JP2003306487A - Method for producing 3-acylamino-thiophene derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for the industrial production of a 3-acylamino- thiophene derivative from 2-carboxymethyl-3-amino-thienyl in high yield by 3 steps comprising amidation, demethylation and decarbonation. <P>SOLUTION: The improvement of the production method comprises the use of pyridine as the base to be used in the amidation reaction, the selection of a proper reaction solvent, the setting of the aging temperature in two steps, etc. The method is industrially advantageous because the 3 reaction stages can be carried out in the same reactor without separating the reaction product in each unit operation. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to the formula (1) (formula 5).

[0002]

[Chemical 5]

2-carboxymethyl-3-amino-thienyl represented by the general formula (2)

[0004]

[Chemical 6]

(In the formula, R represents a hydrogen atom, an optionally substituted alkyl group or an alkoxy group, an optionally substituted aromatic or non-aromatic hydrocarbon ring, an optionally substituted aromatic group. Or a non-aromatic heterocycle is shown) as a raw material, and using pyridine as a base catalyst for the amidation reaction, the reaction is carried out by the general formula (3)
(Chemical formula 7)

[0006]

[Chemical 7]

(Wherein R is the same as above) 3
-A method for producing an acylamino-thiophene derivative, which is produced by an amidation reaction of a compound represented by the formula (1):

[0008]

[Chemical 8]

(Wherein R is as defined above), which is formed by the hydrolysis reaction of an intermediate 2-carboxymethyl-3-acylamino-thiophene derivative represented by the formula and a compound represented by the general formula (4). General formula (5)

[0010]

[Chemical 9]

(Wherein R is as defined above), the reaction is continuously carried out without performing each isolation operation of the intermediate 2-carboxyl-3-acylamino-thiophene derivative. And a method for producing a 3-acylamino-thiophene derivative represented by the general formula (3).

[0012]

2. Description of the Related Art 2-Alkyl-3-acylamino-thiophene derivatives are known to have a controlling effect against various plant diseases (JP-A-9-235282 (European Patent Publication 0737682 A1)). And this 2-alkyl-
As a method for producing a 3-acylamino-thiophene derivative, a method of directly introducing an alkyl group into the 2-position of the 3-acylamino-thiophene derivative represented by the general formula (3) is generally known [tetrahedron.・ Letter (Tetrahed
ron Letters, 34,5715-5718 (1993))]. As described above, the 3-acylamino-thiophene derivative represented by the general formula (3) is useful as an intermediate for an agricultural / horticultural fungicide.

As a method for producing a 3-acylamino-thiophene derivative represented by the general formula (3), 2-carboxymethyl-3-amino-thienyl represented by the formula (1) is used as a starting material, and an amine or the like is first prepared. The base is subjected to an amidation reaction with the acid chloride represented by the general formula (2) to obtain a 2-carboxymethyl-3-acylamino-thiophene derivative represented by the general formula (4). A method is generally known in which a 2-carboxyl-3-acylamino-thiophene derivative represented by the general formula (5) is obtained by a hydrolysis reaction due to causticity, and then a decarboxylation reaction is further performed by heating. There is.

As described above, 3- represented by the general formula (3)
The acylamino-thiophene derivative is subjected to a total of three steps of reaction to give 2-carboxymethyl-3 represented by the formula (1).
Made from -amino-thienyl. It is known that the reaction of the second step and the third step in the latter half of these can be carried out by a continuous reaction using pyridine, although [SYNTHESIS Communications, 48
7-489 (1981)]], this method still requires the operation of isolating the intermediate in the first step. Usually, the 2-carboxymethyl-3-acylamino-thiophene derivative represented by the general formula (4) can be crystallized by directly charging the reaction solution with water, and then filtered to obtain crystals. You can take it out. However, there is a problem that the filtration is also difficult.

[0015]

The problem to be solved by the present invention is to use the 2-carboxymethyl-3-amino-thienyl represented by the formula (1) as a raw material to obtain the compound represented by the general formula (4). -Carboxymethyl-3-acylamino-thiophene derivative, via the 2-carboxyl-3-acylamino-thiophene derivative represented by the general formula (5),
An object of the present invention is to provide a method capable of industrially and easily producing a 3-acylamino-thiophene derivative represented by the general formula (3) in a high yield by a three-step reaction of amidation, demethylation and decarboxylation.

