JP3152573B2 - Method for producing 1,2-benzisothiazol-3-ones - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

This invention relates to 2- (alkylthio)
The present invention relates to a novel production method for producing 1,2-benzisothiazol-3-ones using benzonitrile as an intermediate . 1, 2-benzisothiazole-3-ones are antimicrobial agents, compounds useful as antifungal agents.

[0002]

2. Description of the Related Art Conventionally, 1,2-benzisothiazole-
The following methods are known as methods for producing 3-ones.

(A) Bull. Chem. Soc. Jpn., 55, 1183-
7 (1982) This method produces 2- (methylthio) benzamide from 2- (methylthio) benzchloride and oxidizes it with periodic acid to produce 2- (methylsulfinyl) benzamide. This is a method of cyclizing this with thionyl chloride to obtain the desired 1,2-benzisothiazol-3-one.

[0004]

Embedded image

(B) Org. Prep. Proced. Int., 15,315-3
19 (1983) This is a method for obtaining 1,2-benzisothiazol-3-one using thiosalicylic acid as a starting material and four steps.

[0006]

Embedded image

(C) Ger. Offen. 3500577, (1986) In this method, thiosalicylic acid is used as a starting material, and finally, cyclization is carried out using caustic soda to obtain the desired 1,2-benzisothiazol-3-one. Is considered a way to get

[0008]

Embedded image

[0009]

However, these known methods have the following disadvantages. In the method (A), 2- (methylthio) used as a raw material is used.
There are problems with inexpensive production methods and stability of benzoyl chloride. In addition, it is necessary to use expensive periodic acid, which is dangerous in handling, and has many reaction steps. The methods (B) to (C) use expensive thiosalicylic acid and have a large number of reaction steps, and therefore cannot be said to be industrially satisfactory. Thus, it has been difficult to industrially produce 1,2-benzisothiazol-3-ones by any known method.

[0010] Accordingly, an object of the present invention is to provide a simple and economical method of using 1,2-benzisothiazol-3-ones without using any industrially advantageous, expensive and highly hazardous substances. Ru Oh <br/> to the child provides a process for producing.

[0011]

Means for Solving the Problems The present inventors have made intensive studies in view of the above situation. As a result, the 2- (alkylthio) benzonitrile represented by the general formula (I) is reacted with a halogenating agent in the presence of water, whereby the 1,2-benzyl represented by the general formula (II) is reacted. Isothiazole-3-
It was found that ons could be obtained in one step.

[0012]

Embedded image

(Wherein R ¹ represents an alkyl group having 1 to 4 carbon atoms, R ² represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms,
Represents an alkoxy group having 1 to 4 carbon atoms, a nitro group, a carboxyl group or an ester thereof, or a halogen atom. )

Further, the present inventors have prepared a heterogeneous system of a 2-halobenzonitrile represented by the general formula (III) and an alkanethiol represented by the general formula (IV) in the presence of a base. It was noted that 2- (alkylthio) benzonitrile represented by the above general formula (I) can be easily obtained by the reaction.

[0015]

Embedded image

The 2- (alkylthio) benzonitrile represented by the general formula (I) produced by the above reaction is reacted with a halogenating agent in the presence of water to obtain a compound represented by the general formula (II). The 1,2-benzisothiazol-3-one represented by the formula (1) was obtained. Furthermore, if the above reaction was carried out in a system of a water-insoluble organic solvent, 2-halobenzonitrile was used as a raw material, The inventors have found that a series of reactions for producing benzisothiazol-3-ones can be carried out in one pot, and have completed the present invention.

[0017]

Embedded image

That is, the gist of the present invention is as follows: (1) 2- (alkylthio) represented by the general formula (I)
Wherein a benzonitrile is reacted with a halogenating agent in the presence of water;
A method for producing 2-benzisothiazol-3-ones,

[0019]

Embedded image

(Wherein, R ¹ represents an alkyl group having 1 to 4 carbon atoms, R ² represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms,
Represents an alkoxy group having 1 to 4 carbon atoms, a nitro group, a carboxyl group or an ester thereof, or a halogen atom. )

[0021]

Embedded image

[0022] (wherein, R ² is R ² in the general formula (I)
And is equivalent. (2) The production method according to (1), wherein the halogenating agent is chlorine, (3) the production method according to (1), wherein the halogenating agent is sulfuryl chloride, (4) the compound of the general formula (I) is 2 The method according to any one of (1) to (3), which is-(methylthio) benzonitrile , and ( 5 ) 2-halobenzonitrile represented by the general formula (III) and a compound represented by the general formula (IV). The alkanethiols represented by the formula (I) are reacted in a heterogeneous system in the presence of a base.
A 2- (alkylthio) benzonitrile represented by the general formula (II), which is further reacted with a halogenating agent in the presence of water. A method for producing 3-ones,

[0023]

Embedded image

(In the formula, X represents a chlorine atom or a bromine atom.
R ² represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms,
Alkoxy groups, nitro groups and carboxyl groups of formulas 1 to 4
Or an ester thereof or a halogen atom. ) R ¹ SH (IV) (In the formula, R ¹ relates represents.) An alkyl group having 1 to 4 carbon atoms.

The 1,2-benzisothiazole of the present invention
The feature of the method for producing 3-ones is that 2- (alkylthio) is easily obtained from 2-halobenzonitrile as a raw material.
By reacting a benzonitrile with a halogenating agent in the presence of water, a cyclization reaction easily occurs, and 1,2-benzisothiazol-3-ones can be produced by a simple process. . Still another feature is that a 2-halobenzonitrile and an alkanethiol are reacted in a heterogeneous system using a water-insoluble organic solvent in the presence of a base to obtain 2- (alkylthio) benzonitrile. The obtained oil layer containing the 2- (alkylthio) benzonitrile is separated from the aqueous layer, and then a halogenating agent is added to the oil layer.
The reaction is carried out in the presence of water to produce 1,2-benzisothiazol-3-ones in one pot.

In the general formulas (I) and (IV), R
¹ represents an alkyl group having 1 to 4 carbon atoms. Examples of the alkyl group represented by R ¹ include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. Of these, preferred examples of R ¹ include a methyl group, an ethyl group, an n-propyl group, and a tert-
Butyl groups can be mentioned.

R ² in the general formulas (I), (II) and (III) is specifically a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, nitro Represents a group, a carboxyl group or an ester thereof, or a halogen atom. Examples of the alkyl group represented by R ² include a methyl group, an ethyl group, an n-propyl group, an isopropyl group,
-Butyl group, isobutyl group, sec-butyl group, ter
A t-butyl group and the like can be mentioned. Examples of the alkoxy group represented by R ² include a methoxy group, an ethoxy group,
Examples include a propoxy group and a butoxy group. R
Illustrating the ester of the carboxyl group represented by ² ,
Examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, and a butoxycarbonyl group. Examples of the halogen atom represented by R ² include a chlorine atom and a bromine atom. Among these, preferred examples of R ² include a hydrogen atom, a methyl group,
Examples include an ethyl group, a tert-butyl group, a methoxy group, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a chlorine atom, and a nitro group.

The compound of the present invention represented by the general formula (I)
Specific examples of (alkylthio) benzonitrile include
For example, the following can be exemplified. 2- (methylthio) benzonitrile, 2- (ethylthio) benzonitrile, 2- (n-propylthio) benzonitrile, 2-
(Tert-butylthio) benzonitrile, 3-methyl-2- (methylthio) benzonitrile, 5-butyl-2
-(Methylthio) benzonitrile, 4-methoxy-2-
(Methylthio) benzonitrile, 2-methylthio-3-
Nitrobenzonitrile, 4-chloro-2- (methylthio) benzonitrile, 4-carboxy-2- (methylthio) benzonitrile, 4-methoxycarbonyl-2-
(Methylthio) benzonitrile, of which 2- (methylthio) benzonitrile, 2- (ethylthio) benzonitrile, 2- (n- Propylthio)
Benzonitrile and 2- (tert-butylthio) benzonitrile are preferably used.

The 2- (alkylthio) benzonitrile represented by the general formula (I) may be obtained by any method. Among them, the method of the present invention is more advantageous. be able to. That is, the method comprises reacting a 2-halobenzonitrile represented by the general formula (III) with an alkanethiol represented by the general formula (IV) in a heterogeneous system in the presence of a base. And 2- (alkylthio) benzonitrile represented by the general formula (I). In the general formula (III), X represents a chlorine atom or a bromine atom, and R ² has the same meaning as R ² in the general formula (I). In the general formula (IV), R ¹ has the same meaning as R ¹ in the general formula (I).

Specific examples of such 2-halobenzonitrile represented by the general formula (III) include 2-chlorobenzonitrile, 2-bromobenzonitrile, 3-methyl-2-chlorobenzonitrile, 5-butyl-2-chlorobenzonitrile, 4-methoxy-2-chlorobenzonitrile, 2-chloro-3-nitrobenzonitrile, 4-
Methoxycarbonyl-2-chlorobenzonitrile and the like can be mentioned.

As the alkanethiols represented by the general formula (IV), methanethiol, ethanethiol, 1-propanethiol, 2-butanethiol and the like can be used, and the amount used is 2-halobenzonitrile. Against
Usually 0.8 to 3.0 times mol, preferably 1.0 to 2.0 times.
The range is twice as high. The amount of alkanethiol used is 0.
When the molar ratio is less than 8 times, the amount of unreacted 2-halobenzonitrile is increased. On the other hand, when the molar ratio is more than 3.0 times, the effect corresponding thereto is not obtained and it is economically disadvantageous.

Examples of the base used in the reaction between 2-halobenzonitrile and alkanethiol include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, sodium methylate, Metal alcoholates such as sodium ethylate are exemplified. Among them, sodium hydroxide is preferably used from an economic viewpoint. In addition, the amount of the base used is usually 0.8 to 3.0 based on 2-halobenzonitrile.
It is in the range of 5 moles, preferably 1.0 to 2.5 moles. When the amount of the base used is less than 0.8 mole, the amount of unreacted 2-halobenzonitrile increases, while
Even if it is used in an amount exceeding 3.5 moles, the effect corresponding thereto cannot be obtained, which is economically disadvantageous.

The method of the present invention for producing 2- (alkylthio) benzonitrile is characterized in that the reaction is carried out in a heterogeneous system in the presence of a base. The reaction between 2-halobenzonitrile and alkanethiol, which are reaction raw materials,
Since the halobenzonitrile is insoluble in water, it is a two-phase reaction. In this case, the addition of a phase transfer catalyst is preferable because the reaction often proceeds smoothly. As the phase transfer catalyst used here, benzyltriethylammonium bromide, benzyltrimethylammonium chloride, hexadecyltriethylammonium bromide, hexadecyltrimethylammonium chloride, dodecyltrimethylammonium chloride, octyltriethylammonium bromide, tetra-n-
Quaternary ammonium salts such as butylammonium bromide, tetra-n-butylammonium chloride, tetraethylammonium chloride, trioctylmethylammonium chloride, hexadecyltriethylphosphonium bromide, hexadecyltributylphosphonium chloride, tetra-n-butylphosphonium bromide, tetra- quaternary phosphonium salts such as n-butylphosphonium chloride, trioctylethylphosphonium bromide, tetraphenylphosphonium bromide,
18-crown-6, dibenzo-18-crown-6,
And crown ethers such as dicyclohexyl-18-crown-6. Among them, quaternary ammonium salts such as tetra-n-butylammonium bromide and tetra-n-butylammonium chloride are preferably used from an economic viewpoint.

When a phase transfer catalyst is used, the amount of the phase transfer catalyst is usually 0.1 to the weight of 2-halobenzonitrile.
005-0.5 times weight, preferably 0.01-0.2
Double weight range. When the amount of the phase transfer catalyst used is 0.0
When the amount is less than 05 times by weight, the catalytic effect is not sufficiently exhibited. On the other hand, when the amount exceeds 0.5 times by weight, the effect corresponding thereto is not obtained, which is economically disadvantageous.

In this method, it is not always necessary to use a reaction solvent. However, in order to facilitate the reaction and to facilitate the separation of the product after the reaction, a water-insoluble solvent is usually used with respect to 1 part by weight of water. In many cases, better results are obtained by using a mixed solvent composed of 0.5 to 10 parts by weight of the organic solvent. The water-insoluble organic solvent is not particularly limited,
Examples thereof include hydrocarbons such as n-hexane, n-heptane, cyclohexane, methylcyclohexane, benzene, toluene, and xylene, and halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, and chlorobenzene. The amount of the solvent to be used is generally 1 to 30 times the weight of 2-halobenzonitrile.

The reaction temperature is usually in the range of 0 to 150 ° C, preferably 20 to 120 ° C. Reaction temperature is 150 ° C
If the temperature exceeds 0 ° C., a side reaction occurs. On the other hand, if the temperature is lower than 0 ° C., the reaction rate is practically too slow, which is not preferable. The reaction time varies depending on the reaction temperature, the type of the phase transfer catalyst and the type of the reaction solvent, and cannot be specified unconditionally, but is usually in the range of 1 to 40 hours.

After completion of the reaction, the separated 2- (alkylthio) benzonitrile can be isolated and purified from the organic solvent layer by a usual treatment such as crystallization. Further, since the aqueous layer is separated while containing the phase transfer catalyst, it can be used repeatedly. Therefore, almost no aqueous waste is discharged outside the system. Furthermore, the separated 2
The oil layer containing-(alkylthio) benzonitrile can be used for producing 1,2-benzisothiazol-3-one as it is.

Next, from the 2- (alkylthio) benzonitrile of the present invention, 1,2-benzisothiazole-3-.
Chlorine, bromine, sulfuryl chloride, sulfuryl bromide and the like can be used as the halogenating agent used in the step of obtaining the ONS, but sulfuryl chloride and chlorine are preferably used from the viewpoint of reaction selectivity. The amount used is usually 0.8 to 3.0 with respect to 2- (alkylthio) benzonitrile.
It is in the range of 1 mole, preferably 1.0 to 2.0 moles. When the amount of the halogenating agent used is less than 0.8 times mol, the amount of unreacted 2- (alkylthio) benzonitrile increases, while when it exceeds 3.0 times mol,
Since side reactions occur and the yield decreases, these are not preferred.

The amount of water used in the step of reacting the halogenating agent to obtain 1,2-benzisothiazol-3-ones is usually 0.8 to 2 (alkylthio) benzonitrile. To 5.0-fold molar, preferably 1.
It is in the range of 0 to 3.0 times mol. When the amount of water added is 0.8
When the molar ratio is less than the molar ratio or when the molar ratio exceeds the 5.0 molar ratio, side reactions occur to lower the yield, which is not preferable.

The reaction solvent used in the step of reacting the halogenating agent to obtain 1,2-benzisothiazol-3-ones is not particularly limited as long as it is a solvent inert to the reaction. Specific examples include hydrocarbons such as n-hexane, n-heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene,
Examples thereof include halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, and chlorobenzene.
In this case, when the same solvent as used in the production of 2- (alkylthio) benzonitrile is used,
-2 from halobenzonitrile and alkanethiol
The step of obtaining-(alkylthio) benzonitrile and the step of reacting 2- (alkylthio) benzonitrile with a halogenating agent to obtain 1,2-benzisothiazol-3-ones are all performed in one pot. Can be
Extremely efficient. The amount of the solvent to be used is generally 1 to 30 times by weight relative to 2- (alkylthio) benzonitrile.

The reaction temperature is usually in the range of -20 to 170 ° C, preferably in the range of 0 to 150 ° C. When the reaction temperature exceeds 170 ° C., side reactions become a problem, while
If the temperature is lower than -20 ° C, the reaction rate is practically too slow, which is not preferable. The reaction time varies depending on the reaction temperature and the type of the reaction solvent, and cannot be unconditionally determined, but is usually in the range of 1 to 40 hours.

From the reaction mixture thus obtained,
As a method for isolating and purifying the desired 1,2-benzisothiazol-3-ones, crystallization can be carried out as is or extraction and recrystallization can be carried out as usual. However, the present invention is not limited to this.

Specific examples of the 1,2-benzisothiazol-3-one represented by the general formula (II), which is the target compound thus obtained, are as follows. . 1,2-benzisothiazol-3-one,
7-methyl-1,2-benzisothiazol-3-one, 5-butyl-1,2-benzisothiazol-3-one
On, 6-methoxy-1,2-benzisothiazole-
3-one, 7-nitro-1,2-benzisothiazol-3-one, 6-chloro-1,2-benzisothiazol-3-one, 6-carboxy-1,2-benzisothiazol-3-one On, 6-methoxycarbonyl-1,2
-Benzisothiazol-3-one.

[0044]

EXAMPLES The present invention will be described in more detail with reference to the following examples, which should not be construed as limiting the invention thereto.

Production Example 1 Synthesis of 2- (methylthio) benzonitrile 27.5 g (0.2 g) of 2-chlorobenzonitrile was placed in a 500 ml four-necked flask equipped with a stirrer, thermometer and condenser under a nitrogen atmosphere. Mol), 100 g of monochlorobenzene, and 5.5 g of a 50% by weight aqueous solution of tetra-n-butylammonium bromide. Separately, 9.6 g (0.24 mol) of sodium hydroxide and 35.0 g of water were separately prepared.
g was charged into another container under a nitrogen atmosphere, and 11.5 g (0.24 mol) of methanethiol was charged under stirring at room temperature for about 1 hour. 56.1 g (0.24 mol) of a 30% by weight aqueous solution of methyl mercaptan / sodium salt thus obtained was added to the four-necked flask with stirring, and the mixture was reacted for 2 hours while refluxing. After completion of the reaction, the reaction solution was cooled to room temperature, and the solvent was distilled off.
29.2 g of (methylthio) benzonitrile (boiling point: 139
１４０140 ° C./7 mmHg). The yield based on 2-chlorobenzonitrile was 98%.

Example 1 Synthesis of 1,2-benzisothiazol-3-one 2- (methylthio) benzonitrile was placed in a 500 ml four-necked flask equipped with a stirrer, a thermometer, and a condenser.
9.8 g (0.2 mol), monochlorobenzene 100
g, 4.32 g (0.24 mol) of water and 29.7 g (0.22 mol) of sulfuryl chloride in 5 to 5 g with stirring.
After the addition at 15 ° C, the mixture was heated to 70 to 80 ° C and reacted for 1 hour. After completion of the reaction, the reaction solution was cooled to room temperature, and the precipitated white crystals were washed with monochlorobenzene and dried to obtain 1,2-benzisothiazol-3-one.
0 g (melting point 157-158 ° C) were obtained. 2- as raw material
The yield based on (methylthio) benzonitrile was 96%.

Example 2 Synthesis of 1,2-benzisothiazol-3-one (one-pot reaction) In a 500 ml four-necked flask equipped with a stirrer, a thermometer, and a condenser, 2-chlorobenzonitrile was placed under a nitrogen atmosphere. 27.5 g (0.2 mol), monochlorobenzene 1
00 g and 2.25 g of a 50% by weight aqueous solution of tetra-n-butylammonium bromide were charged. Separately, 9.6 g (0.24 mol) of sodium hydroxide and 35.0 g of water were separately prepared.
g was charged into another container under a nitrogen atmosphere, and 11.5 g (0.24 mol) of methanethiol was charged under stirring at room temperature for about 1 hour. 56.1 g (0.24 mol) of a 30% by weight aqueous solution of methyl mercaptan / sodium salt thus obtained was added to the four-necked flask with stirring, and the mixture was reacted for 2 hours while refluxing. After the reaction, 40-50 ° C
The liquid was separated into a water layer (lower layer) and an oil layer (upper layer) by heating. 100 g of monochlorobenzene and 3.6 g of water were added to this oil layer.
(0.2 mol) was added thereto, and 27.0 g (0.2 mol) of sulfuryl chloride was added at 5 to 15 ° C. with stirring, followed by heating to 70 to 80 ° C. and reacting for 1 hour. After completion of the reaction, the reaction solution was cooled to room temperature, and the precipitated white crystals were washed with monochlorobenzene and dried, and 29.3 g of 1,2-benzisothiazol-3-one (melting point: 157 to 15)
8 ° C.). The yield based on the starting material 2-chlorobenzonitrile was 97%.

Example 3 Synthesis of 1,2-benzisothiazol- 3 -one (one-pot reaction) The sulfuryl chloride in Example 2 was replaced with chlorine.
Example 2 except that the blowing was changed to 2 g (0.2 mol).
In the same manner as described above, 25.7 g of 1,2-benzisothiazol-3-one was obtained. The yield based on 2-chlorobenzonitrile was 85%.

Examples 4 to 9 Synthesis of 1,2-benzisothiazol-3- ones The procedure of Example 1 was repeated except that the starting materials were changed to 2- (alkylthio) benzonitrile compounds shown in Table 1. 1,2-benzisothiazol-3-ones were obtained.

[0050]

[Table 1]

[0051]

According to the production method of the present invention, 1,2-benzisothiazole-3 which is important as an antibacterial agent, an antifungal agent, etc.
-Ons can be obtained by an easy process without complicated operations and without using expensive raw materials. Furthermore, if 2-halobenzonitrile is used as a raw material and the reaction to obtain the target product via 2- (alkylthio) benzonitrile is performed in one pot, a higher yield can be obtained in a shorter process than before, It is economically advantageous.

────────────────────────────────────────────────── ─── of the front page continued (72) inventor Shigeki Sakagami Hyogo Prefecture Kako-gun, Harima-cho, Miyanishi 346 address of 1 Sumitomo Seika Chemicals Co., Ltd. first in the Institute (58) investigated the field (Int.Cl. ^7, DB name) C07D 275/04-275/06 B01J 31/02 C07B 61/00 CA (STN) REGISTRY (STN) WPI (DIALOG)

Claims (5)

(57) [Claims] 1. A compound represented by the general formula (II), characterized by reacting a 2- (alkylthio) benzonitrile represented by the general formula (I) with a halogenating agent in the presence of water. A method for producing 1,2-benzisothiazol-3-ones. Embedded image (In the formula, R ¹ represents an alkyl group having 1 to 4 carbon atoms, R ²
Represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, and 1 to 4 carbon atoms.
Represents an alkoxy group, a nitro group, a carboxyl group or an ester thereof, or a halogen atom. ) (Wherein, R ² has the same meaning as R ² in formula (I).) 2. The method according to claim 1, wherein the halogenating agent is chlorine. 3. The method according to claim 1, wherein the halogenating agent is sulfuryl chloride. 4. The production method according to claim 1, wherein the compound of the general formula (I) is 2- (methylthio) benzonitrile. 5. A heterogeneous reaction between a 2-halobenzonitrile represented by the general formula (III) and an alkanethiol represented by the general formula (IV) in a heterogeneous system in the presence of a base. 1,2-benz represented by the general formula (II), characterized in that 2- (alkylthio) benzonitrile represented by the formula (I) is obtained and further reacted with a halogenating agent in the presence of water. A method for producing isothiazol-3-ones. Embedded image (Wherein, X represents a chlorine atom or a bromine atom, and R ² represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a nitro group, a carboxyl group or an ester thereof, or a halogen atom. R ¹ SH (IV) (wherein, R ¹ represents an alkyl group having 1 to 4 carbon atoms.) (Wherein, R ¹ represents the same meaning as R ¹ in the general formula (IV), R ² represents the same meanings as R ² in the general formula (III).) Embedded image (Wherein, R ² has the same meaning as R ² in formula (I).)