JPH11269141A - Fluorobenzoic acid containing sulfur and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new 3-fluoro-4-aminosulfonylbenzoic acid and its synthetic intermediate and a new fluorobenzoic acid containing sulfur, and to provide a method for producing them. SOLUTION: The 3-fluoro-4-aminosulfonylbenzoic acid is obtained by reacting (3-fluoro-4-methylthio) benzoic acid with a chlorinating agent to form (3-fluoro-4- chloromethylthio) benzoic acid expressed by the formula [(n) is 1-3 integer], then hydrolyzing (3-fluoro-4-chloromethylthio)benzoic acid to form 3-fluoro-4- mercaptobenzoic acid, oxidizing 3-fluoro-4-mercaptobenzoic acid by a chlorinating agent in the presence of water to form 3-fluoro-4-chlorosulfonylbenzoic acid and then aminating the 3-fluoro-4-chlorosulfonylbenzoic acid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel fluorobenzoic acid, 3-fluoro-4-aminosulfonylbenzoic acid, a synthetic intermediate thereof, a novel sulfur-containing fluorobenzoic acid, and a process for producing the same. .

[0002] 3-Fluoro-4-aminosulfonylbenzoic acid is a compound expected to be useful as an intermediate of pharmaceuticals. For example, oxazole-based heterocyclic compounds having antipyretic action, analgesic action, anti-inflammatory action and the like. It can be used as an intermediate for synthesizing an aromatic compound.

[0003]

2. Description of the Related Art 3-Fluoro-4-aminosulfonylbenzoic acid is a novel fluorobenzoic acid, and its synthesis method is not known.

An object of the present invention is to provide a novel 3-fluoro-4-aminosulfonylbenzoic acid, novel sulfur-containing fluorobenzoic acids which are synthetic intermediates thereof, and a process for producing the same.

[0005]

SUMMARY OF THE INVENTION In view of the above-mentioned circumstances, the present inventors have provided an industrially advantageous, simple and economical method for producing 3-fluoro-4-aminosulfonylbenzoic acid. We studied diligently.

As a result, the inventors of the present invention have found a reaction for introducing a methylthio group into an aromatic ring (JP-A-5-33113).
4), a method of converting a methylthio group into a sulfonyl halide group (JP-A-8-291133), a method of converting a methylthio group into a mercapto group by performing a hydrolysis reaction after halogenation (JP-A-9-40636), and an aromatic compound. By appropriately combining a method of converting a formyl group into a carboxyl group without converting a methylthio group bonded to the ring, industrially, conveniently and economically, 3-fluoro-4-
The present inventors have found that aminosulfonylbenzoic acid can be produced, and have also found novel sulfur-containing fluorobenzoic acids that are synthetic intermediates thereof, and have completed the present invention.

That is, the present invention provides the following sulfur-containing fluorobenzoic acids and a method for producing the same.

[0008] 1. (3-fluoro-4-methylthio)
benzoic acid.

[0009] 2. (3-fluoro-4-methylthio)
A process for producing (3-fluoro-4-methylthio) benzoic acid, comprising oxidizing benzaldehyde with an oxidizing agent under alkaline conditions.

[0010] 3. Item 2 wherein the oxidizing agent is hydrogen peroxide.
The method for producing (3-fluoro-4-methylthio) benzoic acid according to the above.

4. A method for producing (3-fluoro-4-methylthio) benzoic acid, comprising reacting 3,4-difluorobenzoic acid with an alkali metal salt of methyl mercaptide.

5. 3-Fluoro-4-chlorosulfonylbenzoic acid.

6. (3-fluoro-4-methylthio)
A process for producing 3-fluoro-4-chlorosulfonylbenzoic acid, comprising oxidizing benzoic acid with a chlorinating agent in the presence of water.

7. (3-fluoro-4-methylthio)
A process for producing 3-fluoro-4-chlorosulfonylbenzoic acid, comprising oxidizing benzaldehyde with a chlorinating agent in the presence of water.

[8] A process for producing 3-fluoro-4-chlorosulfonylbenzoic acid, comprising oxidizing 3-fluoro-4-mercaptobenzoic acid with a chlorinating agent in the presence of water.

9. 3-Fluoro-4-mercaptobenzoic acid.

10. (3-fluoro-4-methylthio)
Reaction of benzoic acid with a chlorinating agent yields the formula

[0018]

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(Wherein, n represents an integer of 1 to 3), and (3-fluoro-4-chloromethylthio) benzoic acid represented by the formula (3). A method for producing 3-fluoro-4-mercaptobenzoic acid, comprising hydrolyzing benzoic acids.

11. 3-Fluoro-4-aminosulfonylbenzoic acid.

12. A process for producing 3-fluoro-4-aminosulfonylbenzoic acid, comprising aminating 3-fluoro-4-chlorosulfonylbenzoic acid.

