JP2003040875A - Method for producing 1,2-benzoisothiazolin-3-one compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To an industrially advantageous method for producing safely producing a 1,2-benzoisothiazolin-3-one compound useful in bioactivation. SOLUTION: This method for producing 1,2-benzoisothiazolin-3-one compound represented by general formula (a) (wherein R<1> is a 1-12C alkyl group, a 3-12C alkyl group or a 6-12C aromatic group; R<2> is a 1-8C alkyl group or a 3-8C cycloalkyl group, a 1-8C alkoxy group, a halogen atom or nitro group and R<2> may be mutually same or different; n is 0 or an integer of 1-4) comprises reacting a 2-sulfenamoyl benzoic acid ester represented by general formula (b) (wherein R<3> is a 1-6c alkyl group or a 3-6C cycloalkyl group) with amines represented by general formula (c).

Description

Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a 1,2-benzisothiazolin-3-one compound. More specifically, the present invention relates to a method for efficiently producing a 1,2-benzisothiazolin-3-one compound by reacting a 2-sulfenamoylbenzoate compound with an amine. [0002] It is known that 1,2-benzisothiazolin-3-one compounds have various physiological activities.
5-chloro and 6-chloro-1,2-benzisothiazoline-3-
On has been reported to have antibacterial and antibacterial activities (Adv. Heterocycl. Chem., 14, 58 (1972)). Furthermore, among various 1,2-benzisothiazole compounds derived from 1,2-benzisothiazolin-3-one,
Compounds having a substituent on the isothiazole ring are also important compounds that have been reported to have various pharmacological effects (Adv. Heterocycl. Che).
m., 14, 58 (1972); J. Med. Chem., 29, 359 (198
6)). In particular, 1,2-benzisothiazolin-3-one compounds having a substituent on the nitrogen atom at the 2-position have antibacterial and antibacterial activities (Bull. Chem. Soc. Jpn., 55, 1183 (1982);
J. Med. Chem., 28, 1772 (1985)) and a platelet coagulation preventing effect (J. Med. Chem., 28, 1661 (1985)). Conventionally, 1,2-benzisothiazolin-3-one compounds have been prepared by treating dithiosalicylic acid or thiosalicylic acid with chlorine or bromine and then reacting with amines (US Pat. No. 2870015; Belgian Patent 565380,
No. 617384; German Patent No. 1135468), a method in which thiosalicylic esters are treated with chlorine or bromine and then reacted with amines (Japanese Patent Application Laid-Open No. Sho 46-5516; German Patent No. 2119930; J. Org). Chem., 40, 2029 (1975)) or a method of reacting thiosalicylic amides with chlorine (Farmaco, Ed. Sci., 16, 509 (1961); 18, 732 (196).
3); 19, 254 (1964); 22, 935, 989, 999 (1967); 2
3,468 (1968); British Patent No. 848130; US Patent No. 37614
No. 89), but toxic chlorine and bromine must be used, and there is a problem of corrosion of the production equipment. Therefore, development of a safe production method is desired. Also, 1,2-benzodithiol-3-one and 1,2-benzodithiol-3-one
A method of producing from 1-oxide is also known (J. Che
m. Soc., 123, 170 (1923); Tetrahedron Lett., 37, 5
337 (1996)), all of these compounds are special reagents, are not readily available, and are unsuitable as industrially practiced methods. SUMMARY OF THE INVENTION The present invention overcomes the drawback of using a toxic chlorine gas, which is a conventional method, in producing a 1,2-benzisothiazolin-3-one compound. It is an object of the present invention to provide an industrially advantageous method for producing a 1,2-benzoisothiazolin-3-one compound. The present inventors have conducted intensive studies on a method for producing a 1,2-benzisothiazolin-3-one compound, and as a result, have found that a 2-sulfenamoyl benzoate compound and an amine It has been found that a 1,2-benzisothiazolin-3-one compound can be obtained safely and easily by causing a cyclization reaction by reacting the above, and the present invention has been completed based on this finding. That is, according to the present invention, the following general formula (a): (In the formula, R ¹ is an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 12 carbon atoms, or a carbon atom having 6 to 1 carbon atoms.
