JP2023136302A - 3-aminobenzoisothiazole derivative and production method thereof - Google Patents
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 21
- WIJQCPIRWXSWQG-UHFFFAOYSA-N 1,2-benzothiazol-3-amine Chemical class C1=CC=C2C(N)=NSC2=C1 WIJQCPIRWXSWQG-UHFFFAOYSA-N 0.000 title 1
- 125000005843 halogen group Chemical group 0.000 claims abstract description 27
- -1 3-aminobenzo[c]isothiazole-5-sulfonamide derivative Chemical class 0.000 claims abstract description 23
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 21
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims description 72
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 37
- 239000007810 chemical reaction solvent Substances 0.000 claims description 34
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 15
- 229910021529 ammonia Inorganic materials 0.000 claims description 15
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 15
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 14
- 150000003460 sulfonic acids Chemical class 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 239000012046 mixed solvent Substances 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical class C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims description 2
- JSKJAICVFPRVHJ-UHFFFAOYSA-N 2,1-benzothiazol-3-amine Chemical compound C1=CC=CC2=C(N)SN=C21 JSKJAICVFPRVHJ-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 95
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 239000007788 liquid Substances 0.000 description 50
- 238000003756 stirring Methods 0.000 description 32
- 239000007787 solid Substances 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 239000013078 crystal Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 238000000967 suction filtration Methods 0.000 description 7
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000000542 sulfonic acid group Chemical group 0.000 description 3
- ZPANXIHYBLDJNI-UHFFFAOYSA-N 3-amino-1,2-benzothiazole-5-sulfonic acid Chemical compound C1=C(S(O)(=O)=O)C=C2C(N)=NSC2=C1 ZPANXIHYBLDJNI-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000011549 crystallization solution Substances 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- HLCPWBZNUKCSBN-UHFFFAOYSA-N 2-aminobenzonitrile Chemical compound NC1=CC=CC=C1C#N HLCPWBZNUKCSBN-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000005849 sulfamoylation reaction Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
Description
本開示は、３－アミノベンゾイソチアゾール誘導体及びその製造方法に関する。 The present disclosure relates to 3-aminobenziisothiazole derivatives and methods for producing the same.
３－アミノベンゾイソチアゾール誘導体は種々の用途に使用される。例えば、３－アミノベンゾイソチアゾール－５－スルホン酸が市販されており、医薬品、試薬等の中間体として有用とされている。３－アミノベンゾイソチアゾール－５－スルホン酸は、２－アミノベンゾニトリル（ＯＡＢＮ）にスルホン酸基を導入し、硫化水素ガスの存在下、過酸化水素を作用させて得られる。しかしながら、３－アミノベンゾイソチアゾール－５－スルホン酸の水酸基を直接アミノ化する方法及びアミノ化された化合物は知られていない。 3-Aminobenziisothiazole derivatives are used for various purposes. For example, 3-aminobenziisothiazole-5-sulfonic acid is commercially available and is said to be useful as an intermediate for pharmaceuticals, reagents, and the like. 3-Aminobenzisothiazole-5-sulfonic acid is obtained by introducing a sulfonic acid group into 2-aminobenzonitrile (OABN) and reacting it with hydrogen peroxide in the presence of hydrogen sulfide gas. However, a method for directly aminating the hydroxyl group of 3-aminobenziisothiazole-5-sulfonic acid and an aminated compound are not known.
本発明者らの検討によれば、３－アミノベンゾイソチアゾール－５－スルホン酸におけるベンゾイソチアゾールの５位に存在するスルホン酸基部分がハロゲン化された３－アミノベンゾ［ｃ］イソチアゾール－５－クロルスルホニル誘導体、及び上記クロルスルホニル基がスルファモイル化された３－アミノベンゾ［ｃ］イソチアゾール－５－スルホンアミド誘導体はいずれも新規化合物である。 According to studies by the present inventors, 3-aminobenzo[c]isothiazole-5 in which the sulfonic acid group moiety present at the 5-position of benzisothiazole in 3-aminobenzisothiazole-5-sulfonic acid is halogenated -Chlorsulfonyl derivatives and the 3-aminobenzo[c]isothiazole-5-sulfonamide derivatives in which the chlorsulfonyl group is sulfamoylated are both new compounds.
本開示の一実施形態が解決しようとする課題は、新規な３－アミノベンゾイソチアゾール誘導体を提供することである。
本開示の別の実施形態が解決しようとする課題は、新規な３－アミノベンゾイソチアゾール誘導体の製造方法を提供することである。
The problem to be solved by one embodiment of the present disclosure is to provide a novel 3-aminobenziisothiazole derivative.
A problem to be solved by another embodiment of the present disclosure is to provide a novel method for producing a 3-aminobenziisothiazole derivative.
上記課題を解決するための手段には、以下の態様が含まれる。 Means for solving the above problems include the following aspects.
＜１＞ 下記一般式（３）で表される３－アミノベンゾ［ｃ］イソチアゾール－５－スルホンアミド誘導体。 <1> A 3-aminobenzo[c]isothiazole-5-sulfonamide derivative represented by the following general formula (3).
一般式（３）中、Ｒ１、Ｒ２、及びＲ３はそれぞれ独立に、水素原子、炭素数１～４のアルキル基、ハロゲン原子、又は、ハロアルキル基を表す。 In general formula (3), R 1 , R 2 and R 3 each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a halogen atom, or a haloalkyl group.
