JP2018127411A - Indolobenzothiazine compounds and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide indolobenzothiazine-5-oxide and indolobenzothiazine-5,5-dioxide compounds, and methods for producing the same.SOLUTION: An indolobenzothiazine compound having a sulfide bond is reacted with an oxidizing agent to produce an indolobenzothiazine compound having a sulfone bond or sulfoxide bond, represented by formula (A) (R-Rare H, a C1-6 alkyl group, a C1-6 alkoxyl group, a halogen atom, a nitro group or a cyano group, where Rand R, Rand Ror Rand Rmay be coupled to form a ring; n is 1 or 2).SELECTED DRAWING: None

Description

  The present invention relates to a novel indolobenzothiazine compound and a method for producing the same.

  It has been reported that sulfonamide compounds having a nitrogen-sulfur (VI) bond in the molecule have antibacterial action, herbicidal activity, and various physiological activities (Non-patent Document 1). Similarly, a sulfinamide compound having a nitrogen-sulfur (IV) bond has been reported as a derivative having physiological activity such as a blood pressure lowering effect (Non-patent Document 2). The indole skeleton is a basic constituent skeleton of many physiologically active compounds regardless of natural or synthetic (Patent Document 1, Non-Patent Document 3). N-sulfonyl indole substituted on the nitrogen atom with a sulfonyl group can be regarded as a compound having both the sulfonamide and indole structures described above. Similarly, N-sulfinylindole substituted on the nitrogen atom with a sulfinyl group can be regarded as a compound having both the above sulfinamide and indole structures.

The present inventors have previously found and reported that an indolobenzothiazine compound, which is a tetracyclic heterocyclic compound, can be produced by a reaction of pyrrolobenzothiazine and 2,5-dimethoxytetrahydrofuran (non-patent document). Reference 4). In the indolopyridine benzothiazine compounds, thiazine ring -S- is -SO ₂ - as long obtained indolopyridine benzothiazine 5,5-dioxide compounds substituted in the a N- sulfonyl indole moiety in the molecule Therefore, it can be expected to have the same function as sulfonamide. Similarly, if an indolobenzothiazine-5-oxide compound in which -S- of the thiazine ring is substituted with -SO- is obtained, since it is a compound having an N-sulfinylindole moiety in the molecule, sulfinamide It can be expected to have the same function.

-S- thiazine ring -SO ₂ of fused heterocyclic compounds similar - as compounds substituted in, and pyrrolo benzothiazine 5,5-dioxide compound are known, the pyrrolo benzothiazine -5, As an example of the synthesis of a 5-dioxide compound, an intramolecular cyclization reaction of a 2- (N-pyrrolylsulfonyl) benzoic acid derivative has been reported (Non-patent Document 5). However, there is no report at all regarding the production method of indolobenzothiazine-5-oxide compound or indolobenzothiazine-5,5-dioxide compound.

U.S. Patent No. 2004/0223963

Antibacterial and antifungal chemistry, Hiroshi Horiguchi, p.237, Sankyo Publishing (1982). S. S. Klioze and W. J. Novick, Jr., J. Med. Chem., 21, 1978, 400. N. Terzioglu, R. M. van Rijn, R. A. Bakker, I. J. De Esch, and R. Leurs, Bioorg. Med. Chem. Lett., 14, 5251 (2004). Proceedings of the 96th Annual Meeting of the Chemical Society of Japan, 3PB172 (2016). C. Song, D. W. Knight, and M. A. Whatton, Tetrahedron Lett., 45, 9573 (2004).

  An object of the present invention is to provide a novel indolobenzothiazine compound, indolobenzothiazine-5-oxide, indolobenzothiazine-5,5-dioxide compound, and a production method thereof. Another object of the present invention is to provide an industrially advantageous method for producing them.

  As a result of intensive studies, the present inventors reacted the indolobenzothiazine compound with an oxidizing agent to produce an indolobenzothiazine-5-oxide compound or indolobenzothiazine-5, We found that 5-dioxide compounds can be synthesized. This invention is made | formed based on the said knowledge.