2 represents an aromatic group. R ² is an alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms,
8 alkoxyl group, a halogen atom, a nitro group, when R ² are a plurality, each R ² may being the same or different, n is an integer of 0 or 1 to 4) In a process for producing a 1,2-benzisothiazolin-3-one compound represented by the following general formula (II): (Wherein, ^{R 2} is an alkyl group or a cycloalkyl group having 3 to 8 carbon atoms of 1 to 8 carbon atoms, an alkoxyl group having 1 to 8 carbon atoms, a halogen atom, a nitro group, ^{when R 2} are a plurality And each R ² may be the same or different, and n is 0 or an integer of 1 to 4. R ³ is an alkyl group having 1 to 6 carbon atoms or a cycloalkyl having 3 to 6 carbon atoms. A 2-sulfenamoyl benzoate compound represented by the following general formula (c): (In the formula, R ¹ is an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 12 carbon atoms, or
2 represents an aromatic group. The present invention provides a method for producing a 1,2-benzisothiazolin-3-one compound, which comprises reacting an amine represented by the formula (1). BEST MODE FOR CARRYING OUT THE INVENTION 1,2-
In the above general formula (A) representing a benzoisothiazolin-3-one compound, R ¹ represents an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 12 carbon atoms, or an aromatic group having 6 to 12 carbon atoms. . These alkyl groups are
It may have a substituent such as a hydroxyl group, an alkoxyl group and a dialkylamino group. Specific examples of the alkyl group or cycloalkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a butyl group, a hexyl group, a cyclohexyl group, a hydroxyethyl group, an ethoxyethyl group, and a hydroxypropyl group. And the like. Further, specific examples of the aromatic group include a phenyl group, a benzyl group, a naphthyl group, and the like. These aromatic groups include a halogen atom, an alkyl group,
It may have a substituent such as an alkoxyl group and a dialkylamino group. R ² represents an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkoxyl group having 1 to 8 carbon atoms, a halogen atom, or a nitro group. Illustrative examples of the alkyl group or cycloalkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a pentyl group, a butyl group,
Examples include an s-butyl group, a t-butyl group, a cyclobutyl group, a hexyl group, a cyclohexyl group, and a benzyl group. Specific examples of the alkoxyl group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and a hexyloxy group. n shows 0 or the integer of 1-4. In addition, the above-mentioned general formula (II) which represents a 2-sulfenamoylbenzoic acid ester compound used as a reaction substrate
In the above, R ³ represents an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms. Illustrative examples of the alkyl group or cycloalkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a pentyl group, a butyl group, an s-butyl group, a t-butyl group, a hexyl group,
Examples include a cyclohexyl group, an ethoxyethyl group, and a benzyl group. The novel synthesis reaction of the present invention can be represented by the following reaction formula (d). Embedded image The production of the 1,2-benzisothiazolin-3-one compound is preferably carried out in the presence of a reaction solvent. In this case, the reaction solvent is methanol, ethanol,
The reaction is performed in a solvent such as isopropanol, acetonitrile, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, and anisole. These solvents are used alone or in the form of a mixed solvent. The temperature in the above-mentioned manufacturing method is 20 ° C. to 15
The reaction can be carried out at a temperature of about 0 ° C., but if the temperature is too low, the reaction time is delayed, and if the temperature is too high, the decomposition reaction and side reactions increase, so that the reaction is preferably carried out in the range of 50 ° C. to 100 ° C. The reaction time depends on the reaction temperature and cannot be determined unconditionally, but usually 2 to 8 hours is sufficient. As described above, the 1,2-benzisothiazolin-3-one compounds represented by, for example, the chemical formulas (1) to (5) can be produced by the reaction of the present invention. Embedded image Next, the present invention will be described in detail with reference to examples. It should be noted that the embodiments of the present invention are representative ones for easy understanding of the present invention, and the present invention is not limited to these. Compounds (1) to (5) produced by the following Examples correspond to Compounds (1) to (5) shown above, and were identified by comparing melting points and various spectral data with known ones. did. Example 1 Methyl 2-sulfenamoylbenzoate (146 mg, 0.8 mmol) and benzylamine (214 mg, 2.0 mmol) were dissolved in toluene (5 ml) in a glass container having an inner volume of 30 ml. Heat for 4 hours. The toluene was distilled off under reduced pressure, and the crude product was purified by silica gel chromatography (elution solvent: methylene chloride: acetone: methanol = 100: 5: 1) to give 1,2-benzoisothiazoline-3 of the compound (1). The -one was obtained in a yield of 120 mg and a yield of 64%. This compound could be further purified by recrystallization using isopropanol. Example 2 The same reaction as in Example 1 was carried out except that ethyl 2-sulfenamoylbenzoate was used in place of methyl 2-sulfenamoylbenzoate, to give the compound (1) of 1,2-benzoisothiazoline-3- ON was obtained with a yield of 43%. Example 3 Methyl 2-sulfenamoylbenzoate (146 mg, 0.8 mmol) and p-methoxybenzylamine (274 mg, 2.0 mmol) were placed in a glass container having an internal volume of 30 ml.
