3-aminobenzisothiazole derivatives and their manufacturing method

Abstract

To provide a 3-aminobenzo[c]isothiazole-5-sulfonamide derivative as a novel compound, and a production method thereof.SOLUTION: The invention provides a 3-aminobenzo[c]isothiazole-5-sulfonamide derivative represented by the general formula (3) in the figure, and a production method thereof. In the general formula (3), R1, R2 and R3 each independently represent a hydrogen atom, a C1-4 alkyl group, a halogen atom, or a haloalkyl group.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to 3-aminobenzisothiazole derivatives and methods for producing the same. [Background technology]

[0002] 3-Aminobenzisothiazole derivatives are used for various purposes. For example, 3-aminobenzisothiazole-5-sulfonic acid is commercially available and is considered useful as an intermediate for pharmaceuticals, reagents, etc. 3-Aminobenzisothiazole-5-sulfonic acid can be obtained by introducing a sulfonic acid group into 2-aminobenzonitrile (OABN) and then reacting it with hydrogen peroxide in the presence of hydrogen sulfide gas. However, a method for directly amminating the hydroxyl group of 3-aminobenzisothiazole-5-sulfonic acid and the resulting aminated compound are not known. Summary of the Invention [Problem to be solved by the invention]

[0003] According to the investigations of the present inventors, both 3-aminobenzo[c]isothiazole-5-chlorosulfonyl derivatives in which the sulfonic acid group at the 5-position of the benzisothiazole in 3-aminobenzisothiazole-5-sulfonic acid is halogenated, and 3-aminobenzo[c]isothiazole-5-sulfonamide derivatives in which the chlorosulfonyl group is sulfamoylated, are novel compounds.

[0004] A problem to be solved by one embodiment of the present disclosure is to provide a novel 3-aminobenzisothiazole derivative. Another problem to be solved by another embodiment of the present disclosure is to provide a method for producing a novel 3-aminobenzisothiazole derivative. [Means for solving the problem]

[0005] The means for solving the above problems include the following aspects.

[0006] <1> A 3-aminobenzo[c]isothiazole-5-sulfonamide derivative represented by the following general formula (3):

[0007] [ka]

[0008] In general formula (3), R 1 , R 2 , and R 3 each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a halogen atom, or a haloalkyl group.

[0009] <2> 3-aminobenzo[c]isothiazole-5-chlorosulfonyl derivatives represented by the following general formula (2):

[0010] [ka]

[0011] In general formula (2), R 1 , R 2 , and R 3 each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a halogen atom, or a haloalkyl group.

[0012] <3> A method for producing a 3-aminobenzo[c]isothiazole-5-sulfonamide derivative represented by the following general formula (3), comprising a step of reacting a benzisothiazole derivative represented by the following general formula (1) with a reaction solvent containing a halogenated sulfonic acid to obtain a 3-aminobenzo[c]isothiazole-5-halogenated sulfonyl derivative represented by the following general formula (2-2), wherein the content of solvents other than the halogenated sulfonic acid is less than 1 mass% with respect to the total amount of the reaction solvent.

[0013] [ka]

[0014] In general formula (1), R 1 , R 2 , and R 3 each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a halogen atom, or a haloalkyl group. In general formula (2-2), R 1 , R 2 , and R 3 each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a halogen atom, or a haloalkyl group; R 4 represents a halogen atom.

[0015] [ka]

[0016] In general formula (3), R 1 , R 2 , and R 3 each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a halogen atom, or a haloalkyl group.

[0017] <4> The method further comprises a step of reacting the 3-aminobenzo[c]isothiazole-5-halogenated sulfonyl derivative represented by the general formula (2-2) with a reaction solvent containing ammonia without isolating it to obtain the 3-aminobenzo[c]isothiazole-5-sulfonamide derivative represented by the general formula (3). <3> 3. A method for producing the 3-aminobenzo[c]isothiazole-5-sulfonamide derivative according to claim 1.

