JPH0613503B2 - Process for producing 3-hydroxy-2-thiophenecarboxylic acid derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel production method for producing a 3-hydroxy-2-thiophenecarboxylic acid derivative with high selectivity and high yield.

[Problems to be Solved by Prior Art and Invention]

The 3-hydroxy-2-thiophenecarboxylic acid derivative is
It is a useful compound that can be widely used as an intermediate for agricultural chemicals and pharmaceuticals.

In particular, the above compounds are valuable as a raw material for N- [2 '-(3'-methoxy) -thienylmethyl] -N-chloroaceto-2,6-dimethylanilide, which has a low dosage and controls weeds in a wide range. It is expensive.

As a conventional method for producing a 3-hydroxy-2-thiophenecarboxylic acid derivative, West German Patent No. 1,020,641 discloses that after reacting an α-halogenoacrylic acid ester and a mercaptoacetic acid ester in an alcohol solution of potassium hydroxide,
A method is known in which the reaction product is acidified to obtain the desired product, 3-hydroxy-2-thiophenecarboxylic acid ester.

However, the α-halogenoacrylic acid ester used in the above method is an unstable compound that is easily polymerized, and moreover, in the presence of a base, it easily undergoes a side reaction such as hydrolysis or saponification, so that the desired product is obtained. There was a problem that the yield was low at 40 to 82% and the selectivity was extremely low.

[Means for solving problems]

The present inventors have succeeded in producing a 3-hydroxy-2-thiophenecarboxylic acid derivative at a high yield by using an α, β-dihalogenopropionic acid derivative instead of the mercaptoacetic acid derivative and the α-halogenoacrylic acid derivative. As a result, they have found that they can be manufactured with high selectivity, and have completed the present invention.

The present invention provides a compound of the general formula (1) AS-CH ₂ COR ₁ (1) (wherein A represents a hydrogen atom, an acyl group or an alkali metal atom, and R ₁ represents a substituted or unsubstituted alkoxy group, a substituted or unsubstituted Alkylthio group, a substituted or unsubstituted phenoxy group, or a substituted or unsubstituted amino group of) and a general formula (2) (However, R ₂ is a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted phenyl group, a nitro group, an alkoxycarbonyl group, R ₃ is an alkyl group and a phenyl group, and X is a halogen atom. The general formula (3) is characterized by reacting an α, β-dihalogenopropionic acid derivative represented by (Wherein, R ₁ and R ₂ are the shows the same group as R ₁ and R ₂ in the general formula) process for the preparation of 3-hydroxy-2-thiophenecarboxylic acid derivative represented by.

One of the raw materials used in the present invention is the above-mentioned general formula.
It is a mercaptoacetic acid derivative represented by (1). In the general formula (1), the acyl group represented by A is not particularly limited in the number of carbon atoms, but in general, those having 2 to 7 carbon atoms are preferable. Generally, suitable examples of the acyl group are acetyl group, propionyl group, iso-propionyl group, n-butyryl group, t-butyryl group, n-valeryl group, irivaleryl group, benzoyl group and cyclohexylcarbonyl group. Etc. Further, the general formula (1)
Examples of the alkali metal atom represented by A include sodium, potassium and lithium.

Further, in the general formula (1), an alkoxy group represented by R ₁ ,
The alkyl residue in the alkylthio group is not particularly limited in its carbon number and linear, branched, etc., but generally, an alkyl group having 1 to 6 carbon atoms is preferable from the viewpoint of easy availability of raw materials. Of these, the most preferable alkoxy group is specifically shown as methoxy group, ethoxy group, n-propoxy group, is
o-propoxy group, n-butoxy group, iso-butoxy group,
Examples thereof include t-butoxy group, n-pentoxy group, n-hexoxy group and the like. Specific examples of the alkylthio group are methylthio group, ethylthio group, n-propylthio group, iso-propylthio group, n-butylthio group, iso-
Examples thereof include a butylthio group, a t-butylthio group, an n-pentylthio group and an n-hexylthio group.