Was dissolved in toluene (5 ml) and heated under reflux for 4 hours. The toluene was distilled off under reduced pressure, and the crude product was purified by silica gel chromatography (elution solvent: methylene chloride: acetone: methanol = 100: 5: 1) to give 1,2-benzoisothiazoline-3 of the compound (2). 132 mg of -one was obtained in a yield of 61%. This compound could be further purified by recrystallization using ethanol. Example 4 The same operation as in Example 3 was carried out except that ethyl 2-sulfenamoylbenzoate was used in place of methyl 2-sulfenamoylbenzoate, and the mixture was reacted for 6 hours to give 1,2 of the compound (2). -Benzisothiazolin-3-one was obtained with a yield of 53%. Example 5 In a 30 ml glass container, methyl 2-sulfenamoylbenzoate (146 mg, 0.8 mmol) and p-chlorobenzylamine (283 mg, 2.0 mmol) were dissolved in toluene (5 ml). Heat at 100 ° C. for 4 hours. The toluene was distilled off under reduced pressure, and the crude product was purified by silica gel chromatography (elution solvent: methylene chloride: acetone: methanol = 100: 5: 1) to obtain 1,2-benzoisothiazoline-3 of the compound (3). -
ON was obtained in a yield of 150 mg and a yield of 68%. This compound could be further purified by recrystallization using ethanol. Example 6 The same operation as in Example 5 was carried out except that methyl 2-sulfenamoylbenzoate was used instead of methyl 2-sulfenamoylbenzoate, and the reaction was carried out for 6 hours to give 1,2 of the compound (3). -Benzisothiazolin-3-one was obtained with a yield of 53%. Example 7 Ethyl 2-sulfenamoylbenzoate (158 mg, 0.8 mmol) and ethanolamine (122 mg, 2.0 mmol) were dissolved in toluene (5 ml) in a glass container having an internal volume of 30 ml, and the solution was dissolved at 100 ° C. Heat for 5 hours.
The toluene was distilled off under reduced pressure, and the crude product was subjected to silica gel chromatography (elution solvent: methylene chloride: acetone:
Purification with methanol = 100: 20: 4) yielded 1,2-benzoisothiazolin-3-one of the compound (4) in a yield of 83 mg and a yield of 53%. This compound could be further purified by recrystallization using ethyl acetate. Example 8 Methyl 2-sulfenamoyl benzoate (146 mg, 0.8 mmol) and 3-hydroxy-1-propylamine (150 mg, 2.0 mm) were placed in a glass container having an internal volume of 30 ml.
ol) in toluene (5 ml), and
Heated for hours. The toluene was distilled off under reduced pressure, and the crude product was purified by silica gel chromatography (elution solvent: methylene chloride: acetone: methanol = 100: 20: 4) to give 1,2-benzoisothiazoline-3 of the compound (5). -On was obtained in a yield of 96 mg and 57%. This compound could be further purified by recrystallization using ethyl acetate. Example 9 The same reaction as in Example 8 was carried out except that ethyl 2-sulfenamoylbenzoate was used in place of methyl 2-sulfenamoylbenzoate, to give 1,2-benzoisothiazoline-3- compound of the compound (5). ON was obtained with a yield of 71%. According to the present invention, a 1,2-benzisothiazolin-3-one compound can be produced in good yield by reacting a 2-sulfenamoylbenzoic acid ester compound with an amine in the present invention. In addition, since it can be safely produced without using toxic chlorine gas, it is most suitable as an industrial method for synthesizing 1,2-benzisothiazolin-3-one compounds.

Claims (1)

[Claim 1] The following general formula (A): (In the formula, R ¹ is an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 12 carbon atoms, or
2 represents an aromatic group. R ² is an alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms,
8 alkoxyl group, a halogen atom, a nitro group, when R ² are a plurality, each R ² may being the same or different, n is an integer of 0 or 1 to 4) A method for producing a 1,2-benzisothiazolin-3-one compound represented by the following general formula (II): (Wherein, ^{R 2} is an alkyl group or a cycloalkyl group having 3 to 8 carbon atoms of 1 to 8 carbon atoms, an alkoxyl group having 1 to 8 carbon atoms, a halogen atom, a nitro group, ^{when R 2} are a plurality And each R ² may be the same or different, and n is 0 or an integer of 1 to 4. R ³ is an alkyl group having 1 to 6 carbon atoms or a cycloalkyl having 3 to 6 carbon atoms. A 2-sulfenamoylbenzoic acid ester compound represented by the following general formula (c): (In the formula, R ¹ is an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 12 carbon atoms, or
2 represents an aromatic group. A) producing a 1,2-benzisothiazolin-3-one compound.