[0018] <5> The reaction solvent containing ammonia is ammonia water or a mixed solvent of ammonia water and tetrahydrofuran. <4> 3. A method for producing the 3-aminobenzo[c]isothiazole-5-sulfonamide derivative according to claim 1. <5> The reaction of the 3-aminobenzo[c]isothiazole-5-halogenated sulfonyl derivative represented by the general formula (2-2) with a reaction solvent containing ammonia is carried out under a temperature condition of -10°C to 5°C. <3> or <4> 3. A method for producing the 3-aminobenzo[c]isothiazole-5-sulfonamide derivative according to claim 1. [Effects of the Invention]

[0019] According to one embodiment of the present invention, a novel 3-aminobenzisothiazole derivative can be provided. According to another embodiment of the present disclosure, there can be provided a method for producing a novel 3-aminobenzisothiazole derivative. DETAILED DESCRIPTION OF THE INVENTION

[0020] The contents of the present disclosure will be described below. The following description of the components may be based on representative embodiments of the present disclosure, but the present invention is not limited to the following embodiments. In the present disclosure, a numerical range stated using "to" indicates a numerical range that includes the numbers before and after "to" as the lower and upper limits. When there are multiple substances corresponding to each component, the amount of each component described in this disclosure means the total amount of the multiple substances unless otherwise specified. In the numerical ranges described in stages in the present disclosure, the upper or lower limit value described in a certain numerical range may be replaced with the upper or lower limit value of another numerical range described in stages. Furthermore, in the numerical ranges described in the present disclosure, the upper or lower limit value described in a certain numerical range may be replaced with a value shown in the examples. In the present disclosure, a combination of two or more preferred embodiments is a more preferred embodiment. In this specification, chemical structural formulas may be described as simplified structural formulas in which hydrogen atoms are omitted. In the present disclosure, the term "process" includes not only an independent process but also a process that cannot be clearly distinguished from other processes as long as the intended purpose of the process is achieved.

[0021] <3-aminobenzo[c]isothiazole-5-sulfonamide derivative represented by general formula (3)> The 3-aminobenzo[c]isothiazole-5-sulfonamide derivative represented by the following general formula (3) (hereinafter also referred to as "compound represented by general formula (3)") is a novel compound.

[0022] [ka]

[0023] In general formula (3), R 1 , R 2 , and R 3 each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a halogen atom, or a haloalkyl group. Examples of the alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, a propyl group, an n-butyl group, an i-butyl group, and a tert-butyl group, and among these, a methyl group or an ethyl group is preferred. Examples of the halogen atom include F, Cl, and Br, with Cl or F being preferred. Examples of haloalkyl groups include the above alkyl groups in which at least one hydrogen atom has been substituted with a halogen atom, and a preferred example is -CF3.

[0024] The following describes exemplary compounds 1 to 9, which are specific examples of the compound represented by general formula (3), with respect to R in general formula (3). 1 , R 2 , and R 3 However, the compounds represented by general formula (3) are not limited to the following exemplary compounds.

[0025] [ka]

[0026] Among the above example compounds, R1 , R 2 , and R 3 A preferred example is Exemplary Compound 1 in which all of are hydrogen atoms.

[0027] <3-aminobenzo[c]isothiazole-5-chlorosulfonyl derivative represented by general formula (2)> The 3-aminobenzo[c]isothiazole-5-chlorosulfonyl derivative represented by the following general formula (2) (hereinafter also referred to as "compound represented by general formula (2)") is a novel compound.

[0028] [ka]

[0029] In general formula (2), R 1 , R 2 , and R 3 each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a halogen atom, or a haloalkyl group. Examples of the alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, a propyl group, an n-butyl group, an i-butyl group, and a tert-butyl group, and among these, a methyl group or an ethyl group is preferred. Examples of the halogen atom include F, Cl, and Br, with Cl or F being preferred. Examples of haloalkyl groups include the above alkyl groups in which at least one hydrogen atom has been substituted with a halogen atom, and a preferred example is -CF3.

[0030] From the viewpoint of synthesis suitability, the compound represented by general formula (2) is preferably R 1 , R 2 , and R 3 are preferably compounds in which all of the above are hydrogen atoms.

[0031] The compound represented by general formula (2) is useful as an intermediate in synthesizing the compound represented by the above general formula (3), and the compound represented by general formula (3) can be obtained by substituting Cl of the chlorosulfonyl group in general formula (2) with an amino group.

[0032] <Method for producing 3-aminobenzo[c]isothiazole-5-sulfonamide derivative represented by general formula (3)> There are no particular limitations on the method for producing the compound represented by the above general formula (3), and it can be produced by known synthesis methods. Among these, from the viewpoint of higher yield, it is preferable to produce the 3-aminobenzo[c]isothiazole-5-sulfonamide derivative represented by the following general formula (3) (hereinafter also referred to as the "production method of the present disclosure").

[0033] The production method of the present disclosure includes step (I) of reacting a benzisothiazole derivative represented by the following general formula (1) [hereinafter also referred to as "compound represented by general formula (1)") with a reaction solvent containing a halogenated sulfonic acid to obtain a 3-aminobenzo[c]isothiazole-5-halogenated sulfonyl derivative represented by the following general formula (2-2), wherein the content of solvents other than the halogenated sulfonic acid is less than 1 mass% relative to the total amount of the reaction solvent.

[0034] [ka]

[0035] In general formula (1), R 1 , R 2 , and R 3 each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a halogen atom, or a haloalkyl group. R in general formula (1) 1 , R 2 , and R 3 is R in the compound represented by the above-mentioned general formula (2). 1 , R 2 , and R 3The same applies to the preferred examples. In general formula (2-2), R 1 , R 2 , and R 3 each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a halogen atom, or a haloalkyl group; R 4 represents a halogen atom. R in general formula (2-2) 1 , R 2 , and R 3 is R in the compound represented by the above-mentioned general formula (2). 1 , R 2 , and R 3 The same applies to the preferred examples. R in general formula (2-2) 4 represents a halogen atom, and examples of the halogen atom include Cl and Br, with Cl being preferred from the viewpoint of reactivity. R in general formula (2-2) 4 is Cl is the compound represented by the general formula (2) of the present disclosure.

[0036] [Process I] In the above reaction in step I, when a halogenated sulfonic acid group is introduced into the compound represented by general formula (1), a reaction solvent containing a halogenated sulfonic acid (HSO3A, A represents a halogen atom) is used. Examples of halogenated sulfonic acids include chlorosulfonic acid (HSO3Cl) and bromosulfonic acid (HSO3Br), and chlorosulfonic acid is preferred from the viewpoint that a higher yield can be expected. Chlorosulfonic acid is liquid, and its use as a reaction solvent allows for good reactivity in the above scheme. Therefore, the reaction solvent in step I may be chlorosulfonic acid alone, and there is no particular need to use a solvent other than chlorosulfonic acid in combination. Examples of solvents that can be used in combination include halogenated organic solvents. From the viewpoint of reactivity and suppression of side reactions, it is preferable that the content of solvents other than halogenated sulfonic acid is less than 1 mass% relative to the total amount of reaction solvent, and it is more preferable to use only halogenated sulfonic acid as the reaction solvent, excluding the solvent as an unavoidable impurity. It is preferable not to mix water into the reaction solvent, since chlorosulfonic acid reacts violently when it comes into contact with water.

[0037] An example of a specific procedure for step I in which a halogenated sulfonic acid is reacted with a compound represented by general formula (1) as a reaction solvent is described below. Since the reaction between the compound represented by general formula (1) and the halogenated sulfonic acid is an exothermic reaction, the halogenated sulfonic acid is placed in a reaction vessel, and the compound represented by general formula (1) is added while stirring under ice cooling. The rate of divided addition can be 8 g / min to 10 g / min. The reaction is preferably continued while maintaining the temperature of the liquid in the reaction vessel (hereinafter also referred to as liquid temperature) at or below 20° C. The temperature in the reaction vessel is preferably maintained at 0° C. to 20° C., more preferably at 5° C. to 20° C. Stirring and maintaining the liquid temperature in the reaction vessel at the above temperature are continued until the entire amount of the compound represented by general formula (1) is added. The amount of halogenated sulfonic acid used as a reaction solvent relative to the compound represented by general formula (1) can be such that the ratio of the compound represented by general formula (1):halogenated sulfonic acid is 1:6 to 1:6.5 in terms of mass.

[0038] After the entire amount of the compound represented by general formula (1) has been added, the temperature inside the reaction vessel is preferably raised to 30° C. to 45° C., and more preferably 35° C. to 40° C., and the reaction is continued for preferably 1 to 2 hours, and more preferably 1 to 1.5 hours. After the reaction is completed, the liquid temperature in the reaction vessel is preferably cooled to 10°C to 20°C, more preferably to 12°C to 15°C. In a separate step, it is preferable to prepare a crystallization solution by adding appropriate amounts of salt, concentrated hydrochloric acid, and acetone to ice. It is preferable to cool the temperature of the liquid in the reaction vessel filled with the obtained crystallization liquid to -10°C to -2°C, and while continuing stirring, add the previously obtained reaction liquid dropwise while maintaining the liquid temperature at 10°C or less. The drop rate can be 20g / min to 30g / min. After the dropwise addition is complete, it is preferable to carry out stirring for a predetermined period of time while maintaining the liquid temperature in the reaction vessel at 0° C. to 12° C. The stirring time can be 15 to 45 minutes.

[0039] After continuing stirring, the reaction solution containing the compound represented by general formula (2-2) is subjected to suction filtration to remove the remaining reaction solvent. The solid content obtained after removing the reaction solvent and the like by suction filtration contains the compound represented by general formula (2). The obtained solid content containing the compound represented by general formula (2-2) can be used for the synthesis of the compound represented by general formula (3) described below without isolation and drying. The 3-aminobenzo[c]isothiazole-5-halogenated sulfonyl derivative represented by the general formula (2-2) obtained in Step I, preferably the 3-aminobenzo[c]isothiazole-5-chlorosulfonyl derivative represented by the general formula (2), is an unstable compound. Therefore, in the next step, Step II, after the completion of the reaction in Step I, the compound represented by the general formula (2-2) is preferably subjected to the sulfamoylation reaction in Step II as is, without isolating or drying the compound obtained by removing the reaction solvent containing the halogenated sulfonic acid by filtration.

[0040] [Process II] The production method of the present disclosure preferably further comprises, as a step subsequent to step I, step II in which the 3-aminobenzo[c]isothiazole-5-halogenated sulfonyl derivative represented by general formula (2-2) is reacted with a reaction solvent containing ammonia without isolating it to obtain the 3-aminobenzo[c]isothiazole-5-sulfonamide derivative represented by the aforementioned general formula (3). The halogen atom of the sulfonyl halide group introduced into the compound represented by general formula (2-2) obtained in step I is aminated to obtain a compound represented by general formula (3).

[0041] In step II, the compound represented by general formula (2-2) is reacted with a reaction solvent containing ammonia to amminate the halogen atom moiety in the sulfonyl halide group of the compound represented by general formula (2-2), thereby obtaining a compound represented by general formula (3). Examples of the reaction solvent containing ammonia include aqueous ammonia and a mixed solvent of aqueous ammonia and an organic solvent. The concentration of aqueous ammonia as a reaction solvent is preferably 15% by mass to 50% by mass, more preferably 20% by mass to 30% by mass. Examples of organic solvents used in the mixed solvent include acetonitrile, tetrahydrofuran, and isopropyl alcohol. The mixed solvent may have a mixing ratio of aqueous ammonia to the organic solvent in the range of 0.5:1.5 to 1:1.3 in terms of volume. The reaction solvent in Step II is preferably aqueous ammonia or a mixed solvent of aqueous ammonia and tetrahydrofuran. Alternatively, a solution of ammonia in an organic solvent (for example, a solution of ammonia in 2-propyl alcohol) may be used as the reaction solvent.

[0042] First, the reaction solvent is charged into a reaction vessel, and while maintaining the liquid temperature in the reaction vessel at -10°C to 5°C, stirring is continued and the entire amount of solids containing the compound represented by general formula (2-2) obtained in step I is added. That is, the reaction of the 3-aminobenzo[c]isothiazole-5-halogenated sulfonyl derivative represented by the general formula (2-2) with the reaction solvent containing ammonia is preferably carried out under temperature conditions of -10°C to 5°C. In step II, the reaction between ammonia contained in the reaction solvent and the compound represented by general formula (2-2) is an exothermic reaction, so it is preferable to start the reaction by cooling the temperature inside the reaction vessel to, for example, 0°C or below in advance. The temperature inside the reaction vessel is preferably kept at −10° C. to 5° C., more preferably 0° C. to 5° C. The reaction is preferably carried out with continuous stirring for 15 to 60 minutes. Thereafter, it is preferable to continue stirring the liquid in the reaction vessel at a temperature of 15°C to 30°C for 50 to 90 minutes. Next, in order to lower the pH of the reaction system to pH 7 to 8, concentrated hydrochloric acid is added dropwise while the liquid temperature in the vessel is maintained at 20° C. or less, preferably 10 to 20° C., and then water is added dropwise while maintaining the temperature in the vessel at 20° C. or less. After the addition of water, the liquid temperature in the reaction vessel is maintained at 20° C. and stirred for 30 minutes, and then the liquid temperature is lowered to 5° C. and stirred for a further 2 hours. The amount of water added is preferably 5 times or more, more preferably 6 times or more, the amount of concentrated hydrochloric acid added, in volume terms. There are no particular restrictions on the amount of water added, but it can be 6.5 times or less, in volume terms. Thereafter, suction filtration is carried out to separate the compound represented by general formula (3). The separated solid matter is washed with water to obtain yellow crystals of the compound represented by general formula (3).

[0043] The presence of the compound represented by general formula (3) can be confirmed by NMR or the like. Although the compound represented by general formula (2) has not been isolated, it is clear from the reaction scheme below that it is an intermediate of the compound represented by general formula (3) and has the following structure, and it has been confirmed that the compound represented by general formula (2) is a novel compound. 1 , R 2 , and R 3 is as mentioned above.

[0044] [ka]

[0045] The compound represented by general formula (3) and the compound represented by general formula (2) of the present disclosure can be suitably used for various applications, similar to the known compound 3-aminobenzisothiazole-5-sulfonic acid. Furthermore, according to the production method of the present disclosure, the compound represented by general formula (3) can be produced in good yield. [Example]

[0046] The present invention will be described in detail below with reference to examples. The materials, amounts used, ratios, processing details, processing procedures, etc. shown in the following examples can be changed as appropriate without departing from the spirit of the invention. Therefore, the scope of the embodiments of the present disclosure is not limited to the specific examples shown below.

[0047] Example 1 <Synthesis of Compound Represented by General Formula (2): Step I> 502.7 g of chlorosulfonic acid was added to a reaction vessel, and the resulting mixture was stirred under ice cooling with a compound represented by general formula (1), 1 , R 2 , and R 3 81.0 g of the following compound A, in which all of the formulas are hydrogen atoms, was added in portions while maintaining the liquid temperature in the reaction vessel at 20° C. or lower.

[0048] [ka]

[0049] Thereafter, the liquid temperature in the reaction vessel was raised to 40°C and the reaction was carried out for 1.5 hours with continuous stirring. After the reaction was completed, the liquid temperature in the reaction vessel was cooled to 15°C to obtain a reaction liquid.

[0050] A crystallization solution was prepared by adding 80 g of salt, 160 mL (milliliters) of concentrated hydrochloric acid, and 40 mL of acetone to 1,320 g of ice. The obtained crystallization solution was poured into another reaction vessel, and the liquid temperature in the reaction vessel was kept at -5°C. While stirring was continued, the reaction solution obtained earlier was added dropwise to the crystallization solution. The liquid temperature in the reaction vessel into which the crystallization solution was added was maintained at 10°C or below, and stirring was carried out for 30 minutes. After stirring was completed, the precipitated solid was suction filtered to remove the reaction solvent and separate the solid. The filtered solid, containing crystals of the following compound B, which is a compound represented by general formula (2), was used in the synthesis of a compound represented by general formula (3) in the following step II without drying.

[0051] [ka]

[0052] <Synthesis of Compound Represented by General Formula (3): Step II> 200 mL of acetonitrile was placed in a reaction vessel, and 170 mL of 25% by mass aqueous ammonia was then added. The liquid temperature in the reaction vessel was then kept at 0°C to 5°C and stirred to obtain a mixed solvent. The entire amount of the solids containing compound B obtained in step I above was added to the reaction vessel while maintaining the liquid temperature in the reaction vessel at 0°C to 5°C. Stirring was carried out for 30 minutes while maintaining the liquid temperature in the reaction vessel at 0°C to 5°C, and then the liquid temperature in the reaction vessel was raised to 20°C and stirred for an additional hour. Next, 80 mL of concentrated hydrochloric acid was added dropwise while maintaining the liquid temperature in the reaction vessel at 20°C or below to adjust the pH of the reaction system to pH 7 to 8, and then 520 mL of water was added dropwise at the same temperature. The liquid temperature in the reaction vessel was maintained at 20°C and stirred for 30 minutes, and then the liquid temperature was lowered to 5°C and stirred for 2 hours. After stirring was completed, the solid content was separated by suction filtration and washed with 240 mL of water to obtain 87.8 g of yellow crystals of the following exemplary compound-1, which is a compound represented by general formula (3). The reaction rate was 77% and the yield was 71%.

[0053] [ka]

[0054] <Confirmation of Example Compound-1> The spectrum obtained by nuclear magnetic resonance (NMR) of the obtained yellow crystals: 1 H-NMR(DMSO-d6)δ:8.37(s,2H), 8.25(s,2H), 7.54-7.59(d,2H), 7.32-7.37(d,2H), 7.24(s,2H) NMR spectrum confirmed that the compound obtained had the structure of 3-aminobenzo[c]isothiazole-5-sulfonamide.

[0055] Example 2 <Synthesis of Compound Represented by General Formula (2): Step I> A solid content containing the compound B, which is a compound represented by general formula (2), was obtained in the same manner as in Step I of Example 1. The solid content containing crystals of compound B was used in the synthesis of a compound represented by general formula (3) in the following Step II without drying.

[0056] <Synthesis of Compound Represented by General Formula (3): Step II> 1130 mL of a 2-propanol solution containing 2 mol / L of ammonia was charged into a reaction vessel, and stirring was performed while maintaining the liquid temperature in the reaction vessel at 0° C. to 5° C., and the entire amount of the solid content containing compound B obtained above was added while maintaining the liquid temperature in the reaction vessel at 0° C. to 5° C. Stirring was performed for 30 minutes at a liquid temperature of 0° C. to 5° C., and then the liquid temperature was raised to 20° C. and stirring was performed for 1 hour. Next, 80 mL of concentrated hydrochloric acid was added dropwise while maintaining the liquid temperature in the reaction vessel at 20°C or below to adjust the pH of the reaction system to pH 7 to 8, and then 520 mL of water was added dropwise at the same temperature. The liquid temperature in the reaction vessel was maintained at 20°C and stirred for 30 minutes, then the liquid temperature was lowered to 5°C and stirred for 2 hours. After stirring was completed, the solid content was separated by suction filtration and washed with 240 mL of water to obtain 61.8 g of yellow crystals of the compound represented by general formula (3). The reaction rate was 76% and the yield was 50%. When an NMR spectrum was obtained under the same conditions as in Example 1, it was confirmed that the obtained compound had the structure of Exemplified Compound-1.

[0057] Example 3 <Synthesis of Compound Represented by General Formula (2): Step I> A solid content containing the compound B, which is a compound represented by general formula (2), was obtained in the same manner as in Step I of Example 1. The solid content containing crystals of compound B was used in the synthesis of a compound represented by general formula (3) in the following Step II without drying.

[0058] <Synthesis of Compound Represented by General Formula (3): Step II> 170 mL of 25% by mass ammonia water was added to 200 mL of isopropyl alcohol in a reaction vessel, and stirring was performed while maintaining the liquid temperature in the reaction vessel at 0° C. to 5° C. The entire amount of the solid content containing compound B obtained above was added while maintaining the liquid temperature at 0° C. to 5° C. Stirring was performed for 30 minutes while the liquid temperature was kept at 0° C. to 5° C., and then the liquid temperature in the reaction vessel was raised to 20° C. and stirring was performed for 1 hour. Next, 80 mL of concentrated hydrochloric acid was added dropwise while maintaining the liquid temperature in the reaction vessel at 20°C or below to adjust the pH of the reaction system to pH 7 to 8, and then 520 mL of water was added dropwise at the same temperature. The liquid temperature in the reaction vessel was maintained at 20°C and stirred for 30 minutes, then the liquid temperature was lowered to 5°C and stirred for 2 hours. After stirring was completed, the solid content was separated by suction filtration and washed with 240 mL of water to obtain 68.0 g of yellow crystals of the compound represented by general formula (3). The reaction rate was 67% and the yield was 55%. When an NMR spectrum was obtained under the same conditions as in Example 1, it was confirmed that the obtained compound had the structure of Exemplified Compound-1.

[0059] Example 4 <Synthesis of Compound Represented by General Formula (2): Step I> A solid content containing the compound B, which is a compound represented by general formula (2), was obtained in the same manner as in Step I of Example 1. The solid content containing crystals of compound B was used in the synthesis of a compound represented by general formula (3) in the following Step II without drying.

[0060] <Synthesis of Compound Represented by General Formula (3): Step II> A mixed solvent obtained by mixing 200 mL of tetrahydrofuran with 170 mL of 25 mass % aqueous ammonia was charged into a reaction vessel, and stirring was carried out while maintaining the liquid temperature in the reaction vessel at 0° C. to 5° C. The entire amount of compound B obtained above was added while maintaining the liquid temperature at 0° C. to 5° C. Stirring was carried out for 30 minutes at a liquid temperature of 0° C. to 5° C., and then the liquid temperature was raised to 20° C. and stirring was carried out for 1 hour. Next, 80 mL of concentrated hydrochloric acid was added dropwise while maintaining the liquid temperature in the reaction vessel at 20°C or below to adjust the pH of the reaction system to pH 7 to 8, and then 520 mL of water was added dropwise at the same temperature. The liquid temperature in the reaction vessel was maintained at 20°C and stirred for 30 minutes, then the liquid temperature was lowered to 5°C and stirred for 2 hours. After stirring was completed, the solid content was separated by suction filtration and washed with 240 mL of water to obtain 92.7 g of yellow crystals of the compound represented by general formula (3). The reaction rate was 86% and the yield was 75%. When an NMR spectrum was obtained under the same conditions as in Example 1, it was confirmed that the obtained compound had the structure of Exemplified Compound-1.

[0061] As is clear from Examples 1 to 4, the production methods of each Example made it possible to obtain a novel compound represented by general formula (3) and its intermediate, a compound represented by general formula (2). Furthermore, by comparing the examples, it can be seen that in step II of synthesizing the compound represented by general formula (3) from the compound represented by general formula (2), Example 1, in which a mixed solvent of ammonia water and acetonitrile was used, and Example 4, in which a mixed solvent of ammonia water and tetrahydrofuran was used, had better yields.

Claims

1. A 3-aminobenzo[c]isothiazole-5-sulfonamide derivative represented by the following general formula (3): 【Chemistry 1】 In general formula (3), R １ , R ２ , and R ３ each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a halogen atom, or a haloalkyl group.

2. A 3-aminobenzo[c]isothiazole-5-chlorosulfonyl derivative represented by the following general formula (2): 【Chemistry 2】 In general formula (2), R １ , R ２ , and R ３ each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a halogen atom, or a haloalkyl group.

3. The method includes a step of reacting a benzisothiazole derivative represented by the following general formula (1) with a reaction solvent containing a halogenated sulfonic acid to obtain a 3-aminobenzo[c]isothiazole-5-halogenated sulfonyl derivative represented by the following general formula (2-2): A method for producing a 3-aminobenzo[c]isothiazole-5-sulfonamide derivative represented by the following general formula (3), wherein the content of solvents other than halogenated sulfonic acids is less than 1 mass % based on the total amount of the reaction solvent, Furthermore, a method for producing a 3-aminobenzo[c]isothiazole-5-sulfonamide derivative represented by the following general formula (3) includes a step of reacting a 3-aminobenzo[c]isothiazole-5-halogenated sulfonyl derivative represented by the following general formula (2-2) with a reaction solvent containing ammonia to obtain a 3-aminobenzo[c]isothiazole-5-sulfonamide derivative represented by the following general formula (3). 【Transformation 3】 In general formula (1), R １ , R ２ , and R ３ each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a halogen atom, or a haloalkyl group. In general formula (2-2), R １ , R ２ , and R ３ are each independently a hydrogen atom, a group having 1 to 10 carbon atoms, R represents an alkyl group of 4, a halogen atom, or a haloalkyl group; ４ represents a halogen atom. 【Chemistry 4】 In general formula (3), R １ , R ２ , and R ３ each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a halogen atom, or a haloalkyl group.

4. The method for producing a 3-aminobenzo[c]isothiazole-5-sulfonamide derivative according to claim 3, further comprising a step of reacting the 3-aminobenzo[c]isothiazole-5-halogenated sulfonyl derivative represented by the general formula (2-2) with a reaction solvent containing ammonia without isolating it, to obtain the 3-aminobenzo[c]isothiazole-5-sulfonamide derivative represented by the general formula (3).

5. 5. The method for producing a 3-aminobenzo[c]isothiazole-5-sulfonamide derivative according to claim 4, wherein the reaction solvent containing ammonia is aqueous ammonia or a mixed solvent of aqueous ammonia and tetrahydrofuran.

6. The method for producing a 3-aminobenzo[c]isothiazole-5-sulfonamide derivative according to claim 3 or 4, wherein the reaction of the 3-aminobenzo[c]isothiazole-5-halogenated sulfonyl derivative represented by the general formula (2-2) with a reaction solvent containing ammonia is carried out under a temperature condition of −10° C. to 5° C.

Images