  That is, when the present inventors react an indolobenzothiazine with an appropriate oxidizing agent, an oxidation reaction occurs on the sulfur atom of the thiazine ring, and the indolobenzothiazine-5-oxide compound or indo It has been found that a lobenzothiazine-5,5-dioxide compound can be selectively obtained, and the present invention has been completed.

(式中、Ｒ¹〜Ｒ⁴は、水素原子、炭素数１〜６のアルキル基、炭素数１〜６のアルコキシル基、ハロゲン原子、ニトロ基、シアノ基から選ばれる基又は原子を表す。ただしＲ¹とＲ²、Ｒ²とＲ³、あるいはＲ³とＲ⁴は連結して互いに環を成してもよい。ｎは１あるいは２を示す。)
（２）下記一般式(Ｂ)で表されるインドロベンゾチアジン化合物に対し、過カルボン酸、過酸化水素水、および、アルキル過酸化物から選択される酸化剤を反応させることを特徴とする、下記一般式(Ａ１)で表されるインドロベンゾチアジン化合物の製造方法。

(式中、Ｒ¹〜Ｒ⁴は、水素原子、炭素数１〜６のアルキル基、炭素数１〜６のアルコキシル基、ハロゲン原子、ニトロ基、シアノ基から選ばれる基又は原子を表す。ただしＲ¹とＲ²、Ｒ²とＲ³、あるいはＲ³とＲ⁴は連結して互いに環を成してもよい。)

(式中、Ｒ¹〜Ｒ⁴は、水素原子、炭素数１〜６のアルキル基、炭素数１〜６のアルコキシル基、ハロゲン原子、ニトロ基、シアノ基から選ばれる基又は原子を表す。ただしＲ¹とＲ²、Ｒ²とＲ³、あるいはＲ³とＲ⁴は連結して互いに環を成してもよい。)
（３）酸化剤としてｍ−クロロ過安息香酸あるいは過酸化水素水を用いることを特徴とする、(２)に記載のインドロベンゾチアジン化合物の製造方法。
（４）下記一般式(Ｂ)で表されるインドロベンゾチアジン化合物に対し、次亜ハロゲン酸アルカリ塩、その水溶液、および、過ハロゲン酸アルカリ塩から選択される酸化剤を反応させることを特徴とする、下記一般式(Ａ２)で表されるインドロベンゾチアジン化合物の製造方法。

(式中、Ｒ¹〜Ｒ⁴は、水素原子、炭素数１〜６のアルキル基、炭素数１〜６のアルコキシル基、ハロゲン原子、ニトロ基、シアノ基から選ばれる基又は原子を表す。ただしＲ¹とＲ²、Ｒ²とＲ³、あるいはＲ³とＲ⁴は連結して互いに環を成してもよい。)

(式中、Ｒ¹〜Ｒ⁴は、水素原子、炭素数１〜６のアルキル基、炭素数１〜６のアルコキシル基、ハロゲン原子、ニトロ基、シアノ基から選ばれる基又は原子を表す。ただしＲ¹とＲ²、Ｒ²とＲ³、あるいはＲ³とＲ⁴は連結して互いに環を成してもよい。)
（５）下記一般式(Ａ１)で表されるインドロベンゾチアジン化合物に対し、次亜ハロゲン酸アルカリ塩、その水溶液、および、過ハロゲン酸アルカリ塩から選択される酸化剤を反応させることを特徴とする、下記一般式(Ａ２)で表されるインドロベンゾチアジン化合物の製造方法。

(式中、Ｒ¹〜Ｒ⁴は、水素原子、炭素数１〜６のアルキル基、炭素数１〜６のアルコキシル基、ハロゲン原子、ニトロ基、シアノ基から選ばれる基又は原子を表す。ただしＲ¹とＲ²、Ｒ²とＲ³、あるいはＲ³とＲ⁴は連結して互いに環を成してもよい。)

(式中、Ｒ¹〜Ｒ⁴は、水素原子、炭素数１〜６のアルキル基、炭素数１〜６のアルコキシル基、ハロゲン原子、ニトロ基、シアノ基から選ばれる基又は原子を表す。ただしＲ¹とＲ²、Ｒ²とＲ³、あるいはＲ³とＲ⁴は連結して互いに環を成してもよい。)
（６）酸化剤として次亜塩素ナトリウム五水和物を用いることを特徴とする、(４)または(５)に記載のインドロベンゾチアジン化合物の製造方法。 That is, according to the present invention, the following inventions are provided.
(1) An indolobenzothiazine compound represented by the following general formula (A).

