JP2815476B2 - Improved process for producing benzenesulfonamide compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a compound of the formula (III) Wherein R ¹ and R ³ are a hydrogen atom, a chlorine atom or a methyl group, R ² is a hydrogen atom, a chlorine atom or a trifluoromethyl group, and R ⁴ is a nitro group or a trifluoromethyl group. is there. And an improved method for producing the benzenesulfonamide compound represented by the formula:

The benzenesulfonamide compound of the formula (III) is a compound useful as a bactericide in the field of agrochemicals.

[Problems to be solved by conventional technology and invention]

Conventionally, certain sulfonamide compounds are known to have a bactericidal effect.

For example, JP-A-58-219159 discloses the following formula: Wherein X and Y each represent a hydrogen atom or a methyl group, Z represents a methyl group, a halogen atom or a nitro group,
n is an integer of 1 to 3. ] Are disclosed as fungicides.

Also, JP-A-61-200959, 61-200960, 61-205247, 61
According to -205248, 61-233660, 61-271270, etc.
The sulfonamide compound of the formula (III) is disclosed in
Shows an excellent bactericidal effect than the compound described in 19159,
It is considered to be a compound of high industrial value.

The benzenesulfonamide compound is generally produced by condensing the corresponding benzenesulfonyl chlorides with anilines in the presence of equimolar or more pyridine. JP-A-58-219159
In the publication, 3-nitro-4-methyl-N- (2-chloro-5-nitrophenyl) benzenesulfonamide is produced as a method of producing 3-chloro-5-nitroaniline in a toluene solvent in an equimolar amount with 3-chloro-5-nitroaniline. Nitro-4-methylbenzenesulfonyl chloride is condensed under reflux in the presence of an equimolar amount of pyridine. However, in this method, the yield of the target product is at most only about 50%, even though a relatively expensive base such as pyridine is used in an equimolar amount with respect to the reaction substrate.

On the other hand, the production method of the sulfonamide compound of the formula (III) is disclosed in JP-A-61-205247, [Wherein, R ¹ and R ² represent a hydrogen atom or a chlorine atom. ] The following formula (V) is disclosed in JP-A-61-200960. [Wherein, R ⁵ , R ⁶ and R ⁷ represent a hydrogen atom, a chlorine atom or a methyl group. The method for producing a sulfonamide compound is disclosed, according to which the corresponding benzenesulfonyl chlorides and anilines are produced by condensing at a temperature of about 180 ° C. in the presence of pyridine in orthodichlorobenzene. However, the yield is only about 40-50%.

Thus, for example, it is considered that the yield is low in the production of the sulfonamide compound of the formula (III). 1) P-nitroaniline and substituted P-nitroanilines are owing to the strong electron-withdrawing property of the nitro group. The basicity of the amino group is reduced, and the reactivity is significantly reduced.

2) O-Chloro-P-nitroaniline having a chlorine atom at the O-position not only has its reactivity further reduced, but also the chlorine atom at the O-position may cause steric hindrance.

3) Due to the decrease in reactivity on the aniline side, the condensation conditions become correspondingly severe, and it is easy to induce side reactions such as decomposition of raw materials.

4) When water is present in the reaction system, a hydrolysis reaction of benzenesulfonyl chlorides is induced.

And so on.

As a method of improving the condensation reaction yield of anilines and benzenesulfonyl chlorides having reduced reactivity as described above, the present inventors firstly used an inert gas such as nitrogen in the presence of an organic basic catalyst. A method of performing a condensation reaction while blowing into the reaction system has been proposed (JP-A-63-57565).

By this method, the yield of the compound of the formula (III) could be significantly improved. For example, in the condensation of 4-chloro-3-trifluoromethylbenzenesulfonyl chloride with 2-chloro-4-nitroaniline, the reaction is carried out while blowing nitrogen gas into the system in the presence of an organic basic catalyst in O-dichlorobenzene. The desired 4-chloro-
3-trifluoromethyl-N- (2-chloro-4-nitrophenyl) benzenesulfonamide can be produced in a yield of 80% or more.