[0016]

The present inventors have used 2-carboxymethyl-3-amino-thienyl represented by the formula (1) as a starting material to obtain 2-carboxymethyl-3 represented by the general formula (4). -Acylamino-thiophene derivative, represented by the general formula (3) in a three-step reaction of amidation, demethylation and decarboxylation via a 2-carboxyl-3-acylamino-thiophene derivative represented by the general formula (5). Done 3-
As a result of extensive studies on a method for producing an acylamino-thiophene derivative, pyridine was used as a base for the amidation reaction, an appropriate reaction solvent was selected, and the aging temperature was changed to two stages to obtain an intermediate represented by the general formula ( 4-carboxymethyl-3-acylamino-thiophene derivative represented by 4), 2-carboxyl-represented by the general formula (5)
The present invention has been completed because a method of carrying out three reactions in the same reaction system without performing each isolation operation of a 3-acylamino-thiophene derivative was found and further industrially operable.

That is, the present invention uses the formula (1) (Formula 10)

[0018]

[Chemical 10]

2-carboxymethyl-3-amino-thienyl represented by the general formula (2)

[0020]

[Chemical 11]

(In the formula, R represents a hydrogen atom, an alkyl group which may be substituted, an alkoxy group, an aromatic or non-aromatic hydrocarbon ring which may be substituted, and an aromatic group which may be substituted. Or a non-aromatic heterocycle) is used as a raw material, and an amidation reaction, a demethylation reaction, and a decarboxylation reaction in an organic solvent are performed according to the formula (3)
(Chemical formula 12)

[0022]

[Chemical 12]

A method for producing a 3-acylamino-thiophene derivative represented by the formula (wherein R is the same as above), wherein the organic solvent is an aprotic polar solvent, and demethylation is more preferable than amidation reaction. A general formula characterized in that the reaction temperature of the oxidization reaction and the decarboxylation reaction is raised, and three reactions are carried out in the same reaction system without isolation of intermediates produced in the amidation reaction and demethylation reaction. 3 represented by (3)
The present invention provides a method for producing an acylamino-thiophene derivative.

[0024]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below.
In a specific embodiment of the present invention, three reactions are performed by the method shown below.

The amidation reaction of 2-carboxymethyl-3-amino-thienyl represented by the formula (1) with the acid chloride represented by the general formula (2) in the first step is performed by reacting pyridine with a basic group. The reaction is carried out using a solvent as a catalyst. The resulting solution of the 2-carboxymethyl-3-acylamino-thiophene derivative represented by the general formula (4) is used in the next operation.

The reaction in the second step is carried out by heating the reaction solution obtained in the reaction in the first step and using pyridine hydrochloride in the solution as a methylating agent, represented by the general formula (4): A demethylation reaction of a carboxymethyl-3-acylamino-thiophene derivative is performed. The resulting solution of the 2-carboxyl-3-acylamino-thiophene derivative represented by the general formula (5) is used in the next operation.

In the third step reaction, the reaction solution obtained in the second step reaction is further heated to decarboxylate the 2-carboxyl-3-acylamino-thiophene derivative represented by the general formula (5). The reaction is performed, and the 3-acylamino-thiophene derivative represented by the general formula (3) is isolated from the obtained reaction solution to obtain the desired product.

R in the general formulas (2), (3), (4) and (5) is specifically a hydrogen atom or an optionally substituted alkyl group, for example, a methyl group, an ethyl group, Propyl group, isopropyl group, butyl group, isobutyl group, sec-
A butyl group, a tert-butyl group, a hexyl group, a decyl group, a methoxymethyl group, an ethoxymethyl group, an alkyl group such as a phenylmethyl group, and the like, and an optionally substituted alkoxy group represented by R is methoxy. Groups, ethoxy groups, propoxy groups, isopropoxy groups, cyclopropoxy groups, butoxy groups, isobutoxy groups, sec-butoxy groups, tert-butoxy groups, cyclohexyloxy groups, hexyloxy groups, benzyloxy groups, and other alkoxy groups. In the case of an optionally substituted aromatic hydrocarbon ring represented by R, or an optionally substituted non-aromatic hydrocarbon ring, the following (A1) to (A13)