(In the formula, R ^{1 to} R ⁴ represent a group or an atom selected from a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group. R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ may be linked to each other to form a ring, and n represents 1 or 2.)
(2) A feature of reacting an indolobenzothiazine compound represented by the following general formula (B) with an oxidant selected from a percarboxylic acid, a hydrogen peroxide solution, and an alkyl peroxide. A method for producing an indolobenzothiazine compound represented by the following general formula (A1):

(In the formula, R ^{1 to} R ⁴ represent a group or an atom selected from a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group. R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ may be linked to form a ring.)

(In the formula, R ^{1 to} R ⁴ represent a group or an atom selected from a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group. R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ may be linked to form a ring.)
(3) The method for producing an indolobenzothiazine compound according to (2), wherein m-chloroperbenzoic acid or hydrogen peroxide water is used as the oxidizing agent.
(4) reacting an indolobenzothiazine compound represented by the following general formula (B) with an oxidizing agent selected from an alkali hypohalite, an aqueous solution thereof, and an alkali perhalogenate. A method for producing an indolobenzothiazine compound represented by the following general formula (A2):

(In the formula, R ^{1 to} R ⁴ represent a group or an atom selected from a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group. R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ may be linked to form a ring.)

(In the formula, R ^{1 to} R ⁴ represent a group or an atom selected from a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group. R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ may be linked to form a ring.)
(5) reacting an indolobenzothiazine compound represented by the following general formula (A1) with an oxidizing agent selected from alkali hypohalite, aqueous solution thereof, and alkali perhalogenate. A method for producing an indolobenzothiazine compound represented by the following general formula (A2):

(In the formula, R ^{1 to} R ⁴ represent a group or an atom selected from a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group. R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ may be linked to form a ring.)

(In the formula, R ^{1 to} R ⁴ represent a group or an atom selected from a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group. R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ may be linked to form a ring.)
(6) The method for producing an indolobenzothiazine compound according to (4) or (5), wherein sodium hypochlorite pentahydrate is used as the oxidizing agent.

According to the present invention, a novel compound, indolobenzothiazine-5-oxide compound or indolobenzothiazine-5,5-dioxide compound, can be obtained from the indolobenzothiazine compound.
The indolobenzothiazine-5-oxide compound and indolobenzothiazine-5,5-dioxide compound obtained by the present invention are compounds having both an indole skeleton and a sulfinamide structure or a sulfonamide structure. It is useful as a herbicide or herbicide or as a raw material compound.
The indolobenzothiazine-5-oxide compound according to the present invention and the production method of indolobenzothiazine-5,5-dioxide compound are produced by reacting an oxidant with a corresponding indolobenzothiazine compound as a raw material. This is a completely new manufacturing method that has never existed before.

(式中、Ｒ¹〜Ｒ⁴は、水素原子、炭素数１〜６のアルキル基、炭素数１〜６のアルコキシル基、ハロゲン原子、ニトロ基、シアノ基から選ばれる基又は原子を表す。ただしＲ¹とＲ²、Ｒ²とＲ³、あるいはＲ³とＲ⁴は連結して互いに環を成してもよい。) The indolobenzothiazine-5-oxide compound and indolobenzothiazine-5,5-dioxide compound, which are target compounds of the present invention, are compounds represented by the following general formula (A).

(In the formula, R ^{1 to} R ⁴ represent a group or an atom selected from a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group. R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ may be linked to form a ring.)

Specific examples of the alkyl group in the general formula (A) include methyl group, ethyl group, propyl group, isopropyl group, butyl group, t-butyl group, isobutyl group, pentyl group, isopentyl group, hexyl group, isohexyl group, A cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, etc. are mentioned.
Specific examples of the alkoxyl group include methoxy group, ethoxy group, propoxy group, isopropoxy group, cyclopropoxy group, butoxy group, isobutoxy group, t-butoxy group, pentyloxy group, hexyloxy group, cyclohexyloxy group and the like.
Specific examples of the halogen atom include chlorine, fluorine, iodine and bromine.
R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ may be linked to each other to form a ring, which means that each substituent is linked to form a cyclic structure. As a specific example of the ring structure formed as a result, the benzene ring in the benzothiazine ring structure and the ring structure formed by the bond between substituents form a naphthyl ring structure, or a tetrahydronaphthyl ring The case where a structure is comprised is mentioned.
N is 1 or 2.

(式中、Ｒ¹〜Ｒ⁴は、水素原子、炭素数１〜６のアルキル基、炭素数１〜６のアルコキシル基、ハロゲン原子、ニトロ基、シアノ基から選ばれる基又は原子を表す。ただしＲ¹とＲ²、Ｒ²とＲ³、あるいはＲ³とＲ⁴は連結して互いに環を成してもよい。)

(式中、Ｒ¹〜Ｒ⁴は、水素原子、炭素数１〜６のアルキル基、炭素数１〜６のアルコキシル基、ハロゲン原子、ニトロ基、シアノ基から選ばれる基又は原子を表す。ただしＲ¹とＲ²、Ｒ²とＲ³、あるいはＲ³とＲ⁴は連結して互いに環を成してもよい。) In the present invention, an indolobenzothiazine compound represented by the following general formula (A1) is produced by reacting an indolobenzothiazine compound represented by the following general formula (B) with an oxidizing agent. be able to. (Hereafter, it may be abbreviated as “a method for producing a compound represented by the general formula (A1)”.)

(In the formula, R ^{1 to} R ⁴ represent a group or an atom selected from a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group. R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ may be linked to form a ring.)

(In the formula, R ^{1 to} R ⁴ represent a group or an atom selected from a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group. R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ may be linked to form a ring.)

  The substituents in the general formula (A1) and the general formula (B) are the same as those in the general formula (A).

Examples of the oxidizing agent used in the method for producing the compound represented by the general formula (A1) of the present invention include percarboxylic acids such as m-chloroperbenzoic acid, o-chloroperbenzoic acid, perbenzoic acid and peracetic acid, and peroxidation. Examples thereof include hydrogen peroxide, alkyl peroxides such as t-butyl peroxide and cumyl peroxide. In particular, when m-chloroperbenzoic acid or aqueous hydrogen peroxide is used, the target compound can be obtained in good yield.
Hydrogen peroxide water is used together with a catalyst, and examples of the catalyst include methyltrioxorhenium, tungstic acid, molybdic acid, tungstophosphoric acid, molybdophosphoric acid, and the like.

(式中、Ｒ¹〜Ｒ⁴は、水素原子、炭素数１〜６のアルキル基、炭素数１〜６のアルコキシル基、ハロゲン原子、ニトロ基、シアノ基から選ばれる基又は原子を表す。ただしＲ¹とＲ²、Ｒ²とＲ³、あるいはＲ³とＲ⁴は連結して互いに環を成してもよい。)
酸化剤であるｍ−クロロ過安息香酸あるいは過酸化水素水は、市販の化合物である。 Compound (B) which is a raw material in the method for producing the compound represented by the general formula (A1) is a known substance. Compound (B) can be produced, for example, by reacting a Lewis acid with a 2- (N-pyrrolosulphenyl) benzoyl chloride compound represented by the following general formula (D).

(In the formula, R ^{1 to} R ⁴ represent a group or an atom selected from a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group. R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ may be linked to form a ring.)
The oxidizing agent m-chloroperbenzoic acid or hydrogen peroxide water is a commercially available compound.

  The amount of the oxidizing agent used (preparation amount) in the method for producing the compound represented by the general formula (A1) of the present invention is usually 1 time in terms of a molar ratio with respect to the indolobenzothiazine compound represented by the formula (B). Above, preferably 1.1 times or more, more preferably 1.2 times or more, usually 2 times or less, preferably 1.8 times or less, more preferably 1.6 times or less. Even if the oxidizing agent is used in a large excess, the oxidation does not proceed excessively. However, if the oxidizing agent is within the above range, the indrobenzo of the general formula (A1) can be obtained in a higher yield without wasteful use of the oxidizing agent. Thiazine compounds can be produced.

  The concentration of the hydrogen peroxide solution used as the oxidizing agent in the method for producing the compound represented by the general formula (A1) of the present invention is preferably 3% or more, preferably 10% or more, more preferably 30% or more, usually 60%. Hereinafter, it is preferably 50% or less, more preferably 40% or less. At low concentrations, the reaction is slow, and at high concentrations, there is a risk of explosion and the like, and if it is within the above range, an indolobenzothiazine compound can be produced with better yield and safety.

  The method for producing the compound represented by the general formula (A1) is preferably carried out in the presence of a reaction solvent. As the solvent, organic solvents such as methylene chloride, chloroform, 1,2-dichloroethane, 1,1,1-trichloroethane, benzene, toluene, xylene, chlorobenzene, bromobenzene, nitrobenzene, and acetonitrile are used. These solvents are used alone or in the form of a mixed solvent.

The reaction temperature in the method for producing the compound represented by the general formula (A1) can be set to a temperature in the vicinity of −10 ° C. to 100 ° C. At a reaction temperature below this temperature range, the reaction rate becomes slow. When the reaction is carried out under conditions that are too high beyond this temperature range, abnormal decomposition reactions and side reactions increase. The temperature range is more preferably 15 ° C. to 30 ° C., which is around room temperature.
The reaction time depends on the reaction temperature and cannot be determined in general, but usually 10 to 120 minutes is sufficient.

(式中、Ｒ¹〜Ｒ⁴は、水素原子、炭素数１〜６のアルキル基、炭素数１〜６のアルコキシル基、ハロゲン原子、ニトロ基、シアノ基から選ばれる基又は原子を表す。ただしＲ¹とＲ²、Ｒ²とＲ³、あるいはＲ³とＲ⁴は連結して互いに環を成してもよい。)

(式中、Ｒ¹〜Ｒ⁴は、水素原子、炭素数１〜６のアルキル基、炭素数１〜６のアルコキシル基、ハロゲン原子、ニトロ基、シアノ基から選ばれる基又は原子を表す。ただしＲ¹とＲ²、Ｒ²とＲ³、あるいはＲ³とＲ⁴は連結して互いに環を成してもよい。) In the present invention, an indolobenzothiazine compound represented by the following general formula (A2) is produced by reacting an indolobenzothiazine compound represented by the following general formula (B) with an oxidizing agent. be able to. (Hereafter, it may be abbreviated as “a method for producing a compound represented by the general formula (A2) from the general formula (B)”.)

(In the formula, R ^{1 to} R ⁴ represent a group or an atom selected from a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group. R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ may be linked to form a ring.)

(In the formula, R ^{1 to} R ⁴ represent a group or an atom selected from a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group. R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ may be linked to form a ring.)

  The general formula (A2) and the substituent of the general formula (B) in the method for producing the compound represented by the general formula (A2) from the general formula (B) are the same as those in the general formula (A). .

  Examples of the oxidizing agent used in the method for producing the compound represented by the general formula (A2) from the general formula (B) include sodium hypochlorite pentahydrate, sodium hypochlorite aqueous solution, and sodium hypobromite solution. Alkali hypohalite or aqueous solution thereof such as sodium periodate, alkali perhalogenate such as sodium perbromate, etc. Among them, sodium hypobromite pentahydrate is particularly preferable. The target compound is obtained in a yield.

  The oxidizing agent, sodium hypochlorite pentahydrate, is a commercially available compound.

  In the method for producing a compound represented by the general formula (A2) from the general formula (B) of the present invention, the amount of use of the oxidizing agent (charge amount) is based on the indolobenzothiazine compound represented by the formula (B). The molar ratio is usually 2 times or more, preferably 2.2 times or more, more preferably 2.4 times or more, usually 3 times or less, preferably 2.8 times or less, more preferably 2.6 times or less. is there. Within the above range, the indolobenzothiazine compound represented by the general formula (A2) can be produced with higher yield.

  The method for producing the compound represented by the general formula (A2) from the general formula (B) is preferably carried out in the presence of a reaction solvent. As the solvent, organic solvents such as acetonitrile, propionitrile, methanol, ethanol, benzene, toluene, xylene, chlorobenzene, bromobenzene, nitrobenzene, methylene chloride, chloroform, 1,2-dichloroethane are used. These solvents are used alone or in the form of a mixed solvent. Moreover, you may add water as needed.

The reaction temperature in the method for producing the compound represented by the general formula (A2) from the general formula (B) can be set to a temperature in the vicinity of −10 ° C. to 80 ° C. At a reaction temperature below this temperature range, the reaction rate becomes slow. When the reaction is carried out under conditions that are too high beyond this temperature range, abnormal decomposition reactions and side reactions increase. The temperature range is more preferably in the vicinity of room temperature of 15 ° C to 30 ° C.
The reaction time depends on the reaction temperature and cannot be determined in general, but usually 10 to 120 minutes is sufficient.

(式中、Ｒ¹〜Ｒ⁴は、水素原子、炭素数１〜６のアルキル基、炭素数１〜６のアルコキシル基、ハロゲン原子、ニトロ基、シアノ基から選ばれる基又は原子を表す。ただしＲ¹とＲ²、Ｒ²とＲ³、あるいはＲ³とＲ⁴は連結して互いに環を成してもよい。)

(式中、Ｒ¹〜Ｒ⁴は、水素原子、炭素数１〜６のアルキル基、炭素数１〜６のアルコキシル基、ハロゲン原子、ニトロ基、シアノ基から選ばれる基又は原子を表す。ただしＲ¹とＲ²、Ｒ²とＲ³、あるいはＲ³とＲ⁴は連結して互いに環を成してもよい。) In the present invention, the indolobenzothiazine compound represented by the following general formula (A2) is produced by reacting the indolobenzothiazine compound represented by the following general formula (A1) with an oxidizing agent. be able to. (Hereafter, it may be abbreviated as “a method for producing a compound represented by the general formula (A2) from the general formula (A1)”.)

(In the formula, R ^{1 to} R ⁴ represent a group or an atom selected from a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group. R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ may be linked to form a ring.)

(In the formula, R ^{1 to} R ⁴ represent a group or an atom selected from a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group. R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ may be linked to form a ring.)

  The general formula (A1) and the substituent of the general formula (A2) in the method for producing the compound represented by the general formula (A2) from the general formula (A1) are the same as those in the general formula (A). .

  Examples of the oxidizing agent used in the method for producing the compound represented by the general formula (A2) from the general formula (A1) include sodium hypochlorite pentahydrate, sodium hypochlorite aqueous solution, and sodium hypobromite solution. Alkali hypohalite or aqueous solution thereof such as sodium periodate, alkali perhalogenate such as sodium perbromate, etc. Among them, sodium hypobromite pentahydrate is particularly preferable. The target compound is obtained in a yield.

  In the method for producing the compound represented by the general formula (A2) from the general formula (A1) of the present invention, the amount of the oxidizing agent used (preparation amount) is based on the indolobenzothiazine compound represented by the formula (A1). The molar ratio is usually 1 or more, preferably 1.1 or more, more preferably 1.2 or more, and usually 2 or less, preferably 1.5 or less, more preferably 1.3 or less. is there. Within the above range, the indolobenzothiazine compound represented by the general formula (A2) can be produced with higher yield.

  The method for producing the compound represented by the general formula (A2) from the general formula (A1) is preferably carried out in the presence of a reaction solvent. As the solvent, organic solvents such as acetonitrile, propionitrile, methanol, ethanol, benzene, toluene, xylene, chlorobenzene, bromobenzene, nitrobenzene, methylene chloride, chloroform, 1,2-dichloroethane are used. These solvents are used alone or in the form of a mixed solvent. Moreover, you may add water as needed.

The reaction temperature in the method for producing the compound represented by the general formula (A2) from the general formula (A1) can be set to a temperature in the vicinity of −10 ° C. to 80 ° C. At a reaction temperature below this temperature range, the reaction rate becomes slow. When the reaction is carried out under conditions that are too high beyond this temperature range, abnormal decomposition reactions and side reactions increase. The temperature range is more preferably in the vicinity of room temperature of 15 ° C to 30 ° C.
The reaction time depends on the reaction temperature and cannot be determined in general, but usually 2 to 60 minutes is sufficient.

Specific examples of the indolobenzothiazine compounds of general formula (A1) and general formula (A2) obtained in the present invention include compounds represented by the following chemical formulas (1) to (8).

  The indolobenzothiazine compounds of general formula (A1) and general formula (A2) obtained in the present invention are novel compounds and have a sulfinamide structure or sulfonamide structure having an indole ring and a nitrogen-sulfur bond. By having it, it is a compound useful as an antibacterial agent or herbicide.

Next, the present invention will be described in detail by examples. The compounds obtained in the present invention are not limited to the compounds mentioned in this example.
The indolobenzothiazine compounds obtained in the following examples were identified by using various spectra and elemental analysis results as main criteria.
In addition, the compound (1) and the compound (5) produced in the following examples are the compounds of the chemical formula (1) and the chemical formula (5), and their physical property values are melting point, nuclear magnetic resonance spectrum ( ¹ H- NMR, ¹³ C-NMR) and infrared absorption spectrum (IR), respectively.

[Example 1]
Indolo [1,2-b] [1,2] benzothiazin-12-one (50 mg, 0.2 mmol) was dissolved in methylene chloride (10 ml) in a glass container with an internal volume of 50 ml, and m-chloroperbenzoic acid was dissolved. (0.24 mmol) was added and stirred at room temperature for 30 minutes. After completion of the reaction, an aqueous sodium sulfite solution was added, and the mixture was extracted with methylene chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under reduced pressure. The crude product was purified by silica gel chromatography using methylene chloride: ethyl acetate = 30: 1 as an eluent, and the target compound (1), indolo [1,2-b] [1,2] benzothiazin-12-one -5-oxide was obtained in 93% yield.
Melting point 189.9-190.9 ℃ (Recrystallized from ethyl acetate-hexane)
¹ H NMR (CDCl ₃ ) δ 7.35 (1H, td, J = 7.8, 0.9 Hz), 7.56 (1H, td, J = 7.8, 0.9 Hz), 7.85-7.80 (5H, m), 7.95 (1H, dd, J = 6.9, 2.3 Hz), 8.45 (1H, dd, J = 6.9, 2.3 Hz).
¹³ C NMR (CDCl ₃ ) δ 111.8, 118.1, 124.1, 124.4, 128.6, 128.7, 128.9, 129.5, 131.9, 133.4, 134.1, 140.5, 143.1, 174.7.
IR (KBr) ν _max 3060, 3015, 1650, 1537, 1286, 1092, 746 cm ^-1 .
Anal.Calcd for C ₁₅ H ₉ NO ₂ S: C, 67.40; H, 3.39; N, 5.24.
Found: C, 67.45; H, 3.39; N, 5.19.

[Example 2]
Indolo [1,2-b] [1,2] benzothiazin-12-one (50 mg, 0.2 mmol), methyltrioxorhenium (0.008 mmol) in methylene chloride (2 ml) in a glass container with an internal volume of 5 ml 30% aqueous hydrogen peroxide solution (0.3 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, an aqueous sodium sulfite solution was added, and the mixture was extracted with methylene chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under reduced pressure. The crude product was purified by silica gel chromatography using methylene chloride: ethyl acetate = 30: 1 as an eluent, and the target compound (1), indolo [1,2-b] [1,2] benzothiazin-12-one -5-oxide was obtained in 87% yield.