Further, as the substituent of the substituted alkoxy group and the substituted alkylthio group, an inert substituent which does not participate in the reaction of the present invention can be used without any limitation. Particularly preferable substituents are a hydroxyl group, an alkoxy group, an alkylthio group,
Examples thereof include a phenyl group.

Moreover, the substituents of the substituted phenoxy group and the substituted amino group are not particularly limited as long as they are inert to the reaction. As a substituent which can be particularly preferably used, in addition to an alkyl group such as a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, an n-butyl group, an iso-butyl group and a t-butyl group, a halogen atom, Examples thereof include a hydroxyl group, an alkoxy group, an alkylthio group and a phenyl group.

Further, another raw material used in the present invention is the α, β-dihalogenopropionic acid derivative represented by the above general formula (2).

In the general formula (2), the alkyl group represented by R ₁ and R ₂ and the alkyl residue in the carboalkoxy group are not particularly limited in carbon number, straight chain, branched chain, etc. Generally, an alkyl group having 1 to 6 carbon atoms is preferable from the viewpoint of easiness. Generally, the most preferred examples of the alkyl group are methyl group, ethyl group, n-propyl group and iso.
-Propyl group, n-butyl group, iso-butyl group, t-butyl group, n-pentyl group, n-hexyl group and the like. Further, in the general formula (2), examples of the halogen atom represented by R ₂ and X include fluorine, chlorine, bromine, and iodine, and chlorine, bromine, or iodine is particularly preferable. Further, the substituent of the substituted alkyl group is not particularly limited as long as it is a substituent inert in the reaction system. Of which
Specific examples of the substituents that can be particularly preferably used include a halogen atom; a hydroxy group; a methoxy group, an ethoxy group, and n.
-Alkoxy groups such as propoxy group, iso-propoxy group, n-butoxy group; methylthio group, ethylthio group, n-
Examples thereof include an alkylthio group such as a propylthio group and an n-butylthio group; a phenyl group; a phenoxy group. Also,
The substituent of the substituted phenyl group is not particularly limited, and in the present invention, an inert substituent that does not participate in the reaction can be used without any limitation. Particularly preferred substituents are halogen atom; nitro group; hydroxyl group; methyl group, ethyl group, n
-Propyl group, iso-propyl group, n-butyl group, iso-
Examples thereof include an alkyl group such as a butyl group and a t-butyl group; a halogenoalkyl group such as a chloromethyl group, a difluoromethyl group, a trifluoromethyl group, a trichloromethyl group, a trifluoroethyl group and a pentafluoroethyl group; and a phenyl group.

The base used in the present invention is not particularly limited, but specific examples of the base used particularly preferably include potassium hydroxide; alkali metal hydroxides such as sodium hydroxide; sodium methylate. , Sodium ethylate, alkali metal alcoholates such as potassium t-butyrate, pyridine, 1,8-diazabicyclo [5.4.
0] Organic bases such as undeca-7-ene (DBU) and the like can be mentioned.

The method of the present invention is characterized in that the mercaptoacetic acid derivative represented by the general formula (1) and the α, β-dihalogenopropionic acid derivative represented by the general formula (2) are reacted in the presence of a base. .

Generally, the above reaction is preferably carried out in an inert organic solvent. The inert organic solvent is not particularly limited, and known inert organic solvents can be used without particular limitation. Specific examples of inert organic solvents that are particularly preferably used include alcohol solvents such as methanol, ethanol and propanol; aromatic solvents such as benzene, toluene and xylene;
Saturated aliphatic solvents such as pentane, hexane, heptane;
Examples include ether solvents such as diethyl ether, dibutyl ether, dimethoxyethane, diethylene glycol dimethyl ether and tetrahydrofuran.

The amount of the inert organic solvent used is not particularly limited, but generally, the volume ratio of the mercaptoacetic acid derivative and the inert organic solvent is 1: 1 to 1: 100, preferably 1 :.
It is preferable to select it in the range of 1 to 1:20.