[0029]

[Chemical 13]

(Wherein R1 is a trifluoromethyl group, a difluoromethyl group, a methyl group, an ethyl group or a halogen atom, and R2 is a hydrogen atom, a methyl group, a trifluoromethyl group, a halogen atom, a methoxy group or an amino group. R3 is a hydrogen atom, a halogen atom, a methyl group or a methoxy group, R4 is a hydrogen atom, a methyl group, an ethyl group, or a halogen atom, R5 is a trifluoromethyl group,
It is a difluoromethyl group, a methyl group, an ethyl group, a halogen atom or a hydrogen atom, and n means an integer of 0 to 2.
However, when R is (A9), (A10), or (A11), R1 is not a halogen atom. ), Specifically,

Examples of the optionally substituted aromatic hydrocarbon ring include a phenyl group and a substituted phenyl group, and examples of the substituent of the substituted phenyl group include a methyl group, an ethyl group, a propyl group and isopropyl group. Alkyl group such as group, methoxy group, ethoxy group, propoxy group, alkoxy group such as isopropoxy group, chlorine atom, bromine atom,
Fluorine atom, halogen atom such as iodine atom, nitro group,
Cyano group, amino group and the like,

Examples of the non-aromatic hydrocarbon ring which may be substituted include non-aromatic hydrocarbon rings such as cyclopropyl group, cyclopentyl group, cyclohexyl group and cyclohexenyl group.

Examples of the optionally substituted aromatic heterocycle include a pyrazolyl group, a thiazolyl group, an isothiazolyl group, a furyl group, a thienyl group, a pyridyl group, a pyrazinyl group, an oxazolyl group, a pyrrolyl group, a substituted pyrazolyl group,
Examples thereof include a substituted thiazolyl group, a substituted isothiazolyl group, a substituted furyl group, a substituted thienyl group, a substituted pyridyl group, a substituted pyrazinyl group, a substituted oxazolyl group, and a substituted pyrrolyl group.A substituted pyrazolyl group, a substituted thiazolyl group, a substituted isothiazolyl group, a substituted furyl group Group, a substituted thienyl group, a substituted pyridyl group, a substituted pyrazinyl group, a substituted oxazolyl group, a substituted pyrrolyl group, for example, a methyl group, an ethyl group, a propyl group, an alkyl group such as an isopropyl group, a trifluoromethyl group, and difluoromethyl. Haloalkyl groups such as groups, fluorine atoms, chlorine atoms, bromine atoms, halogen atoms such as iodine atoms, amino groups, cyano groups and the like,