＜２＞ 下記一般式（２）で表される３－アミノベンゾ［ｃ］イソチアゾール－５－クロルスルホニル誘導体。 <2> A 3-aminobenzo[c]isothiazole-5-chlorosulfonyl derivative represented by the following general formula (2).
一般式（２）中、Ｒ１、Ｒ２、及びＲ３はそれぞれ独立に、水素原子、炭素数１～４のアルキル基、ハロゲン原子、又は、ハロアルキル基を表す。 In general formula (2), R 1 , R 2 and R 3 each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a halogen atom, or a haloalkyl group.
＜３＞ 下記一般式（１）で表されるベンゾイソチアゾール誘導体と、ハロゲン化スルホン酸を含む反応溶媒とを反応させて、下記一般式（２－２）で表される３－アミノベンゾ［ｃ］イソチアゾール－５－ハロゲン化スルホニル誘導体を得る工程を含み、上記反応溶媒全量に対するハロゲン化スルホン酸以外の溶媒の含有量が１質量％未満である、下記一般式（３）で表される３－アミノベンゾ［ｃ］イソチアゾール－５－スルホンアミド誘導体の製造方法。 <3> 3-Aminobenzo [c ] 3 represented by the following general formula (3), which includes a step of obtaining an isothiazole-5-halogenated sulfonyl derivative, and the content of a solvent other than the halogenated sulfonic acid with respect to the total amount of the reaction solvent is less than 1% by mass. -Production method of aminobenzo[c]isothiazole-5-sulfonamide derivative.
一般式（１）中、Ｒ１、Ｒ２、及びＲ３はそれぞれ独立に、水素原子、炭素数１～４のアルキル基、ハロゲン原子、又は、ハロアルキル基を表す。
一般式（２－２）中、Ｒ１、Ｒ２、及びＲ３はそれぞれ独立に、水素原子、炭素数１～４のアルキル基、ハロゲン原子、又は、ハロアルキル基を表し、Ｒ４はハロゲン原子を表す。
In general formula (1), R 1 , R 2 and R 3 each independently represent 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 represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a halogen atom, or a haloalkyl group, and R 4 is a halogen atom. represents.
一般式（３）中、Ｒ１、Ｒ２、及びＲ３はそれぞれ独立に、水素原子、炭素数１～４のアルキル基、ハロゲン原子、又は、ハロアルキル基を表す。
In general formula (3), R 1 , R 2 and R 3 each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a halogen atom, or a haloalkyl group.
＜４＞ 上記一般式（２－２）で表される３－アミノベンゾ［ｃ］イソチアゾール－５－ハロゲン化スルホニル誘導体を単離することなく、アンモニアを含む反応溶媒と反応させ、上記一般式（３）で表される３－アミノベンゾ［ｃ］イソチアゾール－５－スルホンアミド誘導体を得る工程をさらに含む、＜３＞に記載の３－アミノベンゾ［ｃ］イソチアゾール－５－スルホンアミド誘導体の製造方法。 <4> Without isolating the 3-aminobenzo[c]isothiazole-5-halogenated sulfonyl derivative represented by the above general formula (2-2), it is reacted with a reaction solvent containing ammonia to form the above general formula ( 3) The method for producing a 3-aminobenzo[c]isothiazole-5-sulfonamide derivative according to <3>, further comprising the step of obtaining a 3-aminobenzo[c]isothiazole-5-sulfonamide derivative represented by .
＜５＞ 上記アンモニアを含む反応溶媒は、アンモニア水、又は、アンモニア水とテトラヒドロフランとの混合溶媒である、＜４＞に記載の３－アミノベンゾ［ｃ］イソチアゾール－５－スルホンアミド誘導体の製造方法。
＜５＞ 上記一般式（２－２）で表される３－アミノベンゾ［ｃ］イソチアゾール－５－ハロゲン化スルホニル誘導体と、アンモニアを含む反応溶媒との反応は、－１０℃～５℃の温度条件下で行われる、＜３＞又は＜４＞に記載の３－アミノベンゾ［ｃ］イソチアゾール－５－スルホンアミド誘導体の製造方法。
<5> The method for producing a 3-aminobenzo[c]isothiazole-5-sulfonamide derivative according to <4>, wherein the ammonia-containing reaction solvent is ammonia water or a mixed solvent of ammonia water and tetrahydrofuran. .
<5> The reaction between the 3-aminobenzo[c]isothiazole-5-halogenated sulfonyl derivative represented by the above general formula (2-2) and the reaction solvent containing ammonia is carried out at a temperature of -10°C to 5°C. A method for producing a 3-aminobenzo[c]isothiazole-5-sulfonamide derivative according to <3> or <4>, which is carried out under the following conditions.
本発明の一実施形態によれば、新規な３－アミノベンゾイソチアゾール誘導体を提供することができる。
本開示の別の実施形態によれば、新規な３－アミノベンゾイソチアゾール誘導体の製造方法を提供することができる。
According to one embodiment of the present invention, novel 3-aminobenziisothiazole derivatives can be provided.
According to another embodiment of the present disclosure, a method for producing a novel 3-aminobenziisothiazole derivative can be provided.
