JP2000095768A - Production of 1,2-benzoisothiazolinone compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain in high yield the subject compound useful as an antimicrobial agent or the like using readily available starting materials without using toxic chlorine gas by intramolecularly cyclizing condensation of a specific sulfenamxde compound. SOLUTION: This compound of formula III (e.g. a compound of formula IV) is obtained by intramolecularly cyclizing condensation of a sulfenamide compound of formula I (R1 to R4 are each H or an inert substituent in the intramolecularly cyclizing condensation reaction of the sulfenamide compound; R5 is an inert substituent in the intramolecularly cyclizing condensation reaction of the sulfenamide compound) (e.g. a compound of formula II) pref. in the presence of a base such as an alkali metal hydroxide (e.g. potassium hydroxide) pref. in a solvent such as ethanol pref. at 0-100 deg.C normally for 30 min to 2 h.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a 1,2-benzisothiazolinone compound. More specifically, the present invention relates to a method for producing a 1,2-benzoisothiazolinone compound by efficiently intramolecular cyclizing condensation of a sulfenamide compound obtained by aminating a thiosalicylate compound.

[0002]

2. Description of the Related Art 1,2-Benzoisothiazolinone compounds are known to have various physiological activities. In particular, 5-chloro and 6-chloro-1,2-benzisothiazolinone are antibacterial and antibacterial. Has been reported to be active (Adv. Het
erocycl. Chem., 14, 58 (1972)). Furthermore, 1- (1,2-benzisothiazol-3-yl) piperazine derivatives derived from 1,2-benzisothiazolinone have antipsychotic effects (J. Med. Chem., 29, 359 ( 1986)). In addition, saccharin, a sweetener, can be obtained by oxidizing 1,2-benzoisothiazolinone (J. Chem. Soc., 123, 170 (1923), Chem. Be).
r., 61, 1308 (1928)).

Hitherto, 1,2-benzisothiazolinone compounds have been produced by treating dithiosalicylic acid with chlorine and then reacting it with an amine (US Pat.
No. 70015, Belgian Patent Nos. 565380 and 617384, German Patent No. 1135468), toxic chlorine and bromine must be used, and the development of a safe production method is desired. Further, the production method according to this method has a drawback that in producing an N-unsubstituted benzoisothiazolinone compound, the desired product is not obtained and only disulfenamide is obtained (J. Org. Chem. , 40, 2029 (1975)). Also, a method of producing from 1,2-benzodithiol-3-one or 1,2-benzodithiol-3-one 1-oxide is known (J. Chem. Soc., 123, 170 (1923) , Tetrahedro
n Lett., 37, 5337 (1996)), all of these compounds are special reagents, are not easily available, and are unsuitable for industrial practice.

[0004]

DISCLOSURE OF THE INVENTION The present invention overcomes the drawbacks of using conventional toxic chlorine gas and the drawback that starting materials are difficult to obtain, and provides a method for producing a 1,2-benzoisothiazolinone compound. To provide an industrially advantageous method.

[0005]

Means for Solving the Problems The present inventors have conducted intensive studies on a method for producing a 1,2-benzisothiazoline compound, and have noticed that the thiol group of a thiosalicylate compound is easily aminated. If the resulting sulfenamide compound undergoes an intramolecular condensation cyclization reaction,
They have found that a 1,2-benzoisothiazolinone compound can be obtained safely and easily, and based on this finding, have completed the present invention.

According to the present invention, the general formula (1)

Embedded image (Wherein, R ^{1 to} R ⁴ represent hydrogen or an inert substituent), and a method for producing a 1,2-benzoisothiazolinone compound represented by the general formula (3):

Embedded image (Wherein, R ^{1 to} R ⁴ represent hydrogen or an inert substituent, and R ⁵ represents an inert substituent). , 2-
A benzoisothiazolinone compound is obtained.

More specifically, the present invention provides a compound represented by the general formula (1):

Embedded image (In the formula, R ^{1 to} R ⁴ represent hydrogen or an inert substituent.)
A method for producing a 1,2-benzisothiazolinone compound represented by the general formula (2)

Embedded image (Wherein R ¹ to R ⁴ represents a hydrogen or an inert substituent, R ⁵
Represents an inert substituent. The following general formula (3) obtained by aminating the thiosalicylate compound represented by the formula (3)

Embedded image Wherein R ^{1 to} R ⁴ represent hydrogen or an inert substituent, and R ⁵ represents an inert substituent. , 2-
A method for producing a benzoisothiazolinone compound is provided.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION 1,2-
The general formula (1) representing a benzoisothiazolinone compound
In the above, R ^{1 to} R ⁴ represent hydrogen or an inert substituent. In this case, the inert substituent may be any as long as it is inert to the reaction of the present invention. Such inert substituents include linear or cyclic alkyl groups, alkoxy groups, dialkylamino groups, acyl groups, alkoxy groups, halogen atoms, cyano groups, nitro groups, and the like. The alkyl group bonded to these inert substituents usually has 1 to 6 carbon atoms.

According to the present invention, the sulfenamide compound represented by the general formula (3) is produced by aminating the thiosalicylate compound represented by the general formula (2). In the general formulas (2) and (3), R ^{1 to} R ⁴ represent hydrogen or an inert substituent. In this case, the inert substituent may be any one which is inert to the reaction of the present invention. Such a thing may be used. Such a substituent includes a chain or cyclic alkyl group, alkoxy group, dialkylamino group, acyl group, alkoxy group, halogen atom, cyano group, nitro group and the like. The carbon number of the alkyl group bonded to these inert substituents is usually 1 to 6
It is. R ⁵ represents an organic group, and the organic group in this case includes an aliphatic group, an aromatic group, and a heterocyclic group. The aliphatic group includes an alkyl group and a cycloalkyl group. The alkyl group has 1 to 12 carbon atoms, preferably 1 carbon atom.
~ 6. These alkyl group and cycloalkyl group may have a substituent such as a halogen atom, an alkoxyl group, a dialkylamino group, an acyl group, and an alkoxycarbonyl group. The alkyl group in these inert substituents can be a lower alkyl group having 1 to 6 carbon atoms. Illustrative examples of the aliphatic group include methyl, ethyl, propyl, isopropyl, butyl, hexyl, cyclohexyl, ethoxyethyl, dimethylaminoethyl,
Acetylethyl, methoxycarbonylethyl and the like can be mentioned. The aromatic group includes an aryl group and an arylalkyl group. These aryl groups and arylalkyl groups may have a substituent such as a halogen atom, an alkoxy group, a nitro group, an acyl group, a dialkylamino group, an alkoxycarbonyl group and the like. Specific examples of the aromatic group include phenyl, tolyl, xylyl, naphthyl, benzyl, phenethyl, and their substituted nuclei. Examples of the heterocyclic group include a pyridyl group, a thienyl group, and a furyl group. These heterocyclic groups may also have a substituent such as an alkyl group, a halogen atom, an alkoxy group, a nitro group, a dialkylamino group, an acyl group, and an alkoxycarbonyl group.

The aminating agent may be any substance capable of forming a sulfur-nitrogen bond, such as hydroxylamine-O-sulfonic acid (HOSA), O-acyl or O-acyl.
Sulfonylhydroxylamine compounds, chloramine and the like. The use ratio of the aminating agent is at least 1 equivalent, preferably 1.5 to 2.5 equivalents, per equivalent of the thiosalicylate compound.

The amination reaction is preferably carried out in the presence of a reaction solvent, wherein the reaction solvent is water,
As lower aliphatic alcohols having 1 to 6 carbon atoms, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, isobutanol, te
Examples of ethers such as rt-butanol, pentanol and hexanol include diethyl ether, THF and isopropyl ether, and examples of the nitrogen-containing organic solvent system include acetonitrile and DMF. These solvents are used alone or in the form of a mixed solvent.

The temperature in the amination method is 30.
The reaction can be carried out at a temperature of about 50 to about 50 degrees. However, when the temperature is too low, the reaction time is delayed, and when the temperature is too high, decomposition reactions and side reactions increase. . The reaction time depends on the reaction temperature and cannot be determined unconditionally, but usually 10 minutes to 2 hours is sufficient. The embodiments of the present invention are summarized as follows. 1. General formula (1)

Embedded image (Wherein, R ^{1 to} R ⁴ represent hydrogen or an inert substituent), a method for producing a 1,2-benzoisothiazolinone compound represented by the general formula (3):

Embedded image Wherein R ^{1 to} R ⁴ represent hydrogen or an inert substituent, and R ⁵ represents an inert substituent. , 2-
A method for producing a benzoisothiazolinone compound. 2. The method for producing a 1,2-benzisothiazolinone compound according to claim 1, wherein the intramolecular cyclization condensation is carried out in the presence of a base. 3. The base is uniformly present in the reaction system.
Alternatively, the method for producing a 1,2-benzisothiazolinone compound according to claim 2. 4. The base is an alkali metal hydroxide, an alkaline earth metal hydroxide, or an alkali metal alcoholate.
A method for producing a 1,2-benzisothiazolinone compound according to any one of claims 3 to 4. 5. The method for producing a 1,2-benzoisothiazolinone compound according to any one of claims 1 to 4, wherein the intramolecular cyclization condensation is performed in a solvent. 6. The solvent is selected from methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, isobutanol, tert-butanol, pentanol, hexanol, diethyl ether, tetrahydrofuran, isopropyl ether, pyridine, acetonitrile, dimethylformamide One or two
The method for producing a 1,2-benzisothiazolinone compound according to any one of claims 1 to 5, which is at least one kind. 7. The 1,2-benzoisothiazolinone compound according to any one of claims 1 to 6, wherein the intramolecular cyclization condensation is performed at a temperature of 0 ° C to 100 ° C, preferably 0 ° C to 30 ° C. Manufacturing method.

The present invention will be described in detail with reference to specific examples. According to Production Examples 1 to 5 in which a thiosalicylate compound was converted to a sulfenamide compound by amination, sulfenamide compounds represented by chemical formulas (4) to (8) could be produced.

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According to the present invention, the 1,2-benzisothiazolidinone compound represented by the general formula (1) is prepared by converting the sulfenamide compound represented by the general formula (3) into a molecule in the presence of a base. It can be obtained by performing a cyclization condensation reaction. The base is preferably present in a uniform state in the reaction system, and examples thereof include an alkali metal hydroxide compound, an alkaline earth metal hydroxide compound, and an alkali metal alcoholate compound. Although not particularly limited, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide give preferred results.

In the condensation reaction of the present invention, the solvent used for the reaction is methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, isobutanol, or lower aliphatic alcohol having 1 to 6 carbon atoms. Examples of ethers include butanol, tert-butanol, pentanol, and hexanol. Examples of ethers include diethyl ether, THF, and isopropyl ether. Examples of the nitrogen-containing organic solvent system include pyridine, acetonitrile, and DMF. These solvents are used alone or in the form of a mixed solvent. Although there is no particular limitation, a primary alcohol such as methanol or ethanol gives a preferable result as a solvent in which both the sulfenamides and the base are soluble.

The reaction temperature in the present condensation reaction method is as follows:
The reaction can be carried out at a temperature of about 0 ° C to 100 ° C. However, if the temperature is too low, the reaction time is delayed. If the temperature is too high, the decomposition reaction and side reactions increase. preferable. The reaction time depends on the reaction temperature and cannot be determined unconditionally.
Two hours is enough.

As shown below, the 1,2-benzoisothiazolinone compound represented by the following chemical formula (9) or (10) was produced by the intramolecular cyclization condensation reaction of the present invention.

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[0018]

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 to facilitate understanding of the present invention, and the present invention is not limited to these. The sulfenamide compounds produced in the following examples were all novel compounds, and the results of various spectra and elemental analysis were identified as main criteria. For compounds that are difficult to crystallize, p-nitrobenzaldehyde was reacted and subjected to elemental analysis as an imine compound derivative. Further, the produced compounds (4) to (10) correspond to the compound (4) shown above.
The physical property values are described in the order of melting point, nuclear magnetic resonance spectrum ( ¹ H-NMR), infrared absorption spectrum (IR), and elemental analysis value.

Production Example 1 Potassium hydroxide 2 was placed in a glass container having an internal volume of 100 ml.
2 mmol of methyl thiosalicylate was added to 20 ml of water in which 3 mmol of mmol was dissolved, and 3 mmol of HOSA dissolved in 20 ml of water in which 3 mmol of potassium hydroxide was dissolved was dropped on an ice bath. After stirring for 30 minutes under a nitrogen atmosphere, the precipitated white substance was filtered, dried, and recrystallized from methylene chloride-hexane to obtain a sulfenamide of the compound (4). Yield 72%; Melting point 88-89 ° C; ¹ H-NMR (CDCl ₃ ) 2.61 (brs,
2H), 3.91 (s, 3H), 7.15 (t, 1H, J = 7Hz), 7.56 (t, 1
H, J = 7Hz), 7.94 (d, 1H, J = 8Hz), 8.01 (d, 1H, J = 8H)
z); IR (KBr) 3391, 3299, 1701, 1271, 743 cm ^-1 . Elemental analysis value (%) as C ₈ H ₉ NO ₂ S Measurement value: C, 52.41, H, 4.91, N, 7.34 Calculated value: C, 52.44, H, 4.95, N, 7.69

Production Example 2 Potassium hydroxide 2 was placed in a glass container having an inner volume of 100 ml.
15 ml of water and 15 ml of ethanol
Was mixed with 2 mmol of ethyl thiosalicylate, and 3 mmol of HOSA dissolved in 20 ml of water in which 3 mmol of potassium hydroxide was dissolved was dropped on an ice bath. After stirring for 30 minutes in a nitrogen atmosphere, the mixture was extracted three times with 10 ml of methylene chloride. After the extract was dried over magnesium sulfate, the solvent was removed under reduced pressure, and the crude product was recrystallized from methylene chloride-hexane to obtain the sulfenamide of the compound (5). Yield 98%; melting point 74-75 ° C; ¹ H-NMR (CDCl ₃ ) 1.40 (t, 3
H, J = 7Hz), 2.62 (brs, 2H), 4.38 (q, 2H, J = 7Hz), 7.1
5 (t, 1H, J = 7Hz), 7.56 (t, 1H, J = 7Hz), 7.93 (d, 1
H, J = 8Hz), 8.03 (d, 1H, J = 8Hz); IR (KBr) 3370, 328
1, 1692, 1275, 754 cm ^-1 . Elemental analysis value as C ₉ H ₁₁ NO ₂ S (%) Measurement value: C, 54.57, H, 5.52, N, 6.74 Calculated value: C, 54.80, H, 5.62, N, 7.10

Production Example 3 A reaction was carried out in the same manner as in Production Example 2 except that propyl thiosalicylate was used in place of ethyl thiosalicylate to obtain a sulfenamide of the compound (6). Yield 85%; melting point (as a condensed compound with p-nitrobenzaldehyde) 156-157 ° C .; ¹ H-NMR (CDCl ₃ ) 1.03 (t, 3
H, J = 7Hz), 1.80 (hex, 2H, J = 7Hz), 2.61 (brs, 2H),
4.28 (t, 2H, J = 7Hz), 7.16 (t, 1H, J = 8Hz), 7.56 (t,
1H, J = 7Hz), 7.91 (d, 1H, J = 8Hz), 8.03 (d, 1H, J = 8
Hz); IR (KBr) 3393, 3308, 1699, 1269, 745 cm ^-1 . Condensation compound with p-nitrobenzaldehyde C ₁₇ H ₁₆ N ₂
Elemental analysis value as O ₄ S (%) Measurement value: C, 59.14, H, 4.60, N, 7.97 Calculated value: C, 59.28, H, 4.69, N, 8.14

Production Example 4 A reaction was carried out in the same manner as in Production Example 2 except that isopropyl thiosalicylate was used in place of ethyl thiosalicylate to obtain a sulfenamide of the compound (7). Yield 95%; melting point (as condensed compound with p-nitrobenzaldehyde) 140-141 ° C; ¹ H-NMR (CDCl ₃ ) 1.37 (d, 6
H, J = 6Hz), 2.62 (brs, 2H), 5.25 (hep, 1H, J = 6Hz),
7.15 (t, 1H, J = 7Hz), 7.55 (t, 1H, J = 8Hz), 7.91 (d,
1H, J = 8Hz), 8.01 (d, 1H, J = 8Hz); IR (KBr) 3391, 33
08, 1698, 1271, 1101, 747 cm ^-1 . Condensation compound with p-nitrobenzaldehyde C ₁₇ H ₁₆ N ₂
Elemental analysis value as O ₄ S (%) Measurement value: C, 58.82, H, 4.68, N, 7.90 Calculated value: C, 59.28, H, 4.69, N, 8.14

Preparation Example 5 In Preparation Example 1, instead of methyl thiosalicylate,
Production example 1 using methyl 5-dimethoxythiosalicylate
The reaction was carried out in the same manner as in the above to obtain a sulfenamide of the compound (8). Yield 72%; mp 148-150 ° C; ¹ H-NMR (CDCl ₃ ) 2.67 (br
s, 2H), 3.89 (s, 3H), 3.91 (s, 3H), 4.00 (s, 3H),
7.49 (s, 1H), 7.63 (s, 1H); IR (KBr) 3383, 3289, 16
90, 1503, 1429, 1263, 1181, 1105, 980, 775 cm ^-1 . Elemental analysis value (%) as C ₁₀ H ₁₃ NO ₄ S Measurement value: C, 49.21, H, 5.30, N, 5.38 Calculated value: C, 49.36, H, 5.40, N, 5.76

Examples 1 to 7 1 mmol of the sulfenamide compounds (4) to (7), 1 mmol of a base and 20 ml of a solvent were charged into a glass container having an internal volume of 50 ml, and the mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. The solvent was removed under reduced pressure, 20 ml of water was added, the mixture was neutralized with dilute hydrochloric acid, and then extracted three times with 10 ml of methylene chloride.
After the extract was dried over magnesium sulfate, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography using a mixed solvent of methylene chloride: acetone: methanol (100: 40: 8) as an eluent. The product obtained can be recrystallized from ethanol to further increase the purity. Thus obtained 1,2-benzisothiazolinone of the formula (9) was obtained. Melting point 1
58 ° C (literature 158-159 ° C); ¹ H-NMR (CDCl ₃ ) 7.41-7.46
(m, 1H), 7.61-7.68 (m, 2H), 8.08 (d, 1H, J = 8Hz); ¹³
C-NMR (CDCl ₃ ) 120.8, 124.3, 125.3, 125.9, 131.7, 14
4.8, 169.1; IR (KBr) 3057, 2917, 2697, 1640, 743, 6
08 cm ^-1 . Table 1 shows the respective yields.

[0025]

[Table 1]

Example 8 A sulfenamide compound (8) (1 mmol), potassium hydroxide (1 mmol), ethanol (20 ml) and methylene chloride (10 ml) were charged into a glass container having an inner volume of 50 ml, and the mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. The solvent was removed under reduced pressure, 20 ml of water was added, and the mixture was neutralized with dilute hydrochloric acid.
Extracted three times with methylene chloride. After the extract was dried over magnesium sulfate, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography using a mixed solvent of methylene chloride: acetone: methanol (100: 40: 8) as an eluent. The product obtained can be recrystallized from ethanol to further increase the purity. Thus, 1,2-benzisothiazolinone of the formula (10) was obtained. Yield 72%; Melting point 229-230 ° C (Literature 228-229 ° C); ¹ H-
NMR (CDCl ₃ ) 3.98 (s, 3H), 3.99 (s, 3), 7.02 (s, 1H),
7.44 (s, 1H); IR (KBr) 2932, 2666, 1644,1493, 128
1, 1044 cm ^-1 .

[0027]

According to the present invention, a 1,2-benzoisothiazolinone compound can be produced in good yield by subjecting a sulfenamide compound to intramolecular cyclocondensation in the presence of a base. Therefore, it can be produced safely without using a toxic gas, and is most suitable as an industrial method for synthesizing a 1,2-benzisothiazolidinone compound.

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[Procedure amendment]

[Submission date] December 16, 1999 (1999.12.
16)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claims

[Correction method] Change

[Correction contents]

[Claims]

Embedded image (Wherein, R ^{1 to} R ⁴ are hydrogen or sulfenamidated
A compound which represents an inert substituent in the reaction of intramolecular cyclocondensation of a compound of the formula (1), which comprises the general formula (3)

Embedded image (Wherein, R ^{1 to} R ⁴ are hydrogen or sulfenami
R ⁵ represents an inert substituent in the reaction of intramolecular cyclocondensation of a sulfide compound;
It represents a substituent that is inactive in the reaction of cyclizing condensation . )
A method for producing a 1,2-benzisothiazolinone compound by intramolecular cyclocondensation of a sulfenamide compound represented by the formula:

 ──────────────────────────────────────────────────続 き Continuing from the front page (72) Inventor Masao Shimizu 1-1-1, Higashi, Tsukuba, Ibaraki Pref. Material Engineering Research Institute (72) Inventor Isao Shibuya 1-1-1, Higashi, Tsukuba, Ibaraki Pref. (72) Inventor Yasuo Kama 1-1-1 Higashi, Tsukuba, Ibaraki Pref.

Claims (7)

[Claims] 1. A compound of the general formula (1) (Wherein, R ^{1 to} R ⁴ represent hydrogen or an inert substituent), which is a method for producing a 1,2-benzoisothiazolinone compound represented by the general formula (3): Wherein R ^{1 to} R ⁴ represent hydrogen or an inert substituent, and R ⁵ represents an inert substituent. , 2-
A method for producing a benzoisothiazolinone compound. 2. The method for producing a 1,2-benzoisothiazolinone compound according to claim 1, wherein the intramolecular cyclization condensation is carried out in the presence of a base. 3. The method for producing a 1,2-benzoisothiazolinone compound according to claim 1, wherein the base is uniformly present in the reaction system. 4. The 1,2-benzisothiazo according to any one of claims 1 to 3, wherein the base is an alkali metal hydroxide, an alkaline earth metal hydroxide, or an alkali metal alcoholate. A method for producing a linone compound. 5. The 1,2-compound according to any one of claims 1 to 4, wherein the intramolecular cyclization condensation is carried out in a solvent.
A method for producing a benzoisothiazolinone compound. 6. The method according to claim 1, wherein the solvent is methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, isobutanol, tert-butanol, pentanol, hexanol, diethyl ether, tetrahydrofuran, isopropyl ether, pyridine, acetonitrile, dimethylformamide. The method for producing a 1,2-benzoisothiazolinone compound according to any one of claims 1 to 5, wherein the compound is one or more selected ones. 7. The method according to claim 1, wherein the intramolecular cyclization condensation is carried out at a temperature of 0 ° C. to 100 ° C.
The method for producing a 1,2-benzoisothiazolinone compound according to any one of claims 1 to 6, which is preferably performed at 0 ° C to 30 ° C.