Examples of the non-aromatic heterocyclic ring which may be substituted include a dihydropyranyl group, a dihydrofuryl group, a tetrahydrofuryl group, a 2,3-dihydro-1,4-oxathioin-5-yl group and a substituted dihydro group. Pyranyl group, substituted dihydrofuryl group, substituted tetrahydrofuryl group, substituted 2,
3-dihydro-1,4-oxathiin-5-yl group and the like can be mentioned. Substituted dihydropyranyl group, substituted dihydrofuryl group, substituted tetrahydrofuryl group, substituted 2,3-dihydro-1,4-oxathiin-5- Examples of the substituent of the yl group include alkyl groups such as methyl group, ethyl group, propyl group and isopropyl group, haloalkyl groups such as trifluoromethyl group and difluoromethyl group, halogen atoms such as fluorine atom, chlorine atom and iodine atom. , Amino groups, cyano groups and the like. When R is (A1), R1 at the 3-position is a trifluoromethyl group, difluoromethyl group, methyl group, ethyl group or halogen atom, and R3 at the 5-position is a hydrogen atom, halogen atom, methyl group or methoxy group. And a 4-pyrazolyl group substituted with methyl at the 1-position, for example, 1,3-dimethyl-4-pyrazolyl group, 5-chloro-1,3-dimethyl-4-pyrazolyl group, 5-chloro-1-methyl-3
-Trifluoromethyl-4-pyrazolyl group, 1-methyl-3-trifluoromethyl-4-pyrazolyl group, 1-methyl-3-difluoromethyl-4-pyrazolyl group, 1-
Methyl-3-ethyl-4-pyrazolyl group, 1-methyl-
3-chloro-4-pyrazolyl group, 1-methyl-3-trifluoromethyl-5-methoxy-4-pyrazolyl group and the like, when R is (A2), R1 at the 4-position is a trifluoromethyl group, 5-thiazolyl group which is a difluoromethyl group, a methyl group, an ethyl group or a halogen atom, and R2 at the 2-position is a hydrogen atom, a methyl group, a trifluoromethyl group, a halogen atom, a methoxy group or an amino group, for example, 2-
A methyl-4-trifluoromethyl-5-thiazolyl group,
2-methyl-4-difluoromethyl-5-thiazolyl group, 4-trifluoromethyl-5-thiazolyl group, 2,
4-dimethyl-5-thiazolyl group, 2-methyl-4-ethyl-5-thiazolyl group, 2-amino-4-methyl-5
-Thiazolyl group, 2-methoxy-4-methyl-5-thiazolyl group, 2-chloro-4-methyl-5-thiazolyl group, etc., and when R is (A3), R1 at the 2-position is trifluoromethyl. Group, a difluoromethyl group, a methyl group, an ethyl group or a halogen atom and R4 at the 5-position is a hydrogen atom, a methyl group, an ethyl group or a halogen atom, for example, a 2-methyl-3-furyl group , 2,5-dimethyl-3-furyl group, 2-chloro-3-furyl group, 2-
Trifluoromethyl-3-furyl group, etc., when R is (A4), R1 at the 3-position is a trifluoromethyl group, difluoromethyl group, methyl group, ethyl group or halogen atom, and R4 at the 5-position Is a hydrogen atom, a methyl group or a halogen atom, a 2-thienyl group, for example, 3-methyl-2.
-Thienyl group, 3,5-dimethyl-2-thienyl group, 3
-Chloro-2-thienyl group, 3-iodo-2-thienyl group, etc. are mentioned, and when R is (A5), R5 at the 2-position is a trifluoromethyl group, difluoromethyl group, methyl group, ethyl group, halogen. A phenyl group, which is an atom or a hydrogen atom,
That is, 2-trifluoromethylphenyl group, 2-difluoromethylphenyl group, 2-methylphenyl group, 2
-Ethylphenyl group, 2-fluorophenyl group, 2-chlorophenyl group, 2-bromophenyl group, 2-iodophenyl group, phenyl group, and when R is (A6),
R1 at the 2-position is a trifluoromethyl group, a difluoromethyl group, a methyl group, an ethyl group or a halogen atom 3-
Pyridyl group, that is, 2-trifluoromethyl-3-
A pyridyl group, a 2-difluoromethyl-3-pyridyl group,
2-methyl-3-pyridyl group, 2-ethyl-3-pyridyl group, 2-fluoro-3-pyridyl group, 2-chloro-3
-Pyridyl group, 2-bromo-3-pyridyl group, 2-iodo-3-pyridyl group, and when R is (A7), 2
-Chloro-3-pyrazinyl group, when R is (A8), R3 at the 3-position is a trifluoromethyl group, a difluoromethyl group, a methyl group, an ethyl group or a 4-thienyl group which is a halogen atom, That is, 3-trifluoromethyl-4-thienyl group, 3-difluoromethyl-4-thienyl group, 3-methyl-4-thienyl group, 3-ethyl-
4-thienyl group, 3-fluoro-4-thienyl group, 3-
A chloro-4-thienyl group, a 3-bromo-4-thienyl group, a 3-iodo-4-thienyl group, and R is (A
In the case of 9), R1 at the 6-position is a 3,4-dihydro-2H-pyran-5-yl group which is a trifluoromethyl group, a difluoromethyl group, a methyl group or an ethyl group, that is, 6
-Trifluoromethyl-3,4-dihydro-2H-pyran-5-yl group, 6-difluoromethyl-3,4-dihydro-2H-pyran-5-yl group, 6-methyl-3,4-
Dihydro-2H-pyran-5-yl group, 2-ethyl-
3,4-dihydro-2H-pyran-5-yl group, and when R is (A10), R1 at the 6-position is a trifluoromethyl group, a difluoromethyl group, a methyl group or an ethyl group 2,3 -Dihydro-1,4-oxathiin-5-yl group, 2,3-dihydro-1,4-oxathiin-4-oxide-5-yl group or 2,3-dihydro-1,4-
An oxathiin-4,4-dioxide-5-yl group, such as a 6-methyl-2,3dihydro-1,4-oxathiin-5-yl group, 6-methyl-2,3-dihydro-1,4- An oxathiin-4-oxide-5-yl group,
A 6-methyl-2,3-dihydro-1,4-oxathiin-4,4-dioxide-5-yl group and the like can be mentioned. R
Is (A11), R1 at the 5-position is a trifluoromethyl group,
Difluoromethyl group, methyl group, ethyl group 2,3
-Dihydro-4-furyl group, that is, 5-trifluoromethyl-2,3-dihydro-4-furyl group, 5
-Difluoromethyl-2,3-dihydro-4-furyl group, 5-methyl-2,3-dihydro-4-furyl group, 5
—Ethyl-2,3-dihydro-4-furyl group, and when R is (A12), R1 at the 3-position is a trifluoromethyl group, a difluoromethyl group, a methyl group, an ethyl group or a halogen atom. An isothiazolyl group, i.e.
3-trifluoromethyl-4-isothiazolyl group, 3-
Difluoromethyl-4-isothiazolyl group, 3-methyl-4-isothiazolyl group, 3-ethyl-4-isothiazolyl group, 3-fluoro-4-isothiazolyl group, 3-chloro-4-isothiazolyl group, 3-bromo-4- Examples thereof include an isothiazolyl group and a 3-iodo-4-isothiazolyl group.

The number of equivalents of the acid chloride represented by the general formula (2) used in the amidation reaction is usually 1 equivalent to the 2-carboxymethyl-3-amino-thienyl represented by the formula (1). It is above, preferably 1 to 1.5 equivalents, more preferably 1 to 1.1 equivalents.

The equivalent number of the aprotic polar solvent such as pyridine used is usually 0.1 to 100 relative to 2-carboxymethyl-3-amino-thienyl represented by the formula (1).
The amount is 1 to 20 times by weight, preferably 1 to 1.5 equivalents, more preferably 1 to 1.5 equivalents, still more preferably 1 to 1.1 equivalents.

The order of adding these components is not limited, but it is preferable to add the acid chloride represented by the general formula (2) dropwise since the reaction in the first step is an exothermic reaction.

The method of dropping the acid chloride represented by the general formula (2) can be carried out continuously or intermittently.

When the acid chloride represented by the general formula (2) is dropped, the dropping time is 1 to 50 hours, preferably 1 to 10 hours.

Examples of the solvent used in the reaction include 1,3-dimethyl-2-imidazolidinone, N, N-dimethylformamide, N, N-dimethylacetamide,
N-methylpyrrolidone etc. are mentioned. Preferably 1,
It is 3-dimethyl-2-imidazolidinone.

The reaction temperature is 10 to 9 in the first stage reaction.
The temperature is 9 ° C, preferably 20 to 60 ° C, more preferably 40 to 60 ° C. The reaction temperature for the second and third steps is 100 to 200 ° C., preferably 120.
To 140 ° C.

The reaction time in the first stage reaction is 0.1 to 50 hours, preferably 1 to 24 hours. Two
The reaction in the third and third steps is 1 to 50 hours, preferably 5 to 24 hours.

The pressure in the three-step reaction may be normal pressure or reduced pressure. The post-treatment of the reaction solution after the decarboxylation reaction in the third step can be carried out according to a conventional method. For example, after removing salts as necessary by filtration or the like, a poor solvent may be added directly to carry out crystallization to take out the desired product. If necessary, silica gel column chromatography, purification such as recrystallization, etc. can be performed to obtain a highly pure product.

[0044]

EXAMPLES The contents of the present invention will be specifically described below with reference to examples, but the present invention is not limited to the methods described in the examples.

In the following, the analytical conditions by high performance liquid chromatography are as follows.

[0046] Column: YMC-PACK ODS-A A-314 Eluent: acetonitrile / water (phosphate buffer pH 3.0) Temperature: 40 ° C Flow rate: 1 ml / min Detector: UV 254nm

Example 1 20 g of 2-carboxymethyl-3-amino-thienyl
(0.13 mol) and pyridine 10.2 g (0.13 mol)
mol) with 1,3-dimethyl-2-imidazolidinone 3
Dissolve in 3.4 g and with stirring benzoyl chloride 18.
1 g (0.13 mol) was added dropwise at 60 ° C over 1 hour, and then the mixture was reacted at 60 ° C for 1 hour. Then 1 reaction mixture
After heating to 35 ° C. and reacting for 8 hours, the reaction liquid was cooled to 90 ° C. While stirring the reaction solution, 145 g of water was added dropwise to crystallize. Then, cool the reaction solution to 30 ° C., and
Crystallization was performed at 0 ° C. for 2 hours, and filtration was performed to obtain 4- (thieni-3-).
Yield) carbamoyl-benzene brown crystals were obtained. Crystals after drying were 25.9 g, purity 97% (0.12 mol)
Met. (Reaction yield 98%, Step isolation yield 97%)

Example 2 20 g of 2-carboxymethyl-3-amino-thienyl
(0.13 mol) and pyridine 10.2 g (0.13 mol)
(mol) was dissolved in 33.4 g of N, N-dimethylformamide, and 18.1 g of benzoyl chloride (0.
13 mol) was added dropwise at 60 ° C over 1 hour, and then 6
The reaction was carried out at 0 ° C for 1 hour. After that, the reaction liquid was heated to 135 ° C., reacted for 8 hours, and then cooled to 90 ° C. While stirring the reaction solution, 145 g of water was added dropwise to crystallize. Then, the reaction solution was cooled to 30 ° C., and crystallized at 30 ° C. for 2 hours and filtered to obtain a brown crystal of 4- (thien-3-yl) carbamoyl-benzene. The crystals were 12.5 g after drying and had a purity of 97% (0.06 mol).
(Reaction yield 48%, Step isolation yield 47%)

Example 3 20 g of 2-carboxymethyl-3-amino-thienyl
(0.13 mol) and pyridine 10.2 g (0.13 mol)
mol) was dissolved in 33.4 g of N, N-dimethylacetamide, and 18.1 g of benzoyl chloride (0.
13 mol) was added dropwise at 60 ° C over 1 hour, and then 6
The reaction was carried out at 0 ° C for 1 hour. After that, the reaction liquid was heated to 135 ° C., reacted for 8 hours, and then cooled to 90 ° C. While stirring the reaction solution, 145 g of water was added dropwise to crystallize. Then, the reaction solution was cooled to 30 ° C., and crystallized at 30 ° C. for 2 hours and filtered to obtain a brown crystal of 4- (thien-3-yl) carbamoyl-benzene. The crystals were 20.0 g after drying and had a purity of 97% (0.10 mol).
(Reaction yield 76%, Step isolation yield 75%) Example 4

20 g (0.13 mol) of 2-carboxymethyl-3-amino-thienyl and 10.2 g of pyridine
(0.13 mol) of N-methylpyrrolidone 33.4 g
Dissolved in, and stirred with benzoyl chloride 18.1 g
(0.13 mol) was added dropwise at 60 ° C over 1 hour, and then the mixture was reacted at 60 ° C for 1 hour. After that, the reaction solution is 135 ℃
The reaction solution was cooled to 90 ° C. after being heated up to react for 8 hours. While stirring the reaction solution, 145 g of water was added dropwise to crystallize. Then, the reaction solution was cooled to 30 ° C., crystallized at 30 ° C. for 2 hours, and filtered to give 4- (thien-3-yl).
Carbamoyl-benzene brown crystals were obtained. The crystals were 25.6 g after drying and had a purity of 97% (0.12 mol). (Reaction yield 97%, Step isolation yield 96%)

Example 5 20 g of 2-carboxymethyl-3-amino-thienyl
(0.13 mol) and pyridine 10.2 g (0.13 mol)
mol) with 1,3-dimethyl-2-imidazolidinone 3
1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid chloride 2 dissolved in 3.4 g with stirring
7.3 g (0.13 mol) was added dropwise at 60 ° C over 1 hour, and then reacted at 60 ° C for 1 hour. After that, the reaction liquid was heated to 135 ° C., reacted for 8 hours, and then cooled to 90 ° C. While stirring the reaction solution, 145 g of water was added dropwise to crystallize. Then cool the reaction solution to 30 ° C,
By crystallization at 30 ° C. for 2 hours and filtration, 4- (thieni-3)
-Yl) Carbamoyl-1-methyl-3-trifluoromethylpyrazole brown crystals were obtained. Crystals after drying 3
It was 3.6 g and the purity was 97% (0.12 mol).
(Reaction yield 94%, Process isolation yield 93%)

[0052]

INDUSTRIAL APPLICABILITY As described above, according to the method of the present invention, a 3-acylamino-thiophene derivative represented by the general formula (3), which is useful as an intermediate for agricultural and horticultural fungicides, can be prepared by a simple method. A high-purity product can be produced, which is an excellent production method.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Kenichi Sato             30 Asamu-cho, Omuta City, Fukuoka Prefecture             In the company F-term (reference) 4C023 GA03                 4C063 AA01 BB09 CC92 DD12 DD22                       DD34 DD61 DD62 DD75 DD78                       DD87 EE05

Claims (7)

[Claims] 1. Formula (1) (Formula 1) 2-carboxymethyl-3-amino-thienyl represented by the general formula (2) (Chemical Formula 2) (In the formula, R represents a hydrogen atom, an optionally substituted alkyl group, an alkoxy group, an optionally substituted aromatic or non-aromatic hydrocarbon ring, an optionally substituted aromatic or non-aromatic group. A heterocycle of group I) is used as a raw material, and an amidation reaction, a demethylation reaction, and a decarboxylation reaction in an organic solvent are performed to obtain a compound represented by the general formula (3) 3] (In the formula, R is the same as above) 3-acylamino-
A method for producing a thiophene derivative, wherein the organic solvent is an aprotic polar solvent, the reaction temperature of demethylation reaction and decarboxylation reaction is higher than that of amidation reaction, and amidation reaction and demethylation reaction are performed. 3-acylamino-represented by the general formula (3), characterized in that three reactions are carried out in the same reaction system without isolation of the intermediate produced in
Method for producing thiophene derivative. 2. R is the following (A1) to (A13) (Chemical formula 4) [Chemical formula 4] (In the formula, R1 is a trifluoromethyl group, a difluoromethyl group, a methyl group, an ethyl group, or a halogen atom,
R2 is hydrogen atom, methyl group, trifluoromethyl group, halogen atom, methoxy group or amino group, R3 is hydrogen atom, halogen atom, methyl group or methoxy group, R4 is hydrogen atom, methyl group, ethyl group Or a halogen atom, R5 is a trifluoromethyl group, a difluoromethyl group, a methyl group, an ethyl group, a halogen atom or a hydrogen atom, and n means an integer of 0 to 2. However, R is
In the case of (A9), (A10) and (A11), R1 is not a halogen atom. 2. The method according to claim 1, wherein 3. The R is (A1) or (A5).
The method described. 4. R is (A1) (provided that R1 is a trifluoromethyl group and R3 is a hydrogen atom), or (A5)
(However, R5 is a hydrogen atom.) The method according to claim 2. 5. The organic solvent is 1,3-dimethyl-2-imidazolidinone, N, N-dimethylformamide, N, N
-Dimethylacetamide, or N-methylpyrrolidone, The method according to any one of claims 2 to 4. 6. The method according to claim 4, wherein the organic solvent is 1,3-dimethyl-2-imidazolidinone. 7. The reaction temperature of the first step amidation reaction is 4
The method according to any one of claims 1 to 6, wherein the reaction temperature of the demethylation reaction in the second step and the decarboxylation reaction in the third step is 120 to 140 ° C at 0 ° C to 60 ° C.