以下、本開示の内容について説明する。
以下に記載する構成要件の説明は、本開示の代表的な実施態様に基づいてなされることがあるが、本発明は以下の実施態様に限定されない。
本開示において「～」を用いて記載した数値範囲は、「～」の前後の数値を下限値及び上限値として含む数値範囲を表す。
本開示において記載される各成分の量は、当該成分に該当する物質が複数存在する場合、特に断らない限り、当該複数の物質の合計量を意味する。
本開示において段階的に記載されている数値範囲において、ある数値範囲で記載された上限値又は下限値は、他の段階的な記載の数値範囲の上限値又は下限値に置き換えてもよい。また、本開示に記載されている数値範囲において、ある数値範囲で記載された上限値又は下限値は、実施例に示されている値に置き換えてもよい。
本開示において、２以上の好ましい態様の組み合わせは、より好ましい態様である。
本明細書における化学構造式は、水素原子を省略した簡略構造式で記載する場合がある。
本開示において「工程」との語は、独立した工程だけでなく、他の工程と明確に区別できない場合であっても工程の所期の目的が達成されれば、本用語に含まれる。
The contents of the present disclosure will be explained below.
Although the description of the constituent elements described below may be made based on typical embodiments of the present disclosure, the present invention is not limited to the following embodiments.
In the present disclosure, a numerical range described using "~" represents a numerical range that includes the numbers before and after "~" as the lower limit and upper limit.
The amount of each component described in this disclosure means the total amount of the plurality of substances, unless otherwise specified, when there is a plurality of substances corresponding to the component.
In the numerical ranges described step by step in the present disclosure, the upper limit or lower limit described in a certain numerical range may be replaced with the upper limit or lower limit of another numerical range described step by step. Furthermore, in the numerical ranges described in this disclosure, the upper limit or lower limit described in a certain numerical range may be replaced with the value shown in the Examples.
In the present disclosure, a combination of two or more preferred embodiments is a more preferred embodiment.
The chemical structural formulas in this specification may be written as simplified structural formulas in which hydrogen atoms are omitted.
In the present disclosure, the term "step" is included not only in an independent step but also in the case where the intended purpose of the step is achieved even if the step cannot be clearly distinguished from other steps.
＜一般式（３）で表される３－アミノベンゾ［ｃ］イソチアゾール－５－スルホンアミド誘導体＞
下記一般式（３）で表される３－アミノベンゾ［ｃ］イソチアゾール－５－スルホンアミド誘導体（以下、「一般式（３）で表される化合物」とも称する）は新規化合物である。
<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 the general formula (3)") is a new compound.
一般式（３）中、Ｒ１、Ｒ２、及びＲ３はそれぞれ独立に、水素原子、炭素数１～４のアルキル基、ハロゲン原子、又は、ハロアルキル基を表す。
炭素数１～４のアルキル基としては、メチル基、エチル基、プロピル基、ｎ－ブチル基、ｉ－ブチル基、tert－ブチル基が挙げられ、なかでも、メチル基又はエチル基が好ましく挙げられる。
ハロゲン原子としては、Ｆ、Ｃｌ、Ｂｒ等が挙げられ、Ｃｌ又はＦが好ましく挙げられる。
ハロアルキル基としては、上記アルキル基の水素原子の少なくとも１つがハロゲン原子に置換された基が挙げられ、－ＣＦ３が好ましく挙げられる。
In general formula (3), R 1 , R 2 and R 3 each independently represent 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 methyl group, ethyl group, propyl group, n-butyl group, i-butyl group, and tert-butyl group, of which methyl group or ethyl group is preferably mentioned. .
Examples of the halogen atom include F, Cl, Br, etc., with Cl or F being preferred.
Examples of the haloalkyl group include groups in which at least one hydrogen atom of the above alkyl group is substituted with a halogen atom, and -CF 3 is preferably mentioned.
以下に、一般式（３）で表される化合物の具体例である例示化合物－１～例示化合物－９について、一般式（３）におけるＲ１、Ｒ２、及びＲ３を明示することで開示するが、一般式（３）で表される化合物は、下記例示化合物に限定されない。 Below, Exemplified Compound-1 to Exemplified Compound-9, which are specific examples of the compound represented by the general formula (3), will be disclosed by clearly specifying R 1 , R 2 , and R 3 in the general formula (3). However, the compound represented by general formula (3) is not limited to the exemplified compounds below.
上記例示化合物のなかでも、合成適性の観点からは、Ｒ１、Ｒ２、及びＲ３の全てが水素原子である例示化合物－１が好ましく挙げられる。 Among the above-mentioned exemplified compounds, from the viewpoint of synthesis suitability, exemplified compound-1 in which all of R 1 , R 2 , and R 3 are hydrogen atoms is preferred.
＜一般式（２）で表される３－アミノベンゾ［ｃ］イソチアゾール－５－クロルスルホニル誘導体＞
下記一般式（２）で表される３－アミノベンゾ［ｃ］イソチアゾール－５－クロルスルホニル誘導体（以下、「一般式（２）で表される化合物」とも称する）は新規化合物である。
<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 "the compound represented by the general formula (2)") is a new compound.