By the way, in the improved method, pyridine was considered as the most preferred base as the organic basic catalyst. In fact, such a description is made in the application patent. Certainly, pyridine remains the preferred base. However, as a result of further detailed examination of this condensation reaction, when pyridine was used as a base,
It has been found that a certain problem arises in industrializing the method. That is, when pyridine is used as a base, crystals of pyridine hydrochloride generated with the progress of the reaction adhere to the upper part of the reactor and further to the condenser, and the amount gradually increases with the progress of the reaction. And this hydrochloride does not dissolve easily in the refluxing solvent, so if the scale becomes large, it may sometimes cause troubles such as clogging of the condenser, which is one of the problems in industrialization . Furthermore, the absolute amount of pyridine as a catalyst in the reaction system decreases, and the reaction rate decreases.

Considering the mechanism of the adhesion of this pyridine hydrochloride to capacitors, etc., one is that the pyridine hydrochloride generated in the reaction system scatters in the gas phase part by sublimation by the flow of inert gas such as nitrogen. And solidify in a low temperature place,
One is that the reaction temperature is usually higher than the boiling point of pyridine, so the concentration of pyridine in the gas phase is relatively high. It is considered either to form and fix the hydrochloride.

[Means for solving the problem]

In view of the problems in the reaction operation in the condensation reaction under the pyridine catalyst as described above, the present inventors have proposed a base which does not lower the yield of the condensation reaction and does not cause trouble due to the fixation of the hydrochloride. The diligent catalyst was studied diligently.

As a result, it was found that when β-picoline or γ-picoline was used as the base, no attachment of the hydrochloride to the condenser portion was observed during the condensation reaction, and the reaction itself proceeded more smoothly. Also, when α-picoline was used as a base among picolins, a consolidation phenomenon of hydrochloride was observed as in pyridine. Such findings have not been known at all, and the present invention has been completed by further developing these findings.

That is, the present invention provides a compound of the formula (I) [Wherein, R ¹ and R ³ represent a hydrogen atom, a chlorine atom or a methyl group, and R ² represents a hydrogen atom, a chlorine atom or a trifluoromethyl group. A benzenesulfonyl chloride represented by the formula (II): [In the formula, R ⁴ represents a nitro group or a trifluoromethyl group. With an aniline represented by the formula (III) [Wherein, R ¹ , R ² , R ³ and R ⁴ are each represented by the formulas (I) and (I
In the method for producing a benzenesulfonamide compound represented by the same
An improved process for the preparation of a benzenesulfonamide compound of the formula (III), characterized by using picoline or γ-picoline.

 Hereinafter, the method of the present invention will be described in detail.

Benzenesulfonyl chlorides of formula (I) and formula (II)
In the condensation reaction with an aniline of formula (I), these compounds are used in a proportion of 1 mole of the compound of the formula (I) to the compound of the formula (II).
0.5 to 2 mol, preferably 0.7 to 1.3 mol is used. When the use ratio is out of this range, not only is it likely to increase by-products, but also industrially disadvantageous in terms of raw material unit consumption.

In the method of the present invention, the condensation reaction between the compound of the formula (I) and the compound of the formula (II) is usually carried out in an organic solvent. The organic solvent to be used is not particularly limited as long as it is inert to the reaction, but is usually toluene, xylene, monochlorobenzene or O.sub.2 in consideration of simplification of a method for isolating the desired product after the reaction. Aromatic hydrocarbons such as dichlorobenzene or halogenated hydrocarbon solvents are used. Of course, the condensation reaction proceeds almost without using any solvent, but in this case, depending on the substrate of the reaction, the substrate concentration becomes extremely high, so that side reactions such as decomposition are easily induced, and therefore, the yield is low. In addition, the organic solvent may be deteriorated in quality, and the organic solvent is desirably used industrially because of problems in handling the condensed mass. Formula (I)
0.4 parts by weight or more per 1 part by weight of the compound is preferred. The upper limit of the amount used is not particularly limited, but using too much not only lowers the substrate concentration and lowers the reaction rate, but also raises an industrial disadvantage in terms of volumetric efficiency. I can't get it. Therefore, usually compounds of formula (I) 1
It is used in an amount of 5 parts by weight or less, more preferably 2 parts by weight or less based on parts by weight.

In the present invention, the condensation reaction is carried out in the presence of a basic catalyst, and is characterized in that β-picoline or γ-picoline is used as the basic catalyst. This prevents troubles due to the fixation of the hydrochloride of the substance, further promotes the smooth progress of the reaction, and leads to improvement in yield and quality.

Usually, β-picoline or γ-picoline used in the present invention is used alone, but both can be used in combination. If the amount of β-picoline or γ-picoline is too small, the effect as a base is small and the smooth progress of the reaction is suppressed, and it is practically meaningless to use too much. Therefore, it is generally used in the range of 0.01 to 1.0 mole ratio, preferably 0.1 to 0.5 mole ratio, relative to the compound of the formula (I).

In the condensation reaction of the present invention, the reaction substrates represented by the formulas (I) and (II)
A compound, a base catalyst and, if necessary, a solvent are charged into a reaction vessel, and the mixture is heated and maintained at 130 to 200 ° C, preferably 140 to 180 ° C, and stirred at the same temperature, preferably for 3 to 15 hours.
At that time, it is necessary to forcibly remove hydrogen chloride generated outside the reaction system. For this purpose, in the present invention, the reaction is performed while blowing an inert gas into the reaction solution.

By introducing this inert gas into the reaction system, the hydrogen chloride generated in the reaction can be quickly removed out of the system, and the smooth progress of the reaction is promoted. As a result, the desired sulfonamide can be obtained in high yield. Compounds can be prepared. Hydrogen chloride produced by the reaction is β-picoline or γ as a base.
-It is thought that this salt forms a salt with picoline, which is easily decomposed under relatively high temperature conditions, and that only hydrogen chloride is removed from the reaction system by accompanying an inert gas. Examples of the inert gas include common inert gases such as air, nitrogen, carbon dioxide, helium and argon, and nitrogen gas is often used. The amount of inert gas blown cannot be uniquely determined by the scale of the reaction, etc., but β-
What is necessary is just to set in the range which can prevent the loss accompanying remarkable entrainment of picoline or γ-picoline or a solvent.

After the reaction, there are various methods for isolating the target sulfonamide compound of the formula (III) from the reaction mixture. One example is as follows.

If necessary, the reaction solution is charged with an appropriate amount of the same solvent and warm water used in the condensation reaction, and cooled to room temperature.
The precipitated crystals are collected by filtration to obtain the desired product, benzenesulfonamide, which is subjected, if necessary, to column chromatography or recrystallization.

Examples of the compound of the formula (III) which can be produced by the method of the present invention include the following benzenesulfonamides.

2-chloro-N- (2-chloro-4-nitrophenyl) benzenesulfonamide, 3-chloro-N- (2-
Chloro-4-nitrophenyl) benzenesulfonamide, 4-chloro-N- (2-chloro-4-nitrophenyl) benzenesulfonamide, 2,5-dichloro-N-
(2-chloro-4-nitrophenyl) benzenesulfonamide, 3,4-dichloro-N- (2-chloro-4-nitrophenyl) benzenesulfonamide, 2,4,5-trichloro-N- (2-chloro -4-nitrophenyl) benzenesulfonamide, 2-chloro-4-methyl-N- (2
-Chloro-4-nitrophenyl) benzenesulfonamide, 3-chloro-4-methyl-N- (2-chloro-4-
Nitrophenyl) benzenesulfonamide, 2-methyl-5-chloro-N- (2-chloro-4-nitrophenyl) benzenesulfonamide, 4-methyl-N- (2-
Chloro-4-nitrophenyl) benzenesulfonamide, 2,4-dimethyl-N- (2-chloro-4-nitrophenyl) benzenesulfonamide, 3-trifluoromethyl-N- (2-chloro-4-nitrophenyl ) Benzenesulfonamide, 3-trifluoromethyl-4-chloro-N- (2-chloro-4-nitrophenyl) benzenesulfonamide, 2-chloro-5-trifluoromethyl-N- (2-chloro-4- Nitrophenyl) benzenesulfonamide, 2,4-dichloro-5-trifluoromethyl-N- (2-chloro-4-nitrophenyl) benzenesulfonamide, 2-chloro-N- (2-chloro-4-
Trifluoromethylphenyl) benzenesulfonamide, 3-chloro-N- (2-chloro-4-trifluoromethylphenyl) benzenesulfonamide, 4-chloro-N- (2-chloro-4-trifluoromethylphenyl) benzene Sulfonamide, 2,5-dichloro-N-
(2-chloro-4-trifluoromethylphenyl) benzenesulfonamide, 3,4-dichloro-N- (2-chloro-4-trifluoromethylphenyl) benzenesulfonamide, 3-chloro-4-methyl-N- (2-chloro-4-trifluoromethylphenyl) benzenesulfonamide, 2-methyl-5-chloro-N- (2-chloro-
4-trifluoromethylphenyl) benzenesulfonamide, 3-trifluoromethyl-N- (2-chloro-4
-Trifluoromethylphenyl) benzenesulfonamide, 3-trifluoromethyl-4-chloro-N- (2-
Chloro-4-trifluoromethylphenyl) benzenesulfonamide, 2-chloro-5-trifluoromethyl-
N- (2-chloro-4-trifluoromethylphenyl)
Benzenesulfonamide, 2,4-dichloro-5-trifluoromethyl-N- (2-chloro-4-trifluoromethylphenyl) benzenesulfonamide and the like.