In the present invention, the above-mentioned mercaptoacetic acid and α, β-
The order of addition of the dihalogenopropionic acid derivative to the reaction system is not particularly limited, but after (A) the mercaptoacetic acid derivative and the base are mixed in advance, this is mixed with the α, β-dihalogenopropionic acid derivative. To react,
(B) A method in which the mercaptoacetic acid derivative and the α, β-dihalogenopropionic acid derivative are mixed in advance and then mixed with a base to carry out the reaction is more selective and has a higher yield.
Preferred for obtaining a hydroxy-2-thiophenecarboxylic acid derivative.

Further, in the above-mentioned mixing of the raw material and the base, it is preferable to dissolve the raw material and the base in an inert organic solvent in advance, respectively, and then perform the mixing so that the effect of the present invention can be further improved.

In the present invention, the molar ratio of the mercaptoacetic acid derivative and the α, β-dihalogenopropionic acid derivative is not particularly limited, but is generally 1: 0.01 to 1: 100, preferably 1: 0.1 to 1:10. It is suitable to use in the range of.

The amount of the base used in the present invention is not particularly limited, but in general, the molar ratio of the base to the mercaptoacetic acid derivative is 1: 0.01 to 1:10, preferably 1: 0.1 to. It is preferable to determine it so that the range is 1: 1.

In the present invention, the reaction temperature is not particularly limited and can be selected in a wide temperature range, but it is generally preferable to select from the range of -70 ° C to 150 ° C, preferably the range of -10 ° C to 80 ° C. Also, the reaction time depends on the reaction conditions,
It is generally suitable for 1 to 40 hours, preferably 4 to 20 hours.

The method for purifying the 3-hydroxy-2-thiophenecarboxylic acid derivative obtained by the method of the present invention is not particularly limited. Generally, after neutralizing the base with an acidic aqueous solution of hydrochloric acid, acetic acid, sulfuric acid, etc., extraction with an inert solvent such as ether, benzene, toluene, methylene chloride, chloroform, carbon tetrachloride, etc., drying, atmospheric distillation, vacuum distillation , Can be purified by recrystallization or chromatography.

<Effect> In the method of the present invention, the mercaptoacetic acid derivative and the α, β-dihalogenopropionic acid derivative are directly mixed in the presence of a base and reacted to increase the amount of the 3-hydroxy-2-thiophenecarboxylic acid derivative. It can be produced with high yield and selectivity.

The 3-hydroxy-2-thiophenecarboxylic acid derivative obtained in the present invention has 0-alkylation, as shown in Reference Examples.
A 3-alkoxythiophene derivative can be obtained through hydrolysis and decarboxylation.

The following examples are provided to describe the present invention more specifically, but the present invention is not limited to these examples.

(Example 1) In a 1-three-necked flask equipped with a stirrer, 106 g (1.0 mole) of methyl thioglycolate, 157 g (1.0 mole) of methyl 2,3-dichloropropionate and 200 ml of methanol.
Was added and placed in a thermostat kept at 10 ° C. Subsequently, a solution of 800 g of methanol in which 128 g (3.2 mole) of sodium hydroxide was dissolved was gradually added dropwise over 1 hour. After the dropping, the mixture was further stirred at room temperature for 2 hours. After removing the solvent methanol by atmospheric distillation, neutralize with 500 ml of dilute hydrochloric acid,
Extracted with benzene. The benzene layer was washed with 500 ml of water and then dried. After removing benzene, methyl 3-hydroxy-2-thiophenecarboxylate, a pale yellow solid,
6.4 g was obtained with a purity of 99%. The yield was 98.1% based on the starting material, methyl thioglycolate.

(Example 2) 600 ml of a methanol solution prepared by dissolving 72 g (0.5 mole) of potassium salt of methyl thioglycolate and 61.6 g (1.1 mole) of potassium hydroxide in a 1-three-necked flask equipped with a stirrer was adjusted to 0 ° C. It was installed in a constant temperature bath kept at. Then, 86.4 g (0.55 mol) of methyl 2,3-dibromopropionate
e) was added dropwise over about 1 hour. After the dropping, the mixture was further stirred at room temperature for 3 hours. After removing methanol as a solvent under reduced pressure, 400 ml of ether was added and further neutralized with a dilute aqueous acetic acid solution. The ether layer was washed with water and then dried. After removing the ether, 3-hydroxy-2- which is a pale yellow solid.
78.1 g of methyl thiophenecarboxylate was obtained. The yield was 98.8% with respect to the potassium salt of methyl thioglycolate as a raw material.