一般式（２）中、Ｒ１、Ｒ２、及びＲ３はそれぞれ独立に、水素原子、炭素数１～４のアルキル基、ハロゲン原子、又は、ハロアルキル基を表す。
炭素数１～４のアルキル基としては、メチル基、エチル基、プロピル基、ｎ－ブチル基、ｉ－ブチル基、tert－ブチル基が挙げられ、なかでも、メチル基又はエチル基が好ましく挙げられる。
ハロゲン原子としては、Ｆ、Ｃｌ、Ｂｒ等が挙げられ、Ｃｌ又はＦが好ましく挙げられる。
ハロアルキル基としては、上記アルキル基の水素原子の少なくとも１つがハロゲン原子に置換された基が挙げられ、－ＣＦ３が好ましく挙げられる。
In general formula (2), R 1 , R 2 and R 3 each independently represent 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 methyl group, ethyl group, propyl group, n-butyl group, i-butyl group, and tert-butyl group, of which methyl group or ethyl group is preferably mentioned. .
Examples of the halogen atom include F, Cl, Br, etc., with Cl or F being preferred.
Examples of the haloalkyl group include groups in which at least one hydrogen atom of the above alkyl group is substituted with a halogen atom, and -CF 3 is preferably mentioned.
一般式（２）で表される化合物としては、合成適性の観点からは、Ｒ１、Ｒ２、及びＲ３の全てが水素原子である化合物が好ましく挙げられる。 As the compound represented by the general formula (2), from the viewpoint of synthesis suitability, a compound in which all of R 1 , R 2 , and R 3 are hydrogen atoms is preferably mentioned.
一般式（２）で表される化合物は、上記一般式（３）で表される化合物を合成する際の中間体として有用であり、一般式（２）におけるクロルスルホニル基のＣｌをアミノ基に置換することで、一般式（３）で表される化合物が得られる。 The compound represented by the general formula (2) is useful as an intermediate when synthesizing the compound represented by the above general formula (3), and Cl of the chlorosulfonyl group in the general formula (2) is replaced with an amino group. By substitution, a compound represented by general formula (3) can be obtained.
＜一般式（３）で表される３－アミノベンゾ［ｃ］イソチアゾール－５－スルホンアミド誘導体の製造方法＞
上記一般式（３）で表される化合物の製造方法には特に制限はなく、公知の合成方法により製造できる。
なかでも、収率がより高いという観点からは、以下に示す一般式（３）で表される３－アミノベンゾ［ｃ］イソチアゾール－５－スルホンアミド誘導体の製造方法（以下、「本開示の製造方法」とも称する）により製造されることが好ましい。
<Method for producing 3-aminobenzo[c]isothiazole-5-sulfonamide derivative represented by general formula (3)>
There are no particular restrictions on the method for producing the compound represented by the above general formula (3), and the compound can be produced by any known synthesis method.
Among these, from the viewpoint of higher yield, the method for producing a 3-aminobenzo[c]isothiazole-5-sulfonamide derivative represented by the general formula (3) shown below (hereinafter referred to as "the production method of the present disclosure" (also referred to as "method") is preferable.
本開示の製造方法は、下記一般式（１）で表されるベンゾイソチアゾール誘導体〔以下、「一般式（１）で表される化合物」とも称する）と、ハロゲン化スルホン酸を含む反応溶媒とを反応させて、下記一般式（２－２）で表される３－アミノベンゾ［ｃ］イソチアゾール－５－ハロゲン化スルホニル誘導体を得る工程（Ｉ）を含み、上記反応溶媒全量に対するハロゲン化スルホン酸以外の溶媒の含有量が１質量％未満である。 The manufacturing method of the present disclosure comprises a benziisothiazole derivative represented by the following general formula (1) (hereinafter also referred to as "compound represented by general formula (1)") and a reaction solvent containing a halogenated sulfonic acid. (I) to obtain a 3-aminobenzo[c]isothiazole-5-halogenated sulfonyl derivative represented by the following general formula (2-2) by reacting the halogenated sulfonic acid with respect to the total amount of the reaction solvent. The content of other solvents is less than 1% by mass.
一般式（１）中、Ｒ１、Ｒ２、及びＲ３はそれぞれ独立に、水素原子、炭素数１～４のアルキル基、ハロゲン原子、又は、ハロアルキル基を表す。
一般式（１）におけるＲ１、Ｒ２、及びＲ３は、既述の一般式（２）で表される化合物におけるＲ１、Ｒ２、及びＲ３と同じであり、好ましい例も同様である。
一般式（２－２）中、Ｒ１、Ｒ２、及びＲ３はそれぞれ独立に、水素原子、炭素数１～４のアルキル基、ハロゲン原子、又は、ハロアルキル基を表し、Ｒ４はハロゲン原子を表す。
一般式（２－２）におけるＲ１、Ｒ２、及びＲ３は、既述の一般式（２）で表される化合物におけるＲ１、Ｒ２、及びＲ３と同じであり、好ましい例も同様である。
一般式（２－２）におけるＲ４は、ハロゲン原子を表し、ハロゲン原子としては、Ｃｌ、Ｂｒが挙げられ、反応性の観点からは、Ｃｌが好ましい。
一般式（２－２）におけるＲ４がＣｌである化合物が、既述の本開示の一般式（２）で表される化合物である。
In general formula (1), R 1 , R 2 and R 3 each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a halogen atom, or a haloalkyl group.
R 1 , R 2 , and R 3 in general formula (1) are the same as R 1 , R 2 , and R 3 in the compound represented by general formula (2) described above, and preferred examples are also the same. be.
In general formula (2-2), R 1 , R 2 , and R 3 each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a halogen atom, or a haloalkyl group, and R 4 is a halogen atom. represents.
R 1 , R 2 , and R 3 in the general formula (2-2) are the same as R 1 , R 2 , and R 3 in the compound represented by the general formula (2) described above, and preferred examples are also The same is true.
R 4 in the general formula (2-2) represents a halogen atom, and examples of the halogen atom include Cl and Br, with Cl being preferred from the viewpoint of reactivity.
A compound in which R 4 in general formula (2-2) is Cl is a compound represented by general formula (2) of the present disclosure described above.
〔工程Ｉ〕
工程Ｉにおける上記反応では、一般式（１）で表される化合物にハロゲン化スルホン酸基を導入する際には、ハロゲン化スルホン酸（ＨＳＯ３Ａ、Ａはハロゲン原子を表す）を含む反応溶媒を用いる。
ハロゲン化スルホン酸としては、クロルスルホン酸（ＨＳＯ３Ｃｌ）、ブロムスルホン酸（ＨＳＯ３Ｂｒ）等が挙げられ、より高い収率を期待できるという観点からは、クロルスルホン酸が好ましい。
クロルスルホン酸は液状であり、反応溶媒として用いることで、上記スキームの良好な反応性が得られる。従って、工程Ｉにおける反応溶媒は、クロルスルホン酸のみでよく、クロルスルホン酸以外の溶媒の併用は特に必要はない。併用し得る溶媒としては、ハロゲン系有機溶剤が挙げられる。反応溶媒全量に対するハロゲン化スルホン酸以外の溶媒の含有量は１質量％未満であることが、反応性及び副反応の抑制の観点から好ましく、不可避不純物としての溶媒を除き、ハロゲン化スルホン酸のみを反応溶媒として用いることがより好ましい。
なお、クロルスルホン酸は、水と接触すると激しく反応するため、反応溶媒に水を混入させないことが好ましい。
[Process I]
In the above reaction in Step I, when introducing a halogenated sulfonic acid group into the compound represented by general formula (1), a reaction solvent containing halogenated sulfonic acid (HSO 3 A, A represents a halogen atom) is used. Use.
Examples of the halogenated sulfonic acid include chlorosulfonic acid (HSO 3 Cl), bromesulfonic acid (HSO 3 Br), and the like, and chlorosulfonic acid is preferable from the viewpoint that a higher yield can be expected.
Chlorsulfonic acid is in a liquid state, and by using it as a reaction solvent, good reactivity in the above scheme can be obtained. Therefore, the reaction solvent in Step I may be only chlorosulfonic acid, 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. It is preferable that the content of the solvent other than the halogenated sulfonic acid to the total amount of the reaction solvent is less than 1% by mass from the viewpoint of reactivity and suppression of side reactions. It is more preferable to use it as a reaction solvent.
In addition, since chlorosulfonic acid reacts violently when it comes into contact with water, it is preferable not to mix water into the reaction solvent.
反応溶媒としてハロゲン化スルホン酸と一般式（１）で表される化合物とを反応させる工程Ｉの具体的な手順の一例を以下に記載する。
一般式（１）で表される化合物とハロゲン化スルホン酸との反応は、発熱反応であるため、反応容器内にハロゲン化スルホン酸を投入し、氷冷下で撹拌しながら、一般式（１）で表される化合物を添加する。
分割添加の速度は、８ｇ／ｍｉｎ～１０ｇ／ｍｉｎとすることができる。
反応は、反応容器内の液の温度（以下、液温とも称する）を２０℃以下に維持しながら継続することが好ましい。反応容器内の温度は、０℃～２０℃に維持することが好ましく、５℃～２０℃に維持することがより好ましい。
一般式（１）で表される化合物を全量添加するまで、撹拌及び反応容器内の液温を上記温度に維持することを継続する。
一般式（１）で表される化合物に対する反応溶媒としてのハロゲン化スルホン酸の使用量は、質量換算で、一般式（１）で表される化合物：ハロゲン化スルホン酸の比率を１：６～１：６．５とすることができる。
An example of a specific procedure of Step I in which a halogenated sulfonic acid and a compound represented by general formula (1) are reacted as a reaction solvent will be described below.
Since the reaction between the compound represented by the general formula (1) and the halogenated sulfonic acid is an exothermic reaction, the halogenated sulfonic acid is charged into a reaction vessel, and while stirring under ice cooling, the general formula (1) ) is added.
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 container (hereinafter also referred to as liquid temperature) at 20° C. or lower. The temperature inside the reaction vessel is preferably maintained at 0°C to 20°C, more preferably 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 the halogenated sulfonic acid to be used as a reaction solvent for the compound represented by the general formula (1) is the ratio of the compound represented by the general formula (1) to the halogenated sulfonic acid from 1:6 to 1:6 in terms of mass. The ratio can be 1:6.5.
一般式（１）で表される化合物を全量添加した後、反応容器内の温度を３０℃～４５℃、好ましくは３５℃～４０℃に昇温し、反応を継続することが好ましい。反応は、１時間～２時間継続することが好ましく、１時間～１．５時間継続することがより好ましい。
反応終了後、反応容器内の液温を１０℃～２０℃に冷却することが好ましく、１２℃～１５℃に冷却することがより好ましい。
別工程として、氷の中に食塩、濃塩酸、及びアセトンを適量添加して晶析液を調製することが好ましい。
得られた晶析液を満たした反応容器内の液温を－１０℃～－２℃に冷却して撹拌を継続しながら、先に得た反応液の液温を１０℃以下に維持しながら滴下することが好ましい。滴下速度は、２０ｇ／ｍｉｎ～３０ｇ／ｍｉｎとすることができる。
滴下終了後、反応容器内の液温を０℃～１２℃に維持して所定時間撹拌を行うことが好ましい。撹拌時間は、１５分間～４５分間とすることができる。
After adding the entire amount of the compound represented by formula (1), it is preferable to raise the temperature inside the reaction vessel to 30°C to 45°C, preferably 35°C to 40°C, and continue the reaction. The reaction is preferably continued for 1 hour to 2 hours, more preferably 1 hour to 1.5 hours.
After the reaction is completed, the temperature of the liquid in the reaction vessel is preferably cooled to 10°C to 20°C, more preferably 12°C to 15°C.
As a separate step, it is preferable to prepare a crystallization solution by adding appropriate amounts of common salt, concentrated hydrochloric acid, and acetone to ice.
While cooling the liquid temperature in the reaction vessel filled with the obtained crystallized liquid to -10°C to -2°C and continuing stirring, while maintaining the liquid temperature of the previously obtained reaction liquid below 10°C. Dripping is preferred. The dropping rate can be 20 g/min to 30 g/min.
After the dropwise addition is completed, it is preferable to maintain the liquid temperature in the reaction vessel at 0° C. to 12° C. and stir for a predetermined period of time. Stirring time can be from 15 minutes to 45 minutes.
撹拌継続後、吸引ろ過を行って、一般式（２－２）で表される化合物を含む反応液から、残余の反応溶媒を除去する。反応溶媒等を吸引ろ過して除去した後に得られた固形分は、一般式（２）で表される化合物を含む。得られた一般式（２－２）で表される化合物を含む固形分は、単離、及び、乾燥することなく、後述の一般式（３）で示される化合物の合成に使用することができる。
工程Ｉにより得られた一般式（２－２）で表される３－アミノベンゾ［ｃ］イソチアゾール－５－ハロゲン化スルホニル誘導体、好ましくは、一般式（２）で表される３－アミノベンゾ［ｃ］イソチアゾール－５－クロルスルホニル誘導体は、不安定な化合物であるため、次工程である工程ＩＩにおいては、一般式（２－２）で表される化合物は、工程Ｉの反応終了後、ハロゲン化スルホン酸を含む反応溶媒をろ過により除去した後、得られた化合物を、単離、及び、乾燥することなく、反応溶媒と分離された固形分をそのまま工程ＩＩのスルファモイル化反応に供することが好ましい。
After continued stirring, suction filtration is performed to remove the remaining reaction solvent from the reaction solution containing the compound represented by general formula (2-2). The solid content obtained after removing the reaction solvent and the like by suction filtration contains a 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-halogenated sulfonyl derivative represented by the general formula (2) ] Since the isothiazole-5-chlorosulfonyl derivative is an unstable compound, in the next step, Step II, the compound represented by the general formula (2-2) is treated with a halogen after the reaction in Step I is completed. After removing the reaction solvent containing sulfonic acid by filtration, the resulting compound can be subjected to the sulfamoylation reaction in step II without isolating and drying the solid content separated from the reaction solvent. preferable.
〔工程ＩＩ〕
本開示の製造方法は、工程Ｉの次工程として、一般式（２－２）で表される３－アミノベンゾ［ｃ］イソチアゾール－５－ハロゲン化スルホニル誘導体を単離することなく、アンモニアを含む反応溶媒と反応させ、既述の一般式（３）で表される３－アミノベンゾ［ｃ］イソチアゾール－５－スルホンアミド誘導体を得る工程ＩＩをさらに含むことが好ましい。
工程Ｉにより得られた一般式（２－２）で表される化合物に導入されたハロゲン化スルホニル基のハロゲン原子をアミノ化することにより、一般式（３）で表される化合物を得る。
[Step II]
The production method of the present disclosure includes ammonia as the next step of Step I without isolating the 3-aminobenzo[c]isothiazole-5-halogenated sulfonyl derivative represented by general formula (2-2). It is preferable to further include step II of reacting with a reaction solvent to obtain a 3-aminobenzo[c]isothiazole-5-sulfonamide derivative represented by the aforementioned general formula (3).
By aminating the halogen atom of the halogenated sulfonyl group introduced into the compound represented by general formula (2-2) obtained in Step I, a compound represented by general formula (3) is obtained.