The benzenesulfonyl chlorides of the compound of the formula (I) used in the present invention, for example, 3-trifluoromethyl-4-chlorobenzenesulfonyl chloride, As described above, O-chlorobenzotrifluoride can be obtained by reacting chlorosulfonic acid, and 2-chloroanilines of the formula (II) are known compounds as dye intermediates and can be easily obtained.

〔The invention's effect〕

According to the method of the present invention, there is no possibility that the hydrochloride of the base used during the condensation reaction sticks to the condenser or the like to cause a trouble to block the line, and the reaction proceeds smoothly, so that the yield is high. Since a sulfonamide compound can be produced, it is an extremely valuable production method industrially.

〔Example〕

 Hereinafter, the present invention will be described in detail with reference to examples.

Example 1 Synthesis of 4-chloro-3-trifluoromethyl-N- (2-chloro-4-nitrophenyl) benzenesulfonamide using β-picoline as a base catalyst 4-chloro-3-in a 500 ml four-necked flask 69.8 g (0.25 mol) of trifluoromethylbenzenesulfonyl chloride, 43.6 g (0.253 mol) of 2-chloro-4-nitroaniline, 4.65 g (0.05 mol) of β-picoline and 25 g of xylene
And heated to 160 ° C. on an oil bath, and reacted at the same temperature for 10 hours. During this time, nitrogen gas was flowed through the reaction solution at a flow rate of 15 ml / min. During the reaction, no solidification of β-picoline hydrochloride was observed at the top of the reaction flask and at the condenser, and the reaction proceeded smoothly.

After the reaction, 25 g of xylene was charged into the reaction solution, and after cooling to 100 ° C., 100 g of warm water was added, and crystallization was performed while gradually cooling under stirring. After cooling to room temperature, the precipitated crystals are filtered by suction, washed with water, washed with 50 ml of methanol and dried to give pale yellow 4-chloro-3-trifluoromethyl-N- (2-chloro-4 93.1 g of-(nitrophenyl) benzenesulfonamide were obtained.

Yield: 88.7% (vs. 4-chloro-3-trifluoromethylbenzenesulfonyl chloride) As a result of analysis by high performance liquid chromatography, the purity was 99.2%.

Example 2 and Comparative Examples 1 and 2 Example 1 was repeated except that γ-picoline, pyridine or α-picoline was used instead of β-picoline in Example 1.
The same was done. The results are shown in Table 1.

Examples 3 to 6 Table 2 shows the results of a condensation reaction in the presence of β-picoline or γ-picoline with various changes of benzenesulfonyl chloride, substituted aniline and reaction solvent.

During the reaction, nitrogen gas was blown into the system at a rate of 10 to 20 ml / min. Further, the sulfonamide compound produced after the reaction was isolated according to Example 1.

Claims (3)

(57) [Claims] (1) Formula (I) [Wherein, R ¹ and R ³ represent a hydrogen atom, a chlorine atom or a methyl group, and R ² represents a hydrogen atom, a chlorine atom or a trifluoromethyl group. A benzenesulfonyl chloride represented by the formula (II): [In the formula, R ⁴ represents a nitro group or a trifluoromethyl group. With an aniline represented by the formula (III) [Wherein R ¹ , R ² , R ³ and R ⁴ are the same as those of the formulas (I) and (II), respectively] In the method for producing a benzenesulfonamide compound represented by the formula:
-An improved method for producing a benzenesulfonamide compound of the formula (III), characterized in that the use of picoline or [gamma] -picoline eliminates the sticking of by-product hydrochloride and prevents the exhaust pipe from being blocked. 2. The method according to claim 1, wherein the amount of β-picoline or γ-picoline used is in the range of 0.01 to 1.0 molar ratio based on the aniline of the formula (II). 3. The method according to claim 1, wherein the reaction is carried out in a stream of an inert gas.