13. (3-fluoro-4-methylthio)
Reaction of benzoic acid with a chlorinating agent yields the formula

[0023]

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(Wherein n represents an integer of 1 to 3), and (3-fluoro-4-chloromethylthio) benzoic acid represented by the formula (3). Hydrolysis of benzoic acids to give 3-fluoro-
After converting to 4-mercaptobenzoic acid, the 3-fluoro-4
-Oxidizing mercaptobenzoic acid with a chlorinating agent in the presence of water to give 3-fluoro-4-chlorosulfonylbenzoic acid, and then aminating the 3-fluoro-4-chlorosulfonylbenzoic acid. 3-fluoro-
A method for producing 4-aminosulfonylbenzoic acid.

[0025]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail according to the following reaction formula.

[0026]

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The first invention of the present application relates to (3-fluoro-4-methylthio) benzoic acid represented by the formula (4) and a method for producing the same.

(3-Fluoro-4-methylthio) benzoic acid is an important compound as an intermediate for synthesizing 3-fluoro-4-aminosulfonylbenzoic acid represented by the formula (8).

This (3-fluoro-4-methylthio) benzoic acid is obtained by oxidizing (3-fluoro-4-methylthio) benzaldehyde represented by the formula (2) with an oxidizing agent under alkaline conditions.

Here, (3-fluoro-4-methylthio) benzaldehyde represented by the formula (2) is obtained by adding 3,4-difluorobenzaldehyde represented by the formula (1) to an alkali metal salt of methyl mercaptide [CH ₃ SM (where M
Represents an alkali metal)]].

The oxidizing agent used for the oxidation reaction of (3-fluoro-4-methylthio) benzaldehyde includes, for example, hydrogen peroxide; organic peracids such as peracetic acid and m-chloroperbenzoic acid; permanganate; Inorganic oxidants such as acid salts and peroxosulfates can be used, but hydrogen peroxide is preferably used from the viewpoints of safety, environmental problems, economical viewpoints, and the like.

The amount of the oxidizing agent varies depending on the type of the oxidizing agent used, and cannot be specified unconditionally. However, the amount of the oxidizing agent is usually 0.8 to 3 (3-fluoro-4-methylthio) benzaldehyde represented by the formula (2). 10 to 10 times mol, preferably 1.0 to 10 times
It is 4.0 times mol. If the amount of the oxidizing agent is less than 0.8 mole, the reaction does not tend to be completed, and if it is used more than 10 moles, the effect corresponding thereto cannot be obtained, which tends to be economically disadvantageous.

The oxidation reaction proceeds smoothly when performed in the presence of an alkali. In particular, when hydrogen peroxide is used as the oxidizing agent, the oxidation reaction proceeds without oxidation of the methylthio group. As the alkali used, sodium hydroxide,
Potassium hydroxide is preferred. The amount of the alkali to be used is generally 0.8 to 10-fold mol, preferably 1.0 to 2.0-fold mol, based on (3-fluoro-4-methylthio) benzaldehyde represented by the formula (2). . If the amount of the alkali used is less than 0.8 mole, the amount of by-products tends to increase, and if it exceeds 10 moles, the effect corresponding thereto cannot be obtained, and it tends to be economically disadvantageous.

The solvent used in the oxidation reaction is not particularly restricted but includes, for example, water; hydrocarbons such as hexane, cyclohexane and heptane; halogenated hydrocarbons such as dichloroethane, dichloromethane and chloroform;
Aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, dichlorobenzene and trichlorobenzene; alcohols such as methanol, ethanol, propanol, isopropanol and butanol; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; Mixtures can be used. Of these, alcohols such as methanol, ethanol, propanol, isopropanol, and butanol are preferable, and methanol is particularly preferably used. The amount of the solvent to be used is not particularly limited, but is usually 0.1 to 20 times the weight of (3-fluoro-4-methylthio) benzaldehyde represented by the formula (2).

The reaction temperature is usually in the range of 0 to 100 ° C, preferably 20 to 50 ° C. If the reaction temperature is lower than 0 ° C., the reaction rate tends to be slow. If the reaction temperature is higher than 100 ° C., a side reaction occurs, which tends to cause a decrease in yield. The reaction time is usually in the range of 0.5 to 10 hours.

As described above, (3-fluoro-4-methylthio) benzoic acid represented by the formula (4) is obtained. The obtained (3-fluoro-4-methylthio) benzoic acid can be isolated by a conventional method such as crystallization.

(3-Fluoro-4-methylthio) benzoic acid can be obtained by converting 3,4-difluorobenzoic acid represented by the formula (3) and an alkali metal salt of methyl mercaptide [CH ₃ S]
M (in the formula, M represents an alkali metal)].

The 3,4-difluorobenzoic acid used as a raw material can be obtained from a commercially available product easily and industrially.

As the alkali metal salt of methyl mercaptide used in the above reaction, sodium salt of methyl mercaptide, potassium salt of methyl mercaptide and the like can be used. From the economic viewpoint, methyl mercaptide sodium salt is preferably used. .