(Example 3) In a two-necked two-necked flask equipped with a stirrer, 1 solution of methanol in which 141 g (3.5 mole) of sodium hydroxide was dissolved was placed in a constant temperature bath kept at 20 ° C. Next, methyl thioglycolate 95.4 g (0.9 mole) and 2,3-dibromobutyric acid 2
A mixed solution of 34 g (0.9 mole) was added dropwise over about 1 hour.

After the dropping, the mixture was further stirred at room temperature for 1 hour. After removing methanol as a solvent under reduced pressure, chloroform was added and further neutralized with a dilute hydrochloric acid aqueous solution. The chloroform layer was washed with water and dried. After removing chloroform, vacuum distillation was performed to obtain 151 g of methyl 5-methyl-3-hydroxy-2-thiophenecarboxylate having a boiling point of 101 ° C./0.5 mmHg as a pale yellow solid. The yield was 97.5% with respect to methyl thioglycolate as a raw material.

(Example 4) Using the raw materials, bases and solvents shown in Table 1, a reaction was carried out under the reaction procedure and reaction conditions shown in Table 1, and the post-treatment method was carried out in the same manner as in Example 1, and 3-hydroxy-2 was used. -A thiophenecarboxylic acid derivative was synthesized. The yields of the resulting products are also shown in Table 1.

In Table 1, the reaction procedure is represented by the symbol "a" in the same manner as in Example 1 except that the method of adding a base to a mercaptoacetic acid derivative and a dihalopropionic acid derivative is represented by the symbol "a". The method of adding the dihalogenopropionic acid derivative is represented by the symbol "b", and
The method of adding a mercaptoacetic acid derivative and a dihalogenopropionic acid derivative into a base as in Example 3 is represented by the symbol "c".

[Reference Example] In a 2-3 neck flask equipped with a stirrer, 106 g (1 mole) of methyl thioglycolate, 157 g (1 mole) of methyl 2,3-dichloropropionate and 400 ml of methanol were added, and the mixture was placed in a constant temperature bath at 10 ° C. installed. Then, methanol 8 g (3.2 mole) of sodium hydroxide was previously dissolved in methanol 8
The 00 ml solution was added dropwise over 1 hour. After dropping, room temperature (25
The reaction is carried out by stirring in an oil bath (90 ° C) for 2 hours.
The solvent methanol was removed.

Subsequently, 1500 ml of acetone was added and stirred, and the reaction product was suspended, and then 151.3 g (1.2 mole) of dimethylsulfate was added.
Was added over about 30 minutes. Keep the reaction temperature at 60 ℃,
After stirring for about 5 hours, acetone was removed.

Then, an aqueous solution of sodium hydroxide 80g (2mole) 100
0 ml was added, and the mixture was stirred at 40 ° C. for about 3 hours.

Then, the reaction solution was neutralized with 500 ml of a 5N hydrochloric acid aqueous solution, and 600 ml of ethyl acetate was added for extraction. The ethyl acetate layer is dried and then distilled off, and the oil bath is heated to 180 ° C, and the boiling point is 160 ° C.
Was collected to obtain 97 g of 3-methoxythiophene.
The yield is 85 with respect to methyl thioglycolate as a raw material
%Met.

Claims (1)

[Claims] 1. A compound represented by the general formula AS-CH ₂ -COR ₁ (wherein A represents a hydrogen atom, an acyl group or an alkali metal atom, R ₁ represents a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkylthio group, A substituted or unsubstituted phenoxy group or a substituted or unsubstituted amino group) and a general formula (However, R ₂ represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted phenyl group, a nitro group, an alkoxycarbonyl group, R ₃ represents an alkyl group, a phenyl group, and X represents a halogen. A general formula characterized by reacting an α, β-dihalogenopropionic acid derivative represented by (However, R R ₁ and R ₂ in the general formula ₁ and R ₂
The same group as the above) is shown.) A method for producing a 3-hydroxy-2-thiophenecarboxylic acid derivative represented by: