JP2010168311A - Method for producing 1,2-benzoisothiazolin-3-one compound - Google Patents

Abstract

【選択図】なし[PROBLEMS] To provide a commercially advantageous 1,2-benzisothiazolin-3-one compound, which is a useful compound for industrial antibacterial agents, etc., for producing a safe and high yield without using harmful reagents. Provide a method.
A 1,3-benzoxathin-4-one-1-oxide compound represented by the following general formula (B) is reacted with an alkylamine which may have a substituent, and the following general formula The 1,2-benzisothiazolin-3-one compound represented by (A) is produced.

[Selection figure] None

Description

  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 1,3-benzoxathin-4-one 1-oxide compound with an amine.

  1,2-Benzisothiazolin-3-one compounds are known to have various physiological activities. For example, 5-chloro and 6-chloro-1,2-benzisothiazolin-3-one have antibacterial and antibacterial activities. It is reported that there is (Non-patent Document 1). Furthermore, among various 1,2-benzisothiazole compounds derived from 1,2-benzisothiazolin-3-one, there are compounds that have various pharmacological actions, including those having substituents on the isothiazole ring moiety. It is an important compound that has been reported (Non-patent document 1, Non-patent document 2, Non-patent document 3). In addition, 1,2-benzisothiazolin-3-one compounds having a substituent on the nitrogen atom at the 2-position have antibacterial and antibacterial effects (Non-patent Documents 4 and 5) and platelet aggregation-preventing actions (non-patented) It is reported to show literature 6). Furthermore, 1,2-benzisothiazolin-3-one and 2-butyl-1,2-benzisothiazolin-3-one are commercially available as industrial antibacterial agents.

  Conventionally, 1,2-benzisothiazolin-3-one compounds are obtained by treating dithiosalicylic acid or thiosalicylic acid with chlorine or bromine and then reacting with amines (Patent Document 1, Patent Document 2, Patent Document 3, Patent Reference 4), a method of treating thiosalicylic acid esters with chlorine or bromine and then reacting with amines (Patent Document 5, Patent Document 6, Non-Patent Document 7), or a method of reacting thiosalicylic acid amides with chlorine ( Non-patent document 8, Non-patent document 9, Non-patent document 10, Non-patent document 11, Non-patent document 12, Non-patent document 13, Non-patent document 14, Patent document 7, Patent document 8) Toxic chlorine and bromine must be used, and there is also a problem of corrosion of the production equipment. Therefore, development of a safe production method is desired. Also, a method of producing from thiosalicylic acid and an azide compound (Non-patent Document 15), a method of producing from thiosalicylic acid amide and hypervalent iodine (Non-patent Document 16), or 1,2-benzodithiol-3-one or 1 , 2-Benzodithiol-3-one 1-oxide is also known (Non-patent document 17, Non-patent document 18), but these compounds are special reagents and are easily available. However, it is not suitable as an industrially implemented method. In the method of producing a 1,2-benzoxazolin-3-one compound by cyclization reaction of thiosalicyl hydroxamic acid (Patent Document 9), the substituent on the nitrogen at the 2-position is limited to hydrogen.

  From the above, when producing a 1,2-benzoxazolin-3-one compound, the desired 1,2-benzoxazolin-3-one can be produced safely without using toxic chlorine gas by a simple synthetic operation. The establishment of a method for producing a compound is eagerly desired.

U.S. Pat. No. 2870015 Belgian Patent No. 565380 Belgian Patent No. 617384 German Patent No. 1135468 JP-A-46-5516 German Patent No. 2119930 British Patent No. 848130 U.S. Pat. No. 3761489 Japanese Patent Application No. 10-176752

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  The present invention overcomes the disadvantage of using toxic chlorine gas, which is a common method, in producing 1,2-benzisothiazolin-3-one compounds, and produces 1,2-benzisothiazolin-3-one compounds. The purpose of the present invention is to provide an industrially advantageous method.

  As a result of intensive studies on a method for producing a 1,2-benzisothiazolin-3-one compound, the present inventors have reacted 1,3-benzooxathinin-4-one 1-oxide compound with amines. Thus, it was found that a 1,2-benzisothiazolin-3-one compound can be obtained safely and easily, and the present invention has been completed based on this finding.

（式中、Ｒ^１は水素原子、炭素数１〜１２のアルキル基、炭素数３〜１２のシクロアルキル基、炭素数７〜１２のアラルキル基、炭素数６〜１２の芳香族基あるいはピリジル基を示す。Ｒ^２〜Ｒ^５は、水素原子、炭素数１〜８のアルキル基、炭素数１〜８のアルコキシル基、ハロゲン原子、あるいはニトロ基を示す。）

（式中、Ｒ^２〜Ｒ^５は、炭素数１〜８のアルキル基、炭素数１〜８のアルコキシル基、ハロゲン原子、あるいはニトロ基を示す。Ｒ^６、Ｒ^７は、水素原子、炭素数１〜１２のアルキル基、炭素数３〜１２のシクロアルキル基、あるいは炭素数６〜１２の芳香族基を示す。また、Ｒ^６、Ｒ^７は連結して環を形成してもよい。）

（式中、Ｒ^１は水素原子、炭素数１〜１２のアルキル基、炭素数３〜１２のシクロアルキル基、炭素数７〜１２のアラルキル基、炭素数６〜１２の芳香族基あるいはピリジル基を示す。） That is, this application provides the following invention.
(1) In a method for producing a 1,2-benzisothiazolin-3-one compound represented by the following general formula (A), 1,3-benzoxathin-4-yl represented by the following general formula (B) A method for producing a 1,2-benzisothiazolin-3-one compound, comprising reacting an on 1-oxide compound with an amine represented by the general formula (C).

(In the formula, R ¹ is a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 12 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, an aromatic group having 6 to 12 carbon atoms, or a pyridyl group. R ^{2 to} R ⁵ represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxyl group having 1 to 8 carbon atoms, a halogen atom, or a nitro group.

(In the formula, R ^{2 to} R ⁵ represent an alkyl group having 1 to 8 carbon atoms, an alkoxyl group having 1 to 8 carbon atoms, a halogen atom, or a nitro group. R ⁶ and R ⁷ represent a hydrogen atom and a carbon number. 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, and R ⁶ and R ⁷ may be linked to form a ring.

(In the formula, R ¹ is a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 12 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, an aromatic group having 6 to 12 carbon atoms, or a pyridyl group. Is shown.)

  By the reaction of the 1,2-benzisothiazolin-3-one compound and amines in the present invention, the 1,2-benzisothiazolin-3-one compound can be produced with high yield. Moreover, since it can be produced safely without using toxic chlorine gas, it is optimal as an industrial method for synthesizing 1,2-benzisothiazolin-3-one compounds. Further, the 1,2-benzoxazolin-3-one compound obtained in the present invention can be used as an antibacterial agent as in the conventional case.

The method for producing a 1,2-benzisothiazolin-3-one compound represented by the following general formula (A) of the present invention is a 1,3-benzoxathin-4-one represented by the following general formula (B). It is characterized by reacting an amine represented by the following general formula (C) with an -oxide compound.

In the general formula (A), R ¹ is a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 12 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, or an aromatic group having 6 to 12 carbon atoms. Group or pyridyl group.
These alkyl groups may have a substituent such as a hydroxyl group, an alkoxyl group, or a dialkylamino group. Specific examples of the alkyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, t-butyl group, hexyl group, octyl group, decyl group, dodecyl group, hydroxyethyl group, ethoxyethyl group, Examples thereof include a hydroxypropyl group. Specific examples of the cycloalkyl group include a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, and a cyclooctyl group. Specific examples of the aralkyl group include a benzyl group, a cumyl group, and a phenethyl group. Specific examples of the aromatic group include a phenyl group and a naphthyl group. These aromatic groups may have a substituent such as a halogen atom, an alkyl group, an alkoxyl group, or a dialkylamino group. Good. Examples of the pyridyl group include a 2-pyridyl group, a 3-pyridyl group, and a 4-pyridyl group.

R ^{2 to} R ⁵ represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxyl group having 1 to 8 carbon atoms, a halogen atom, or a nitro group. Specific examples of the alkyl group include methyl group, ethyl group, propyl group, isopropyl group, pentyl group, butyl group, s-butyl group, t-butyl group, hexyl group and the like. Specific examples of the alkoxyl group include methoxy group, ethoxy group, propoxy group, isopropoxy group, cyclohexyloxy group and the like.

In the general formula (B), R ^{2 to} R ⁵ are the same as R ^{2 to} R ⁵ in the general formula (A).
R ⁶ and R ⁷ represent a hydrogen atom, 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. R ⁶ and R ⁷ may be linked to form a ring. Specific examples of the alkyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, t-butyl group, hexyl group, octyl group, decyl group, dodecyl group, hydroxyethyl group, ethoxyethyl group, Examples thereof include a hydroxypropyl group. Specific examples of the cycloalkyl group include a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, and a cyclooctyl group. Specific examples of the aromatic group include a phenyl group and a naphthyl group. These aromatic groups may have a substituent such as a halogen atom, an alkyl group, an alkoxyl group, or a dialkylamino group. Good. Specific examples of R ⁶ and R ⁷ linked to form a ring include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

In the general formula (C), R ¹ is the same as R ¹ in the general formula (A).

すなわち、2-エチル-1,3-ベンゾオキサチイン-4-オンがプロピオンアルデヒドのチオサリチル酸の環状アセタールとみなすことができるのと同様に、2-エチル-1,3-ベンゾオキサチイン-4-オン 1-オキシドは、プロピオンアルデヒドの2-ヒドロスルフィニル安息香酸の環状アセタールとみなすことができる。したがって、この環状アセタールがアミン類の攻撃によりアセタールの交換反応が起こった後、アルデヒドの再生が起こるとヒドロスルフェニル基が生じることとなるが、このヒドロスルフェニル基は不安定なことよりスルフェン酸に異性化する。スルフェン酸自体もそれほど安定な置換基ではないので、分子内で脱水環化が起こって1,2-ベンゾイソチアゾリン-3-オン化合物が生成する。
したがって、この反応機構等からみて、一般式（Ｂ）で示される化合物として、Ｒ^２〜Ｒ^５が水素原子を用いた化合物（ｂ）だけでなく、該置換基が、炭素数１〜８のアルキル基、炭素数１〜８のアルコキシル基、ハロゲン原子、ニトロ基である化合物を用いた場合にもこれと同様な反応を示すこと、また同様にＲ^６がエチル基、Ｒ^７が水素原子の場合だけでなく、炭素数１〜１２のアルキル基、炭素数３〜１２のシクロアルキル基、あるいは炭素数６〜１２の芳香族基の場合にも上記と同様な反応を示すことは明らかである。
また、他方の原料である一般式（Ｃ）で示される化合物として、Ｒ^１がｎ−ブチルである化合物（ｃ）だけでなく、Ｒ^１が、水素原子、炭素数１〜１２のアルキル基、炭素数３〜１２のシクロアルキル基、炭素数７〜１２のアラルキル基、炭素数６〜１２の芳香族基、あるいはピリジル基の場合の化合物も上記と同様な反応を示すことは明白である。 A novel synthetic reaction for obtaining a 1,2-benzisothiazolin-3-one compound from a 1,3-benzoxathin-4-one 1-oxide compound and an amine compound according to the present invention has not been found so far It is a thing.
The reaction mechanism of this new reaction is represented by 2-ethyl-1,3-benzooxathin-4-one 1-oxide (b) (general formula (B): R ^{2 to} R ⁵ = hydrogen atom, R ⁶ = ethyl group , R ⁷ = hydrogen atom) and n-butylamine (c) (general formula (C): R ¹ = n-butyl) are reacted to give 2-butyl-1,2-benzisothiazolin-3-one (a) A case of synthesizing (general formula A: R ^{2 to} R ⁵ = hydrogen atom, R ¹ = n-butyl) will be described as an example.
This reaction proceeds by the following reaction mechanism.

That is, in the same way that 2-ethyl-1,3-benzooxathin-4-one can be regarded as a cyclic acetal of propionaldehyde thiosalicylic acid, On 1-oxide can be regarded as a cyclic acetal of 2-hydrosulfinylbenzoic acid of propionaldehyde. Therefore, after this cyclic acetal undergoes an acetal exchange reaction by the attack of amines, a hydrosulfenyl group is formed when the aldehyde is regenerated. Isomerized. Since sulfenic acid itself is not a very stable substituent, dehydration cyclization occurs in the molecule to produce a 1,2-benzisothiazolin-3-one compound.
Therefore, in view of this reaction mechanism and the like, as a compound represented by the general formula (B), not only the compound (b) in which R ^{2 to} R ⁵ use a hydrogen atom but also the substituent has 1 to 8 carbon atoms. Even when a compound that is an alkyl group, an alkoxyl group having 1 to 8 carbon atoms, a halogen atom, or a nitro group is used, the same reaction is exhibited. Similarly, R ⁶ is an ethyl group, and R ⁷ is a hydrogen atom. It is clear that the reaction similar to the above is exhibited not only in the case but also in the case of 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. .
Further, as the compound represented by the general formula (C) as the other raw material, not only the compound (c) in which R ¹ is n-butyl, but also R ¹ is a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, It is apparent that compounds having a cycloalkyl group having 3 to 12 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, an aromatic group having 6 to 12 carbon atoms, or a pyridyl group exhibit the same reaction as described above.

  This novel synthesis reaction of the present invention is preferably carried out in the presence of a reaction solvent, in which case the reaction solvent is methylene chloride, chloroform, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, anisole, acetonitrile, The reaction is carried out in a solvent such as tetrahydrofuran or 1,4-dioxane. These solvents are used alone or in the form of a mixed solvent.

  Although the temperature in the production method can be carried out at a temperature in the vicinity of 20 ° C. to 150 ° C., if the temperature is too low, the reaction time will be slow, and if it is too high, decomposition reactions and side reactions will increase. It is preferable to carry out in a range. The reaction time depends on the reaction temperature and cannot be determined in general, but usually 2 to 8 hours is sufficient.

(B) and (C), which are raw materials for the reaction, are known substances.
An example of the production method (B) is a production method in which a known 1,3-benzoxathin-4-one compound is oxidized with sodium periodate or metachloroperbenzoic acid.
(C) may be a commercially available compound.

When the typical example of the benzoxathiin compound obtained by the method of the present invention is exemplified, compounds represented by the following chemical formulas (1) to (40) may be mentioned. However, of course, the present invention is not limited to the production methods of these compounds in view of the above reaction mechanism and the like.

  The compound obtained by the method of the present invention is used as an antibacterial agent as in the prior art.

Next, the present invention will be described in detail with reference to examples.
Examples described below are examples of typical compounds for facilitating the understanding of the present invention, and the present invention is not limited thereto. Further, the produced compounds (1) to (16) correspond to the compounds (1) to (16) shown above, and their physical property values include boiling point or melting point, nuclear magnetic resonance spectrum ( ¹ H -NMR, ¹³ C-NMR) and infrared absorption spectrum (IR), respectively.

Example 1
2-ethyl-1,3-benzoxathin-4-one 1-oxide (210 mg, 1.0 mmol) was dissolved in toluene (10 mL) in a glass container having an internal volume of 25 mL, and n-butylamine (219 mg, 3 0.0 mmol) and heated to 50 ° C. and stirred for 2 hours. The solvent was distilled off under reduced pressure, and this was separated and purified by silica gel column chromatography (solvent, methylene chloride: ethyl acetate = 10: 1), and the target compound 2-butyl-1,2-benzisothiazoline-3-one (1) was obtained (yield: 89%).
Boiling point: 180 ℃ (1.1 × 10 ² Pa).
¹ H NMR (CDCl ₃ , 500 MHz) δ 0.97 (3H, t, J = 7.3 Hz), 1.42 (2H, sextet, J = 7.3 Hz), 1.75 (2H, quintet, J = 7.3 Hz), 3.90 (2H , t, J = 7.3 Hz), 7.40 (1H, t, J = 7.3 Hz), 7.55 (1H, d, J = 8.5 Hz), 7.60 (1H, t, J = 7.3 Hz), 8.04 (1H, d , J = 7.3 Hz).

Example 2
2-ethyl-1,3-benzoxathin-4-one 1-oxide (210 mg, 1.0 mmol) was dissolved in toluene (10 mL) in a glass sealed tube container having an internal volume of 20 mL, and t-butylamine (219 mg) was dissolved. 3.0 mmol), heated to 110 ° C. and stirred for 7 hours. The solvent was distilled off under reduced pressure, and this was separated and purified by silica gel column chromatography (solvent, methylene chloride: acetone: methanol = 100: 5: 1) to give the target compound 2-t-butyl-1,2-benzoate. Isothiazolin-3-one (2) was obtained (yield: 59%).
bp 150 ° C (1.8 × 10 ² Pa).
¹ H NMR (CDCl ₃ , 500 MHz) δ1.71 (9H, s), 7.36 (1H, t, J = 7.3 Hz), 7.50 (1H, d, J = 8.5 Hz), 7.57 (1H, t, J = 7.3 Hz), 7.96 (1H, d, J = 8.5 Hz).

Example 3
2-ethyl-1,3-benzoxathin-4-one 1-oxide (210 mg, 1.0 mmol) was dissolved in toluene (10 mL) in a glass container having an internal volume of 25 mL, and cyclohexylamine (297 mg, 3. 0 mmol) was added and the mixture was heated to reflux for 2 hours. The solvent was distilled off under reduced pressure, and this was separated and purified by silica gel column chromatography (solvent, methylene chloride: ethyl acetate = 10: 1), and the target compound 2-cyclohexyl-1,2-benzisothiazolin-3-one (3) was obtained (yield: 80%).
mp 87.2-88.0 ° C (recrystallized from hexane).
¹ H NMR (CDCl ₃ , 500 MHz) δ1.17 − 1.27 (1H, m), 1.43 − 1.60 (4H, m), 1.74 (1H, d, J = 12.2 Hz), 1.85 − 1.90 (2H, m) , 2.05 (2H, dd, J = 11.0, 3.7 Hz), 4.60 (1H, tt, J = 11.6, 3.9 Hz), 7.39 (1H, t, J = 7.3 Hz), 7.55-7.60 (2H, m), 8.04 (1H, d, J = 8.5 Hz).
¹³ C NMR (CDCl ₃ , 125 MHz) δ25.2, 25.6, 32.9, 53.2, 120.3, 125.3, 125.5, 126.5, 131.4, 140.3, 164.8.

Example 4
2-ethyl-1,3-benzoxathin-4-one 1-oxide (210 mg, 1.0 mmol) was dissolved in toluene (10 mL) in a glass container having an internal volume of 25 mL, and aminoethanol (183 mg, 3. 0 mmol) was added and the mixture was heated to 50 ° C. and stirred for 3 hours. The solvent was distilled off under reduced pressure, and this was separated and purified by silica gel column chromatography (solvent, methylene chloride: acetone: methanol = 100: 40: 8), and the target compound 2- (2-hydroxy) ethyl-1, 2-Benzoisothiazolin-3-one (4) was obtained (yield: 68%).
mp 110.6-112.0 ° C (recrystallized from ethyl acetate-hexane).
¹ H NMR (CDCl ₃ , 500 MHz) δ3.48 (1H, br s), 3.95 (2H, q, J = 4.9 Hz), 4.03 (2H, t, J = 5.5 Hz), 7.38 (1H, t, J = 7.3 Hz), 7.53 (1H, d, J = 7.3 Hz), 7.60 (1H, t, J = 7.3 Hz), 8.00 (1H, d, J = 8.5 Hz).

Example 5
2-ethyl-1,3-benzoxathin-4-one 1-oxide (210 mg, 1.0 mmol) was dissolved in toluene (10 mL) in a glass container having an internal volume of 25 mL, and 3-amino-1-propanol was dissolved. (225 mg, 3.0 mmol) was added, and the mixture was heated to 50 ° C. and stirred for 2 hours. The solvent was distilled off under reduced pressure, and this was separated and purified by silica gel column chromatography (solvent, methylene chloride: acetone: methanol = 100: 40: 8) to give the target compound 2- (3-hydroxy) propyl-1, 2-Benzoisothiazolin-3-one (5) was obtained (yield: 83%).
mp 75.3-76.6 ℃ (Recrystallized from ethyl acetate-hexane).
¹ H NMR (CDCl ₃ , 500 MHz) δ1.92 (2H, quint, J = 6.1 Hz), 3.57 (2H, q, J = 6.1 Hz), 3.62-3.65 (1H, m), 4.08 (2H, t , J = 6.1 Hz), 7.44 (1H, t, J = 7.9 Hz), 7.58 (1H, d, J = 8.5 Hz), 7.64 (1H, d, J = 7.3 Hz), 8.05 (1H, d, J = 7.3 Hz).
¹³ C NMR (CDCl ₃ , 125 MHz) δ31.9, 40.4, 57.8, 120.4, 124.1, 125.7, 126.8, 132.0, 140.3, 166.4.

Example 6
An ammonia dioxane solution (ammonia, equivalent to 5.0 mmol) was added to 2-ethyl-1,3-benzoxathin-4-one 1-oxide (210 mg, 1.0 mmol) in a glass sealed tube container with an internal volume of 20 mL. The mixture was heated to 50 ° C. and stirred for 6 hours. The solvent was distilled off under reduced pressure, and this was separated and purified by silica gel column chromatography (solvent, methylene chloride: acetone: methanol = 100: 20: 4), and the target compound 1,2-benzisothiazolin-3-one ( 6) was obtained (yield: 43%).
mp 153.3-155.9 ° C (recrystallized from ethyl acetate-hexane).
¹ H NMR (CDCl ₃ , 500 MHz) δ 7.45 (1H, ddd, J = 7.8, 5.0, 3.2 Hz), 7.65-7.66 (2H, m), 8.08 (1H, dt, J = 8.1, 1.0 Hz).

Example 7
2-ethyl-1,3-benzoxathin-4-one 1-oxide (210 mg, 1.0 mmol) was dissolved in toluene (10 mL) in a glass container having an internal volume of 25 mL, and benzylamine (322 mg, 3. 0 mmol) was added and the mixture was heated to 50 ° C. and stirred for 2 hours. The solvent was distilled off under reduced pressure, and this was separated and purified by silica gel column chromatography (solvent, methylene chloride: ethyl acetate = 20: 1), and the target compound 2-benzyl-1,2-benzoisothiazoline-3-one (7) was obtained (yield: 91%).
Melting point: 87.0-87.7 ° C (recrystallized from ethyl acetate-hexane).
¹ H NMR (CDCl ₃ , 500 MHz) δ5.06 (2H, s), 7.31 − 7.36 (5H, m), 7.41 (1H, t, J = 7.3 Hz), 7.49 (1H, d, J = 7.3 Hz ), 7.59 (1H, t, J = 7.3 Hz), 8.07 (1H, d, J = 7.3 Hz).
¹³ C NMR (CDCl ₃ , 125 MHz) δ47.5, 120.4, 124.5, 126.8, 128.3, 128.4, 128.8, 131.8, 136.2, 140.4, 165.3.

Example 8
2-ethyl-1,3-benzoxathin-4-one 1-oxide (210 mg, 1.0 mmol) was dissolved in toluene (10 mL) in a glass container having an internal volume of 25 mL, and 2-phenylethylamine (364 mg, 3.0 mmol) was added and heated to 50 ° C. and stirred for 2 hours. The solvent was distilled off under reduced pressure, and this was separated and purified by silica gel column chromatography (solvent, methylene chloride: ethyl acetate = 10: 1), and the target compound 2- (2-phenylethyl) -1,2-benzoate was obtained. Isothiazolin-3-one (8) was obtained (yield: 84%).
¹ H NMR (CDCl ₃ , 500 MHz) δ3.07 (2H, t, J = 7.9 Hz), 4.13 (2H, t, J = 7.3 Hz), 7.22-7.26 (3H, m), 7.30 (2H, t , J = 7.3 Hz), 7.39 (1H, t, J = 7.9 Hz), 7.51 (1H, d, J = 8.5 Hz), 7.59 (1H, t, J = 7.3 Hz), 8.03 (1H, d, J = 8.5 Hz).
¹³ C NMR (CDCl ₃ , 125 MHz) δ35.6, 45.4, 120.3, 124.6, 125.4, 126.6, 126.8, 128.7, 128.9, 131.7, 137.7, 140.2, 165.3.

Example 9
2-ethyl-1,3-benzoxathin-4-one 1-oxide (210 mg, 1.0 mmol) was dissolved in toluene (10 mL) in a glass container having an internal volume of 25 mL, and 1-phenylethylamine (364 mg, 3.0 mmol) and heated to 80 ° C. and stirred for 4 hours. The solvent was distilled off under reduced pressure, and this was separated and purified by silica gel column chromatography (solvent, methylene chloride: ethyl acetate = 20: 1) to give the target compound 2- (1-phenylethyl) -1,2-benzoate. Isothiazolin-3-one (9) was obtained (yield: 96%).
bp 250 ° C (1.6 × 10 ² Pa).
¹ H NMR (CDCl ₃ , 500 MHz) δ1.80 (3H, d, J = 7.3 Hz), 6.07 (1H, q, J = 6.9 Hz), 7.32 (1H, t, J = 7.3 Hz), 7.38 ( 3H, q, J = 7.9 Hz), 7.43 (2H, d, J = 7.3 Hz), 7.48 (1H, t, J = 8.5 Hz), 7.57 (1H, t, J = 8.5 Hz), 8.05 (1H, d, J = 8.5 Hz).
¹³ C NMR (CDCl ₃ , 125 MHz) δ 19.1, 52.2, 120.4, 125.1, 125.4, 126.6, 127.3, 128.2, 128.7, 131.6, 140.2, 140.4, 165.0.
IR (KBr) ν _max 1655, 1593, 1447, 1324, 1305, 1241, 1188, 741, 699, 673, 570 cm ^-1 .

Example 10
2-ethyl-1,3-benzoxathin-4-one 1-oxide (210 mg, 1.0 mmol) was dissolved in toluene (10 mL) in a glass container having an internal volume of 25 mL, and cumylamine (405 mg, 3.0 mmol) was dissolved. ) And heated to reflux for 8 hours. The solvent was distilled off under reduced pressure, and this was separated and purified by silica gel column chromatography (solvent, methylene chloride: ethyl acetate = 20: 1), and the target compound 2-cumyl-1,2-benzisothiazolin-3-one (10) was obtained (yield: 36%).
mp 130.8-131.9 ° C (recrystallized from ethyl acetate-hexane).
¹ H NMR (CDCl ₃ , 500 MHz) δ1.85 (6H, s), 6.34 (1H, s), 7.22 (1H, t, J = 7.3 Hz), 7.26 (1H, t, J = 7.3 Hz), 7.33 (1H, t, J = 8.5 Hz), 7.36 (1H, t, J = 7.3 Hz), 7.50 (3H, d, J = 7.3 Hz), 7.72 (1H, d, J = 8.5 Hz).
¹³ C NMR (CDCl ₃ , 125 MHz) δ29.0, 56.9, 124.8, 126.3, 126.9, 127.4, 127.6, 128.5, 131.0, 135.4, 136.6, 146.5, 166.8.

Example 11
2-ethyl-1,3-benzoxathin-4-one 1-oxide (210 mg, 1.0 mmol) was dissolved in toluene (10 mL) in a glass container having an internal volume of 25 mL, and aniline (279 mg, 3.0 mmol) was dissolved. ) And heated to reflux for 7 hours. The solvent was distilled off under reduced pressure, and this was separated and purified by silica gel column chromatography (solvent, methylene chloride: ethyl acetate = 20: 1), and the target compound 2-phenyl-1,2-benzisothiazoline-3-one (11) was obtained (yield: 75%).
mp 138.5-140.3 ° C (recrystallized from ethyl acetate-hexane).
¹ H NMR (CDCl ₃ , 500 MHz) δ7.33 (1H, t, J = 7.3 Hz), 7.44-7.49 (3H, m), 7.59 (1H, d, J = 7.3 Hz), 7.67 (1H, t , J = 7.3 Hz), 7.71 (2H, d, J = 8.5 Hz), 8.11 (1H, d, J = 8.5 Hz).
¹³ C NMR (CDCl ₃ , 125 MHz) δ120.1, 124.6, 124.8, 125.8, 127.0, 127.2, 129.3, 132.3, 137.2, 139.9, 164.1.

Example 12
2-ethyl-1,3-benzoxathin-4-one 1-oxide (210 mg, 1.0 mmol) was dissolved in toluene (10 mL) in a glass container having an internal volume of 25 mL, and p-methoxyaniline (369 mg, 3.0 mmol) was added, and the mixture was heated to reflux for 4 hours. The solvent was distilled off under reduced pressure, and this was separated and purified by alumina column chromatography (solvent, methylene chloride: hexane = 2: 1) to give the target compound 2- (p-methoxyphenyl) -1,2-benzisothiazoline. -3-one (12 was obtained (yield: 74%).
mp 146.2-147.5 ° C (recrystallized from ethyl acetate-hexane).
¹ H NMR (CDCl ₃ , 500 MHz) δ3.85 (3H, s), 6.99 (2H, dd, J = 7.3, 2.4 Hz), 7.45 (1H, t, J = 7.3 Hz), 7.55 (2H, dd , J = 8.5, 3.7 Hz), 7.58 (1H, d, J = 7.3 Hz), 7.66 (1H, t, J = 7.3 Hz), 8.10 (1H, d, J = 7.3 Hz).
¹³ C NMR (CDCl ₃ , 125 MHz) δ55.6, 114.6, 120.1, 124.6, 125.7, 126.9, 127.2, 129.7, 132.2, 140.0, 158.7, 164.3.

Example 13
2-ethyl-1,3-benzoxathin-4-one 1-oxide (210 mg, 1.0 mmol) was dissolved in toluene (10 mL) in a glass container having an internal volume of 25 mL, and p-methylaniline (321 mg, 3.0 mmol) was added and heated to reflux for 6 hours. The solvent was distilled off under reduced pressure, and this was separated and purified by silica gel column chromatography (solvent, methylene chloride: ethyl acetate = 20: 1) to obtain the target compound 2- (p-methylphenyl) -1,2-benzoate. Isothiazolin-3-one (13) was obtained (yield: 76%).
mp 136.1-136.7 ° C (recrystallized from ethyl acetate-hexane).
¹ H NMR (CDCl ₃ , 500 MHz) δ2.40 (3H, s), 7.27 (2H, d, J = 8.2 Hz), 7.44 (1H, ddd, J = 8.2, 6.9, 0.9 Hz), 7.55-7.59 (3H, m), 7.66 (1H, ddd, J = 8.2, 6.9, 0.9 Hz), 8.10 (1H, dt, J = 8.2, 0.9 Hz).

Example 14
2-ethyl-1,3-benzoxathin-4-one 1-oxide (210 mg, 1.0 mmol) was dissolved in toluene (10 mL) in a glass container having an internal volume of 25 mL, and p-chloroaniline (383 mg, 3.0 mmol) was added and the mixture was heated to reflux for 8 hours. The solvent was distilled off under reduced pressure, and this was separated and purified by silica gel column chromatography (solvent, methylene chloride: ethyl acetate = 5: 1) to give the target compound 2- (p-chlorophenyl) -1,2-benzoisothiazoline. -3-one (14) was obtained (yield: 75%).
mp 122.6-124.0 ° C (recrystallized from ethyl acetate).
¹ H NMR (CDCl ₃ , 500 MHz) δ7.43-7.49 (3H, m), 7.59 (1H, d, J = 8.5 Hz), 7.67 (3H, d, J = 8.5 Hz), 8.10 (1H, d , J = 8.5 Hz).
¹³ C NMR (CDCl ₃ , 125 MHz) δ120.1, 124.6, 125.6, 126.0, 127.3, 129.5, 132.5, 132.6, 135.8, 139.6, 164.1.

Example 15
2-ethyl-1,3-benzoxathin-4-one 1-oxide (210 mg, 1.0 mmol) was dissolved in toluene (10 mL) in a glass container having an internal volume of 25 mL, and 2-aminopyridine (282 mg, 3.0 mmol) was added and the mixture was heated to reflux for 8 hours. The solvent was distilled off under reduced pressure, and this was separated and purified by silica gel column chromatography (solvent, methylene chloride: ethyl acetate = 20: 1) to obtain the target compound 2- (2-pyridyl) -1,2-benzisothiazoline. -3-one (15) was obtained (yield: 45%).
mp 197.4-197.9 ° C (recrystallized from ethyl acetate-hexane).
¹ H NMR (CDCl ₃ , 500 MHz) δ7.15 (1H, ddd, J = 7.3, 4.9, 0.9 Hz), 7.41 (1H, ddd, J = 7.9, 7.0, 0.9 Hz), 7.59 (1H, dt, J = 8.2, 0.9 Hz), 7.66 (1H, ddd, J = 8.2, 7.0, 1.1 Hz), 7.81 (1H, ddd, J = 8.5, 7.3, 1.8 Hz), 8.07 (1H, dt, J = 7.9, 0.9 Hz), 8.42 (1H, ddd, J = 4.9, 1.8, 0.9 Hz), 8.75 (1H, dt, J = 8.5, 0.9 Hz).
¹³ C NMR (CDCl ₃ , 125 MHz) δ114.5, 120.3, 120.7, 125.5, 126.6, 126.8, 132.8, 138.4, 141.0, 147.6, 150.4, 164.0.

Example 16
2-ethyl-7-methoxy-1,3-benzoxathin-4-one 1-oxide (240 mg, 1.0 mmol) was dissolved in methylene chloride (10 mL) in a glass container having an internal volume of 25 mL, and benzylamine was dissolved. (322 mg, 3.0 mmol) was added, and the mixture was heated to 50 ° C. and stirred for 3 hours. The solvent was distilled off under reduced pressure, and this was separated and purified by silica gel column chromatography (solvent, methylene chloride: ethyl acetate = 20: 1), and the target compound 2-benzyl-6-methoxy-1,2-benzisothiazoline was obtained. -3-one (16) was obtained (yield: 100%).
mp 114.4-115.0 ℃ (Recrystallized from ethyl acetate-hexane).
¹ H NMR (CDCl ₃ , 500 MHz) δ3.86 (3H, s), 5.02 (2H, s), 6.90 (1H, d, J = 2.1 Hz), 6.96 (1H, dd, J = 8.7, 2.3 Hz ), 7.30-7.37 (5H, m), 7.95 (1H, d, J = 8.8 Hz).
¹³ C NMR (CDCl ₃ , 125 MHz) δ47.5, 55.8, 103.1, 114.6, 117.7, 127.9, 128.2, 128.4, 128.8, 136.4, 142.6.
Calcd _{C 15 H 13 NO 2 S:} C, 66.40; H, 4.83; N, 5.16.
Found C, 65.22; H, 4.64; N, 5.00.

Example 17
2-Isopropyl-1,3-benzoxathin-4-one 1-oxide (224 mg, 1.0 mmol) was dissolved in toluene (10 mL) in a glass container having an internal volume of 25 mL, and benzylamine (322 mg, 3. 0 mmol) was added and the mixture was heated to 50 ° C. and stirred for 2 hours. The solvent was distilled off under reduced pressure, and this was separated and purified by silica gel column chromatography (solvent, methylene chloride: ethyl acetate = 20: 1), and the target compound 2-benzyl-1,2-benzoisothiazoline-3-one (7) was obtained (yield: 82%).

Example 18
In a glass container having an internal volume of 25 mL, 2-phenyl-1,3-benzoxathin-4-one 1-oxide (258 mg, 1.0 mmol) was dissolved in toluene (10 mL), and benzylamine (214 mg, 2.. 0 mmol) was added and the mixture was heated to 50 ° C. and stirred for 3 hours. The solvent was distilled off under reduced pressure, and this was separated and purified by silica gel column chromatography (solvent, methylene chloride: ethyl acetate = 20: 1), and the target compound 2-benzyl-1,2-benzoisothiazoline-3-one (7) was obtained (yield: 93%).

Example 19
1,3-Benzoxathin-4-one 1-oxide (182 mg, 1.0 mmol) was dissolved in toluene (10 mL) in a glass container having an internal volume of 25 mL, and benzylamine (214 mg, 2.0 mmol) was added. The mixture was heated to 50 ° C. and stirred for 2 hours. The solvent was distilled off under reduced pressure, and this was separated and purified by silica gel column chromatography (solvent, methylene chloride: ethyl acetate = 20: 1), and the target compound 2-benzyl-1,2-benzoisothiazoline-3-one (7) was obtained (yield: 92%).

Example 20
2,2-Dimethyl-1,3-benzoxathin-4-one 1-oxide (210 mg, 1.0 mmol) was dissolved in toluene (10 mL) in a glass container having an internal volume of 25 mL, and benzylamine (214 mg, 2.0 mmol) was added and the mixture was heated to 50 ° C. and stirred for 2 hours. The solvent was distilled off under reduced pressure, and this was separated and purified by silica gel column chromatography (solvent, methylene chloride: ethyl acetate = 20: 1), and the target compound 2-benzyl-1,2-benzoisothiazoline-3-one (7) was obtained (yield: 84%).

Claims (1)

In a method for producing a 1,2-benzisothiazolin-3-one compound represented by the following general formula (A), 1,3-benzoxathinin-4-one represented by the following general formula (B) 1- A process for producing a 1,2-benzisothiazolin-3-one compound, comprising reacting an oxide compound with an amine represented by the general formula (C).

(In the formula, R ¹ is a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 12 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, an aromatic group having 6 to 12 carbon atoms, or pyridyl. R ^{2 to} R ⁵ represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxyl group having 1 to 8 carbon atoms, a halogen atom, or a nitro group.

(In the formula, R ^{2 to} R ⁵ represent an alkyl group having 1 to 8 carbon atoms, an alkoxyl group having 1 to 8 carbon atoms, a halogen atom, or a nitro group. R ⁶ and R ⁷ represent a hydrogen atom and a carbon number. 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, and R ⁶ and R ⁷ may be linked to form a ring.

(In the formula, R ¹ is a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 12 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, an aromatic group having 6 to 12 carbon atoms, or pyridyl. Group.)