The amount of the alkali metal methyl mercaptide used is generally 0.8 to 3 times, preferably 1.0 to 3 times the molar amount of the starting material, 3,4-difluorobenzoic acid represented by the formula (3). It is about 2.5 times mol. If the amount of the alkali metal salt of methyl mercaptide is less than 0.8 moles, the reaction tends to be incomplete, and if it is used more than 3 moles, the effect corresponding thereto is not obtained, and it tends to be economically disadvantageous. is there.

The reaction temperature is generally 0-150 ° C, preferably 20-80 ° C. If the reaction temperature is lower than 0 ° C., the reaction rate tends to be slow. If the reaction temperature is higher than 150 ° C., a side reaction occurs, which tends to cause a decrease in yield. The reaction time is usually in the range of 0.5 to 10 hours.

The above reaction proceeds simply by mixing and stirring 3,4-difluorobenzoic acid and the alkali metal methyl mercaptide, but the reaction proceeds smoothly when a phase transfer catalyst is used. As the phase transfer catalyst, benzyltriethylammonium bromide, benzyltrimethylammonium chloride, hexadecylammonium bromide, hexadecylammonium chloride, dodecyltrimethylammonium chloride, octyltriethylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium Quaternary ammonium salts such as chloride, tetraethylammonium chloride, trioctylmethylammonium chloride; hexadecyltriethylphosphonium bromide, hexadecyltributylphosphonium chloride, tetra-n-butylphosphonium bromide, tetra-n-butylphosphonium chloride, trioctylethylphosphonium Bromide, tetraphenylphosphonium bromide Quaternary phosphonium salts and the like; 18-crown-6, dibenzo-1-crown-6, etc. Crown ethers such as dicyclohexyl-18-crown-6 and the like. Among them, quaternary ammonium salts such as tetra-n-butylammonium bromide and tetra-n-butylammonium chloride are preferably used from an economic viewpoint. When the phase transfer catalyst is used, the amount used is usually from 0.001 to 0.5 times, preferably from 0.005 to 0.2 times, the weight of 3,4-difluorobenzoic acid. is there. If the amount of the phase transfer catalyst used is less than 0.001 times the weight, the catalytic effect tends to be insufficient, while if it exceeds 0.5 times the weight, the effect corresponding thereto cannot be obtained and the economical effect cannot be obtained. Tend to be disadvantageous.

In this case, 3,4-difluorobenzoic acid represented by the formula (3), which is a raw material, is preliminarily converted to an alkali metal salt of 3,4-difluorobenzoic acid with an aqueous solution of sodium hydroxide, potassium hydroxide or the like. When an aqueous solution is used for the reaction, the reaction proceeds more smoothly.

The above reaction proceeds without a solvent or using a solvent. When a solvent is used, the solvent is not particularly limited and includes, for example, hydrocarbons such as hexane, cyclohexane and heptane; halogenated hydrocarbons such as dichloroethane, dichloromethane and chloroform; benzene, toluene, xylene and chlorobenzene. And aromatic hydrocarbons such as dichlorobenzene and trichlorobenzene. When a solvent is used, the amount thereof is not particularly limited, but is usually 0.1 to 3 to 4,4-difluorobenzoic acid represented by the formula (3).
20 times the weight.

As described above, (3-fluoro-4-methylthio) benzoic acid represented by the formula (4) is obtained. The obtained (3-fluoro-4-methylthio) benzoic acid can be isolated by a conventional method such as crystallization.

The second invention of the present application is directed to a third embodiment represented by the following equation (7).
-Fluoro-4-chlorosulfonylbenzoic acid and a method for producing the same.

3-Fluoro-4-chlorosulfonylbenzoic acid is an important compound as a precursor for synthesizing 3-fluoro-4-aminosulfonylbenzoic acid.

The 3-fluoro-4-chlorosulfonylbenzoic acid is obtained by oxidizing (3-fluoro-4-methylthio) benzoic acid represented by the formula (4) with a chlorinating agent in the presence of water. Can be

The amount of water used in this oxidation reaction is usually 2 to 100 times, preferably 3 to 100 times the molar amount of (3-fluoro-4-methylthio) benzoic acid represented by the formula (4).
５０50-fold molar. If the amount of water used is less than 2 moles, the reaction tends to be incomplete, and if it is used in excess of 100 moles, the volumetric efficiency tends to deteriorate, which tends to be economically disadvantageous.

The chlorinating agent used in the oxidation reaction includes
For example, chlorine, sulfuryl chloride and the like can be mentioned. Preferably, chlorine is used from an economic viewpoint.

The amount of the chlorinating agent used is based on the amount of (3-fluoro-4-methylthio) benzoic acid represented by the formula (4).
It is usually 2 to 20 moles, preferably 2.5 to 10 moles. If the amount of the chlorinating agent is less than 2 moles, the reaction tends not to be completed, and if it is more than 20 moles, the effect corresponding thereto cannot be obtained, and it tends to be economically disadvantageous.

The oxidation reaction may be carried out without solvent, but when a solvent is used, the solvent does not react with the resulting 3-fluoro-4-chlorosulfonylbenzoic acid represented by the formula (7). If so, there is no particular limitation. Examples of the solvent include hydrocarbons such as hexane, cyclohexane and heptane; halogenated hydrocarbons such as dichloroethane, dichloromethane and chloroform; aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, dichlorobenzene and trichlorobenzene. Can be mentioned. When a solvent is used, the amount used is not particularly limited, but is usually 0.1 to 20 times the weight of (3-fluoro-4-methylthio) benzoic acid represented by the formula (4). It is.

The reaction temperature is usually in the range of about 0-100 ° C, preferably about 20-80 ° C. If the reaction temperature is lower than 0 ° C., the reaction rate tends to be slow, and if it exceeds 100 ° C., a side reaction occurs and the yield tends to decrease. The reaction time is usually in the range of 0.5 to 10 hours.

The thus obtained 3-fluoro-4
-Chlorosulfonylbenzoic acid can be isolated by a conventional method such as crystallization.

The 3-fluoro-4-chlorosulfonylbenzoic acid of the present invention also oxidizes (3-fluoro-4-methylthio) benzaldehyde represented by the formula (2) with a chlorinating agent in the presence of water. It can also be obtained by: In this oxidation reaction, (3-fluoro-4-methylthio) benzoic acid represented by the above formula (4) is oxidized with a chlorinating agent in the presence of water to convert 3-fluoro-4-chlorosulfonylbenzoic acid. Water, chlorinating agent, solvent, reaction temperature,
The reaction can be carried out in the same manner as in the reaction time.

The 3-fluoro-4-chlorosulfonylbenzoic acid of the present invention is obtained by oxidizing 3-fluoro-4-mercaptobenzoic acid represented by the formula (6) with a chlorinating agent in the presence of water. Can also be obtained. This oxidation reaction is represented by the above formula (4) (3-fluoro-
In the case of oxidizing 4-methylthio) benzoic acid with a chlorinating agent in the presence of water to obtain 3-fluoro-4-chlorosulfonylbenzoic acid, and in the case of water, a chlorinating agent, a solvent, a reaction temperature, and a reaction time, It can be implemented similarly.

The third invention of the present application is directed to the third invention represented by the formula (6).
-Fluoro-4-mercaptobenzoic acid and a method for producing the same.

3-Fluoro-4-mercaptobenzoic acid is an important compound as an intermediate for synthesizing 3-fluoro-4-aminosulfonylbenzoic acid.

The 3-fluoro-4-mercaptobenzoic acid is obtained by converting (3-fluoro-4-methylthio) benzoic acid represented by the formula (4) to a compound represented by the formula (5) -Fluoro-4-chloromethylthio) benzoic acids, and subsequently obtained by hydrolyzing the obtained (3-fluoro-4-chloromethylthio) benzoic acids.

Examples of the chlorinating agent include chlorine and sulfuryl chloride. Preferably, chlorine is used from an economic viewpoint.

The (3-fluoro-4-) represented by the formula (5)
In chloromethylthio) benzoic acids, n is 1 to 3
In either case, the next hydrolysis reaction proceeds smoothly. Therefore, the amount of the chlorinating agent used is based on (3-fluoro-4-methylthio) benzoic acid represented by the formula (4).
It is 1 to 10 moles, preferably 1 to 3 moles. If the amount of the chlorinating agent is less than 1 mole, the reaction tends not to be completed, and if it is used more than 10 moles, the effect corresponding thereto cannot be obtained, and it tends to be economically disadvantageous.

The chlorination step may be performed without a solvent,
When a solvent is used, the solvent is not particularly restricted but includes, for example, hydrocarbons such as hexane, cyclohexane and heptane; halogenated hydrocarbons such as dichloroethane, dichloromethane and chloroform; benzene, toluene and xylene And aromatic hydrocarbons such as chlorobenzene, dichlorobenzene and trichlorobenzene. When using a solvent, the amount used is
Although not particularly limited, (3-fluoro-4-
It is usually 0.1 to 20 times the weight of methylthio) benzoic acid.

The chlorination reaction temperature is usually about 0 to 120.
° C, preferably in the range of about 20-80 ° C. If the reaction temperature is lower than 0 ° C., the reaction rate tends to be slow,
When the temperature exceeds ℃, side reactions tend to occur and the yield tends to decrease. The reaction time is usually in the range of 0.5 to 10 hours.

The resulting (3-fluoro-4-chloromethylthio) benzoic acid represented by the formula (5) can be isolated by a conventional method such as crystallization.
The chlorination reaction solution can be used for the next hydrolysis reaction as it is.

Next, the (3-fluoro-4-chloromethylthio) benzoic acids represented by the formula (5) obtained as described above are hydrolyzed to give a compound represented by the formula (6). 3-Fluoro-4-mercaptobenzoic acid is obtained.

The amount of water used for the hydrolysis is usually 1.0 to 30 times, preferably 2 to 1 times the amount of (3-fluoro-4-chloromethylthio) benzoic acid represented by the formula (5). 0.0 to 10 times mol. If the amount of water used is less than 1.0 mole, the reaction tends to be difficult to complete,
Even if it is used in an amount exceeding 30 moles, the effect corresponding thereto cannot be obtained, and it tends to be economically disadvantageous.

The above hydrolysis reaction proceeds simply by adding water and heating. However, when the hydrolysis reaction is performed in the presence of a lower alcohol, the hydrolysis reaction proceeds more smoothly. As lower alcohols, for example, methanol, ethanol, isopropanol, n-propanol, isobutanol,
n-butanol, sec-butanol and the like have 1 to 1 carbon atoms
4 aliphatic alcohols. Among them,
From an economic viewpoint, methanol is preferably used. The amount of the lower alcohol is not particularly limited, but is usually 0.5 to 10 times the weight of the (3-fluoro-4-chloromethylthio) benzoic acid represented by the formula (5). .

The above hydrolysis reaction proceeds with or without a solvent. When using a solvent,
There is no particular limitation, for example, hydrocarbons such as hexane, cyclohexane and heptane; halogenated hydrocarbons such as dichloroethane, dichloromethane and chloroform; aromatics such as benzene, toluene, xylene, chlorobenzene, dichlorobenzene and trichlorobenzene. Group hydrocarbons. When using a solvent,
The amount used is not particularly limited, but is usually 0.1 to 20 times the weight of the (3-fluoro-4-chloromethylthio) benzoic acid represented by the formula (5).

The hydrolysis reaction temperature is usually about 30 to 20.
0 ° C., preferably in the range of about 60-110 ° C. If the reaction temperature is less than 30 ° C., the reaction rate tends to be slow,
If the temperature exceeds 200 ° C., a side reaction tends to occur and the yield tends to decrease. The reaction time is usually in the range of 0.5 to 10 hours.

As described above, the value represented by the expression (6)
-Fluoro-4-mercaptobenzoic acid is obtained. The obtained 3-fluoro-4-mercaptobenzoic acid can be isolated by a conventional method such as crystallization, but can be used as it is in the next reaction.

The fourth invention of the present application is directed to the third invention represented by the formula (8).
-Fluoro-4-aminosulfonylbenzoic acid and a method for producing the same.

3-Fluoro-4-aminosulfonylbenzoic acid is expected to be useful as an intermediate for synthesizing oxazole heteroaromatic compounds having antipyretic, analgesic and anti-inflammatory activities. Compound.

3-Fluoro-4-aminosulfonylbenzoic acid is obtained by reacting 3-fluoro-4-chlorosulfonylbenzoic acid represented by the formula (7) with aqueous ammonia to aminate a chlorosulfonyl group. be able to.

The amount of the ammonia water used is usually 0.8 to 10 moles, as ammonia pure, based on 3-fluoro-4-chlorosulfonylbenzoic acid represented by the formula (7).
Preferably it is in the range of 1.0 to 10 times mol. If the amount of the aqueous ammonia is less than 0.8 times the molar amount, the reaction does not tend to be completed. If the amount is more than 10 times the molar amount, the effect corresponding thereto cannot be obtained, and it tends to be economically disadvantageous.

The reaction may be carried out without a solvent. When a solvent is used, the solvent is a compound represented by the formula (7):
There is no particular limitation as long as it does not react with fluoro-4-chlorosulfonylbenzoic acid. Examples of the solvent include water; hydrocarbons such as hexane, cyclohexane and heptane; dichloroethane, dichloromethane,
Halogenated hydrocarbons such as chloroform; and aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, dichlorobenzene, and trichlorobenzene. Preferably, water is used from an economic point of view.

When a solvent is used, its amount is not particularly limited, but is usually 0.1 to 20 with respect to 3-fluoro-4-chlorosulfonylbenzoic acid represented by the formula (7). Double weight.

The reaction temperature for the amination is usually about 0 to 100
C, preferably in the range of about 10-50C. If the reaction temperature is lower than 0 ° C., the reaction rate tends to be slow, and 100
When the temperature exceeds ℃, side reactions tend to occur and the yield tends to decrease. The reaction time is usually in the range of 1 minute to 2 hours.

The 3-fluoro-4-aminosulfonylbenzoic acid represented by the formula (8) obtained as described above is
It can be easily isolated by ordinary crystallization or the like.

The 3-fluoro-4-aminosulfonylbenzoic acid of the present invention can also be obtained by converting (3-fluoro-4-methylthio) benzoic acid represented by the formula (4) to a compound represented by the formula (5) using a chlorinating agent. (3-fluoro-4-chloromethylthio) benzoic acids represented by the formula (3-fluoro-4-
Without isolating the (chloromethylthio) benzoic acid, it is hydrolyzed to give 3-fluoro-4-mercaptobenzoic acid, and the obtained 3-fluoro-4-mercaptobenzoic acid is chlorinated in the presence of water. Oxidized by the agent 3
After performing a series of reactions to form -fluoro-4-chlorosulfonylbenzoic acid in one pot, the resulting 3-fluoro-4-chlorosulfonylbenzoic acid can be obtained by amination.

[0080]

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

Reference Example 1 A 1000 ml four-necked flask equipped with a stirrer, a thermometer and a condenser was charged with 142.0 g (1.00 mol) of 3,4-difluorobenzaldehyde, 6 g of tetrabutylammonium bromide and 400 g of chlorobenzene. At 30 ° C. with stirring, 256.6 g (1.10 mol) of a 30% aqueous sodium methyl mercaptide solution was added dropwise over 1 hour. After the temperature of the reaction solution was raised to about 80 ° C., the mixture was stirred for 30 minutes to complete the reaction. After separating the aqueous layer, the solvent was distilled off to obtain 168.0 g of (3-fluoro-4-methylthio) benzaldehyde. The yield based on 3,4-difluorobenzaldehyde was 98.8%.

Example 1 A 1 equipped with a stirrer, thermometer, dropping funnel and cooler
85.0 g of the (3-fluoro-4-methylthio) benzaldehyde obtained in Reference Example 1 in a L four-necked flask.
(0.50 mol), 200 g of methanol and 22.0 g (0.55 mol) of sodium hydroxide were charged and 227 g (1.00 mol) of 15% aqueous hydrogen peroxide at about 30 ° C. with stirring.
Was added dropwise over 1 hour. The reaction solution was acidified by adding sulfuric acid, and the precipitated crystals were separated by filtration and dried to obtain 85.6 g of (3-fluoro-4-methylthio) benzoic acid.
The yield based on (3-fluoro-4-methylthio) benzaldehyde was 92.0%.

The physical properties of the obtained (3-fluoro-4-methylthio) benzoic acid are shown below.

Properties: White crystals Melting point: 194.0-194.1 ° C. NMR δ (DMSO-D6) ppm: 2.55 (s, 3H, SMe) 7.52 to 7.89 (m, 3H, ArH) 11 0.5 to 13.2 (bs, 1H, COOH) IR (KBr) cm ^-1 : 3200 to 2800, 1687, 1423, 1292, 1246, 1214 Elemental analysis: Calculated value (%) C = 51.60, H = 3.79, S = 17.22 Found (%) C = 51.18, H = 3.98, S = 16.97.

Example 2 5 equipped with a stirrer, thermometer, dropping funnel and cooler
In a 00 ml four-necked flask were charged 79.0 g (0.50 mol) of 3,4-difluorobenzoic acid and 220 g (0.55 mol) of a 10% aqueous sodium hydroxide solution, and the mixture was stirred at about 80 ° C. at about 80 ° C. for 30% methyl mercury. 128.3 g (0.55 mol) of an aqueous solution of sodium peptide was added dropwise over 1 hour. The reaction solution was acidified by adding hydrochloric acid, and the precipitated crystals were separated by filtration, washed with water and dried to give (3-fluoro-
91.5 g of 4-methylthio) benzoic acid were obtained. 3,4-
The yield based on difluorobenzoic acid was 98.4%.

When the physical properties of the obtained crystal were measured in the same manner as in Example 1, the results were the same as in Example 1. Therefore, the obtained crystal was (3-fluoro-4-methylthio) benzoic acid. It was confirmed that it was an acid.

Example 3 5 equipped with a stirrer, thermometer, gas injection pipe and cooler
In a 00 ml four-necked flask, (3
-Fluoro-4-methylthio) benzoic acid 85.6 g
(0.46 mol), 300 g of chlorobenzene and 10 of water
0 g was charged. 177.5g of chlorine gas at about 30 ℃
(2.50 mol) was blown in over 3 hours and cooled to 5 ° C., and the precipitated crystals were separated by filtration to obtain 88.9 g of 3-fluoro-4-chlorosulfonylbenzoic acid.
The yield based on (3-fluoro-4-methylthio) benzoic acid was 81.0%.

The physical properties of the obtained 3-fluoro-4-chlorosulfonylbenzoic acid are shown below.

Property: White crystal Melting point: 188.7-189.8 ° C. NMR δ (DMSO-D6) ppm: 7.52-7.89 (m, 3H, ArH) 14.0 (s, 1H, COOH) IR (KBr) cm ^-1 : 3200-2800, 1687, 1443, 1375, 1178 Elemental analysis: Calculated value (%) C = 35.24, H = 1.69, S = 13.44 Actual value (%) C = 35.23, H = 1.73, S = 13.58.

Example 4 In a 500 ml four-necked flask equipped with a stirrer, a thermometer and a cooler, (3-fluoro-4) obtained in Reference Example 1 was added.
-Methylthio) benzaldehyde 80.0 g (0.47
Mol), 300 g of chlorobenzene and 100 g of water. At about 60 ° C., 177.5 g (2.50 mol) of chlorine gas was blown in over 3 hours, and after cooling to 5 ° C., the precipitated crystals were separated by filtration to give 3-fluoro-4-chlorosulfonylbenzoic acid 75%. 0.4 g was obtained. The yield based on (3-fluoro-4-methylthio) benzaldehyde was 67.2%.

The physical properties of the obtained crystals were measured in the same manner as in Example 3. The results were the same as those in Example 3. Therefore, the obtained crystals were 3-fluoro-4-chlorosulfonylbenzoic acid. It was confirmed that it was.

Example 5 A sample equipped with a stirrer, a thermometer, a gas injection pipe and a cooler was prepared.
In a 00 ml four-necked flask, 93.0 g (0.50 mol) of (3-fluoro-4-methylthio) benzoic acid and 250 g of chlorobenzene were charged, and chlorine gas 4 was added at about 40 ° C.
2.6 g (0.60 mol) was blown in over 1 hour, and (3
A reaction solution of a mixture of -fluoro-4-chloromethylthio) benzoic acid and (3-fluoro-4-dichloromethylthio) benzoic acid was obtained.

The reaction mixture was mixed with 50 g of water and 5 g of methanol.
0 g was added and stirred at reflux temperature (about 70 ° C.) for 2 hours. Cyclohexane was added to the reaction solution, and after cooling, the precipitated crystals were separated by filtration to obtain 79.6 g of 3-fluoro-4-mercaptobenzoic acid. (3-fluoro-
The yield based on 4-methylthio) benzoic acid was 92.6%.

The physical properties of the obtained 3-fluoro-4-mercaptobenzoic acid are shown below.

Properties: pale yellow crystal Melting point: 195.3-196.2 ° C. NMR δ (DMSO-D6) ppm: 3.0-4.5 (bs, 1H, SH) 7.6-7.8 (m, 3H, ArH) 11.5 to 13.2 (bs, 1H, COOH) IR (KBr) cm ^-1 : 3200 to 2800, 2594, 1689, 1605, 1570, 1437, 1317 Elemental analysis: Calculated value (%) C = 48.83, H = 2.93, S = 18.62 Found (%) C = 48.88, H = 2.90, S = 18.60.

Example 6 5 equipped with a stirrer, a thermometer, a gas injection pipe and a cooler
The 3-ml obtained in Example 5 was placed in a 00 ml four-necked flask.
79.6 g of fluoro-4-mercaptobenzoic acid (0.4
6 mol), 300 g of chlorobenzene and 100 g of water. 142 g (2.00 mol) of chlorine gas at about 30 ° C
Was blown in over 3 hours and cooled to 5 ° C., and the precipitated crystals were separated by filtration to obtain 105.3 g of 3-fluoro-4-chlorosulfonylbenzoic acid. 3-fluoro-
The yield based on 4-mercaptobenzoic acid was 95.4%.

When the physical properties of the obtained crystal were measured in the same manner as in Example 3, the results were the same as in Example 3. Thus, the obtained crystal was 3-fluoro-4-chlorosulfonylbenzoic acid. It was confirmed that it was.

Example 7 5 equipped with a stirrer, thermometer, dropping funnel and cooler
In a 00 ml four-neck flask, 80.1 g (0.34 mol) of 3-fluoro-4-chlorosulfonylbenzoic acid and 200 g of water were charged, and 28% aqueous ammonia 9% was added at about 30 ° C.
1.0 g (1.50 mol) was added dropwise and stirred for 10 minutes.
The reaction solution was acidified by adding hydrochloric acid, and the precipitated crystals were separated by filtration.
By drying, 66.7 g of 3-fluoro-4-aminosulfonylbenzoic acid was obtained. The yield based on 3-fluoro-4-chlorosulfonylbenzoic acid was 90.7%.

The physical properties of the obtained 3-fluoro-4-aminosulfonylbenzoic acid are shown below.

Property: white crystal Melting point: 267 ° C .- (decomposition) NMR δ (DMSO-D6) ppm: 1.8-5.3 (bs, 2H, NH ₂ ) 7.78-7.95 (m, 3H, ArH) 12.0-14.5 (bs, 1H, COOH) IR (KBr) cm ^-1 : 3390, 3278, 3200-2800, 1705, 1355, 1169 Elemental analysis: Calculated value (%) C = 38.36 , H = 2.76, S = 14.63, N = 6.39 Found (%) C = 38.51, H = 2.69, S = 14.81, N = 6.27.

Example 8 5 equipped with a stirrer, a thermometer, a gas injection pipe and a cooler
In a 00 ml four-necked flask, 93.0 g (0.50 mol) of (3-fluoro-4-methylthio) benzoic acid and 250 g of chlorobenzene were charged, and chlorine gas 4 at about 40 ° C.
2.6 g (0.60 mol) was blown in over 1 hour, and (3
A reaction solution of a mixture of -fluoro-4-chloromethylthio) benzoic acid and (3-fluoro-4-dichloromethylthio) benzoic acid was obtained. 50 g of water and 50 g of methanol were added to the reaction solution, and the mixture was hydrolyzed with stirring at a reflux temperature (about 70 ° C.) for 2 hours to obtain a reaction solution containing 3-fluoro-4-mercaptobenzoic acid. Add about 3
At 0 ° C., 142 g (2.00 mol) of chlorine gas was blown in over 3 hours, and after cooling to 5 ° C., the precipitated crystals were separated by filtration to obtain 123 g of crude 3-fluoro-4-chlorosulfonylbenzoic acid. Was. Thereafter, 96.0 g of the objective 3-fluoro-4-aminosulfonylbenzoic acid was obtained by the same operation method as in Example 7. The yield based on (3-fluoro-4-methylthio) benzoic acid was 87.7%.

When the physical properties of the obtained crystals were measured in the same manner as in Example 7, the results were the same as those in Example 7. Therefore, the obtained crystals were 3-fluoro-4-aminosulfonylbenzoic acid. It was confirmed that it was.

[0103]

Industrial Applicability The present invention provides a novel fluorobenzoic acid, 3-fluoro-4-aminosulfonylbenzoic acid, a synthetic intermediate thereof, a novel sulfur-containing fluorobenzoic acid, and a process for producing the same. It is.

When the method of the present invention is employed, the desired novel compound can be obtained in a high yield by a simple process such as methylthiolation, halogenation, hydrolysis and amination using an industrially available difluoro compound as a starting material. Is obtained. Therefore, its economic and industrial value is extremely high.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07C 319/20 C07C 319/20 323/62 323/62

Claims (13)

[Claims] (1) (3-fluoro-4-methylthio) benzoic acid. 2. A method of oxidizing (3-fluoro-4-methylthio) benzaldehyde with an oxidizing agent under alkaline conditions, wherein (3-fluoro-4-methylthio) is used.
A method for producing benzoic acid. 3. The method for producing (3-fluoro-4-methylthio) benzoic acid according to claim 2, wherein the oxidizing agent is hydrogen peroxide. 4. A method for producing (3-fluoro-4-methylthio) benzoic acid, comprising reacting 3,4-difluorobenzoic acid with an alkali metal salt of methyl mercaptide. 5. A 3-fluoro-4-chlorosulfonylbenzoic acid. 6. A process for producing 3-fluoro-4-chlorosulfonylbenzoic acid, comprising oxidizing (3-fluoro-4-methylthio) benzoic acid with a chlorinating agent in the presence of water. 7. A process for producing 3-fluoro-4-chlorosulfonylbenzoic acid, comprising oxidizing (3-fluoro-4-methylthio) benzaldehyde with a chlorinating agent in the presence of water. 8. A process for producing 3-fluoro-4-chlorosulfonylbenzoic acid, comprising oxidizing 3-fluoro-4-mercaptobenzoic acid with a chlorinating agent in the presence of water. 9. A 3-fluoro-4-mercaptobenzoic acid. 10. The reaction of (3-fluoro-4-methylthio) benzoic acid with a chlorinating agent to give a compound of the formula (Where n represents an integer of 1 to 3).
Fluoro-4-chloromethylthio) benzoic acids and none
Subsequently, the (3-fluoro-4-chloromethylthio)
A method for producing 3-fluoro-4-mercaptobenzoic acid, comprising hydrolyzing benzoic acids. 11. A 3-fluoro-4-aminosulfonylbenzoic acid. 12. A process for producing 3-fluoro-4-aminosulfonylbenzoic acid, which comprises aminating 3-fluoro-4-chlorosulfonylbenzoic acid. 13. The reaction of (3-fluoro-4-methylthio) benzoic acid with a chlorinating agent to give a compound of the formula (Where n represents an integer of 1 to 3).
Fluoro-4-chloromethylthio) benzoic acids and none
Subsequently, the (3-fluoro-4-chloromethylthio)
After hydrolyzing benzoic acids to give 3-fluoro-4-mercaptobenzoic acid, the 3-fluoro-4-mercaptobenzoic acid is oxidized with a chlorinating agent in the presence of water to give 3-fluoro-4-chloro. To sulfonylbenzoic acid, then
A process for producing 3-fluoro-4-aminosulfonylbenzoic acid, comprising aminating the 3-fluoro-4-chlorosulfonylbenzoic acid.