工程ＩＩでは、一般式（２－２）で表される化合物とアンモニアを含む反応溶媒との反応により、一般式（２－２）で表される化合物のハロゲン化スルホニル基におけるハロゲン原子部分がアミノ化され、一般式（３）で表される化合物が得られる。
アンモニアを含む反応溶媒としては、アンモニア水、アンモニア水と有機溶剤との混合溶媒が挙げられる。
反応溶媒としてのアンモニア水は、濃度が１５質量％～５０質量％が好ましく、２０質量％～３０質量％がより好ましい。
混合溶媒に用いられる有機溶剤としては、アセトニトリル、テトラヒドロフラン、イソプロピルアルコール等が挙げられる。
混合溶媒は、アンモニア水と有機溶媒との混合比率を、体積換算で０．５：１．５～１：１．３の範囲とすることができる。
工程ＩＩにおける反応溶媒としては、アンモニア水、又は、アンモニア水とテトラヒドロフランとの混合溶媒が好ましい。
また、アンモニアの有機溶剤溶液（例えば、アンモニアの２－プロピルアルコール溶液等）を反応溶媒として用いてもよい。
In step II, the halogen atom moiety in the halogenated sulfonyl group of the compound represented by general formula (2-2) is converted to amino by the reaction of the compound represented by general formula (2-2) with a reaction solvent containing ammonia. A compound represented by the general formula (3) is obtained.
Examples of the reaction solvent containing ammonia include ammonia water and a mixed solvent of ammonia water and an organic solvent.
The concentration of ammonia water as a reaction solvent is preferably 15% by mass to 50% by mass, more preferably 20% by mass to 30% by mass.
Examples of the organic solvent used in the mixed solvent include acetonitrile, tetrahydrofuran, isopropyl alcohol, and the like.
In the mixed solvent, the mixing ratio of aqueous ammonia and organic solvent can be in the range of 0.5:1.5 to 1:1.3 in terms of volume.
As the reaction solvent in step II, aqueous ammonia or a mixed solvent of aqueous ammonia and tetrahydrofuran is preferable.
Further, a solution of ammonia in an organic solvent (for example, a solution of ammonia in 2-propyl alcohol, etc.) may be used as the reaction solvent.
まず、反応溶媒を反応容器内に投入し、反応容器内の液温を－１０℃～５℃に維持しながら、撹拌を継続し、工程Ｉで得た一般式（２－２）で表される化合物を含む固形分の全量を添加する。
即ち、一般式（２－２）で表される３－アミノベンゾ［ｃ］イソチアゾール－５－ハロゲン化スルホニル誘導体と、アンモニアを含む反応溶媒との反応は、－１０℃～５℃の温度条件下で行われることが好ましい。
工程ＩＩにおける、反応溶媒に含まれるアンモニアと一般式（２－２）で表される化合物との反応は、発熱反応であるため、反応容器内の温度を、例えば、予め０℃以下に冷却し、反応を開始させることが好ましい。
反応容器内の温度は－１０℃～５℃とすることが好ましく、０℃～５℃に維持することがより好ましい。反応は、１５分間～６０分間撹拌を継続して行うことが好ましい。
その後、反応容器内の液温を１５℃～３０℃にて、５０分間～９０分間撹拌を継続することが好ましい。
次いで、反応系のｐＨを、ｐＨ７～８に下げるため、濃塩酸を、容器内の液温を２０℃以下、好ましくは、１０℃～２０℃に保持して滴下し、その後、水を容器内の温度を２０℃以下に維持しながら滴下する。水の滴下後、反応容器内の液温を２０℃に維持して３０分間撹拌した後、液温を５℃に降温し、さらに２時間撹拌する。
水の添加量は、濃塩酸の添加量に対し、体積換算で５倍量以上添加することが好ましく、６倍以上添加することがより好ましい。水の添加量には、特に制限はないが、体積換算で、６．５倍以下とすることができる。
その後、吸引ろ過を行い、一般式（３）で表される化合物を分取する。分取した固形物は、水にて洗浄を行って、一般式（３）で表される化合物の黄色結晶を得ることができる。
First, the reaction solvent was poured into the reaction container, and stirring was continued while maintaining the liquid temperature in the reaction container at -10°C to 5°C. Add the entire amount of solids containing the compound.
That is, the reaction between the 3-aminobenzo[c]isothiazole-5-halogenated sulfonyl derivative represented by the general formula (2-2) and the reaction solvent containing ammonia is carried out at a temperature of -10°C to 5°C. It is preferable that the process be carried out in
Since the reaction between the ammonia contained in the reaction solvent and the compound represented by general formula (2-2) in Step II is an exothermic reaction, the temperature inside the reaction vessel is cooled in advance to, for example, 0°C or less. , preferably to initiate the reaction.
The temperature inside the reaction vessel is preferably maintained at -10°C to 5°C, more preferably between 0°C and 5°C. The reaction is preferably carried out with continuous stirring for 15 to 60 minutes.
Thereafter, it is preferable to maintain the liquid temperature in the reaction vessel at 15° C. to 30° C. and continue stirring for 50 minutes 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 maintaining the liquid temperature in the container at 20°C or less, preferably 10°C to 20°C, and then water is poured into the container. dropwise while maintaining the temperature below 20°C. After dropping water, 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 further stirred for 2 hours.
The amount of water added is preferably 5 times or more, more preferably 6 times or more, in terms of volume, relative to the amount of concentrated hydrochloric acid added. There is no particular limit to the amount of water added, but it can be 6.5 times or less in terms of volume.
Thereafter, suction filtration is performed to separate the compound represented by general formula (3). The separated solid matter can be washed with water to obtain yellow crystals of the compound represented by general formula (3).
