and the acid is an alkaline solution of the salt formed from the 3-aminothiophene represented by the general formula (3) and the acid. The method according to claim 1, wherein 3-aminothiophene represented by the general formula (4) is produced by adding to a two-phase solution of an aqueous solution and an organic solvent.   The metal of 3-aminothiophene-2-carboxylic acid represented by general formula (2) when performing the decarboxylation reaction of the metal salt of 3-aminothiophene-2-carboxylic acid represented by general formula (2) An aqueous salt solution is added to a two-phase solution of an acidic aqueous solution and an organic solvent to produce a salt formed from 3-aminothiophene represented by the general formula (3) and an acid. The method of claim 2.   The method according to any one of claims 1 to 3, wherein, in the general formula (1), R is an alkyl group having 1 to 12 carbon atoms.   The method according to claim 4, wherein R in the general formula (1) is a methyl group or an ethyl group.   The method according to any one of claims 1 to 5, wherein M in the general formula (2) is an alkali metal.   The method according to claim 6, wherein M in the general formula (2) is sodium (Na).   The method according to any one of claims 1 to 7, wherein in the general formula (3), HX is hydrogen chloride (HCl).