[Example 3]
Indolo [1,2-b] [1,2] benzothiazin-12-one (50 mg, 0.2 mmol) was dissolved in acetonitrile (10 ml) in a glass container with an internal volume of 50 ml, and sodium hypochlorite pentahydrate A Japanese product (0.48 mmol) and water (2 mL) were added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, an aqueous sodium sulfite solution was added, and the mixture was extracted with methylene chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under reduced pressure. The crude product was purified by silica gel chromatography using methylene chloride: hexane = 5: 1 as an eluent, and the target compound (5), indolo [1,2-b] [1,2] benzothiazin-12-one- 5,5-dioxide was obtained in a yield of 82%.
Melting point 174.0-175.5 ℃ (Recrystallized from ethyl acetate-hexane)
¹ H NMR (CDCl ₃ ) δ 7.40 (1H, td, J = 7.8, 1.4 Hz), 7.59 (1H, td, J = 7.8, 1.4 Hz), 7.91-7.79 (4H, m), 8.18-8.17 ( 2H, m), 8.36 (1H, dd, J = 7.3, 1.8 Hz).
¹³ C NMR (CDCl ₃ ) δ 115.0, 118.9, 123.7, 124.0, 125.1, 128.4, 129.2, 129.5, 130.9, 133.9, 134.2, 135.1, 137.7, 139.8, 173.2.
IR (KBr) ν _max 3124, 3070, 1656, 1538, 1347, 1133, 746 cm ^-1 .
Anal.Calcd for C ₁₅ H ₉ NO ₃ S: C, 63.59; H, 3.20; N, 4.94.
Found: C, 63.44; H, 3.20; N, 4.93.

[Example 4]
Indolo [1,2-b] [1,2] benzothiazin-12-one-5-oxide (54 mg, 0.2 mmol) was dissolved in acetonitrile (10 ml) in a glass container with an internal volume of 50 ml. Sodium acid pentahydrate (0.24 mmol) and water (2 mL) were added, and the mixture was stirred at room temperature for 5 minutes. After completion of the reaction, an aqueous sodium sulfite solution was added, and the mixture was extracted with methylene chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under reduced pressure. The crude product was purified by silica gel chromatography using methylene chloride: hexane = 5: 1 as an eluent, and the target compound (5), indolo [1,2-b] [1,2] benzothiazin-12-one- 5,5-dioxide was obtained in 93% yield.

  The indolobenzothiazine compounds of general formula (A1) and general formula (A2) obtained in the present invention can be used as antibacterial agents, herbicides and the like.

Claims (6)

An indolobenzothiazine compound represented by the following general formula (A).

(In the formula, R ^{1 to} R ⁴ represent a group or an atom selected from a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group. R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ may be linked to each other to form a ring, and n represents 1 or 2.) The indolobenzothiazine compound represented by the following general formula (B) is reacted with an oxidant selected from percarboxylic acid, hydrogen peroxide solution, and alkyl peroxide, A method for producing an indolobenzothiazine compound represented by the general formula (A1).

(In the formula, R ^{1 to} R ⁴ represent a group or an atom selected from a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group. R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ may be linked to form a ring.)

(In the formula, R ^{1 to} R ⁴ represent a group or an atom selected from a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group. R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ may be linked to form a ring.)   The method for producing an indolobenzothiazine compound according to claim 2, wherein metachloroperbenzoic acid or hydrogen peroxide is used as the oxidizing agent. The following is produced by reacting an indolobenzothiazine compound represented by the following general formula (B) with an oxidant selected from an alkali hypohalite, an aqueous solution thereof, and an alkali perhalogenate. A method for producing an indolobenzothiazine compound represented by the general formula (A2).

(In the formula, R ^{1 to} R ⁴ represent a group or an atom selected from a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group. R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ may be linked to form a ring.)

(In the formula, R ^{1 to} R ⁴ represent a group or an atom selected from a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group. R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ may be linked to form a ring.) The following is produced by reacting an indolobenzothiazine compound represented by the following general formula (A1) with an oxidant selected from an alkali hypohalite, an aqueous solution thereof, and an alkali perhalogenate. A method for producing an indolobenzothiazine compound represented by the general formula (A2).

(In the formula, R ^{1 to} R ⁴ represent a group or an atom selected from a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group. R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ may be linked to form a ring.)

(In the formula, R ^{1 to} R ⁴ represent a group or an atom selected from a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group. R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ may be linked to form a ring.)   The method for producing an indolobenzothiazine compound according to claim 4 or 5, wherein sodium hypochlorite pentahydrate is used as an oxidizing agent.