一般式（３）で表される化合物の存在は、ＮＭＲ等で確認することができる。
なお、一般式（２）で表される化合物は、単離されてはいないが、下記反応スキームより、一般式（３）で示される化合物の中間体であり、下記構造を有することは明らかであり、一般式（２）で表される化合物が新規化合物であることは確認されている。下記一般式（３）及び一般式（２）におけるＲ１、Ｒ２、及びＲ３は既述のとおりである。
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. It has been confirmed that the compound represented by general formula (2) is a new compound. R 1 , R 2 , and R 3 in the following general formulas (3) and (2) are as described above.
本開示の一般式（３）で表される化合物、及び一般式（２）で表される化合物は、公知の化合物である３－アミノベンゾイソチアゾール－５－スルホン酸と同様に、種々の用途に好適に使用することができる。
また、本開示の製造方法によれば、一般式（３）で表される化合物を収率よく製造することができる。
The compound represented by the general formula (3) and the compound represented by the general formula (2) of the present disclosure have various uses, similar to the known compound 3-aminobenziisothiazole-5-sulfonic acid. It can be suitably used for.
Moreover, according to the production method of the present disclosure, the compound represented by general formula (3) can be produced with good yield.
以下、実施例により本発明を詳細に説明する。以下の実施例に示す材料、使用量、割合、処理内容、及び、処理手順等は、趣旨を逸脱しない限り、適宜、変更することができる。したがって、本開示の実施形態の範囲は以下に示す具体例に限定されない。 Hereinafter, the present invention will be explained in detail with reference to Examples. The materials, amounts used, proportions, processing details, processing procedures, etc. shown in the following examples can be changed as appropriate without departing from the spirit. Therefore, the scope of the embodiments of the present disclosure is not limited to the specific examples shown below.
〔実施例１〕
＜一般式（２）で表される化合物の合成：工程Ｉ＞
クロルスルホン酸５０２．７gを反応容器内に投入し、氷冷下、撹拌を継続しながら、一般式（１）で表される化合物であって、Ｒ１、Ｒ２、及びＲ３のいずれもが水素原子である下記化合物Ａ ８１．０gを、反応容器内の液温を２０℃以下に維持しながら、分割添加した。
[Example 1]
<Synthesis of compound represented by general formula (2): Step I>
502.7 g of chlorosulfonic acid was put into a reaction vessel, and while stirring was continued under ice cooling, a compound represented by the general formula (1), in which none of R 1 , R 2 , and R 3 was added, was added. 81.0 g of the following compound A, in which is a hydrogen atom, was added in portions while maintaining the liquid temperature in the reaction vessel at 20° C. or lower.
その後、反応容器内の液温を４０℃に上げて１時間半、撹拌を継続しながら反応を行った。反応終了後、反応容器内の液温を１５℃に冷却して、反応液を得た。 Thereafter, the temperature of the liquid in the reaction vessel was raised to 40° C., and the reaction was carried out for 1.5 hours while stirring was continued. After the reaction was completed, the temperature of the liquid in the reaction vessel was cooled to 15°C to obtain a reaction liquid.
氷１３２０ｇの中に食塩８０ｇ、濃塩酸１６０ｍＬ（ミリリットル）、アセトン４０ｍＬを添加して、晶析液を調製した。得られた晶析液を別の反応容器に投入し、反応容器内の液温を－５℃として撹拌を継続しながら、先に得た反応液を、晶析液中に滴下した。
晶析液が投入された反応容器内の液温を１０℃以下維持して、３０分間撹拌を行った。撹拌終了後、析出した固形分を、吸引ろ過して、反応溶媒を除去し、固形分を分取した。濾過した一般式（２）で表される化合物である下記化合物Ｂの結晶を含む固形分は乾燥することなく、以下の工程ＩＩにおいて、一般式（３）で表される化合物の合成に使用した。
A crystallization solution was prepared by adding 80 g of common salt, 160 mL (milliliter) of concentrated hydrochloric acid, and 40 mL of acetone to 1,320 g of ice. The obtained crystallization liquid was put into another reaction vessel, and the liquid temperature in the reaction vessel was kept at -5°C, and while stirring was continued, the previously obtained reaction liquid was dropped into the crystallization liquid.
The liquid temperature in the reaction vessel into which the crystallization liquid was charged was maintained at 10° C. or less, and stirring was performed for 30 minutes. After the stirring was completed, the precipitated solid content was suction-filtered to remove the reaction solvent, and the solid content was fractionated. The filtered solid content containing crystals of the following compound B, which is a compound represented by general formula (2), was used for the synthesis of a compound represented by general formula (3) in the following step II without drying. .
＜一般式（３）で表される化合物の合成：工程ＩＩ＞
反応容器内にアセトニトリル２００ｍＬを投入し、さらに２５質量％アンモニア水１７０ｍＬを添加した後、反応容器内の液温を０℃～５℃として撹拌を行って混合溶媒を得た。上記工程Ｉで得た化合物Ｂを含む固形分の全量を、反応容器内に、反応容器内の液温を０℃～５℃に維持しながら添加した。反応容器内の液温を０℃～５℃に維持しながら３０分間撹拌し、その後、反応容器内の液温を２０℃に昇温して、さらに１時間撹拌を行った。
次いで、反応系のｐＨをｐＨ７～８に調整するため濃塩酸８０ｍＬを、反応容器内の液温を２０℃以下に保持して滴下し、その後、さらに、水５２０ｍＬを同温度で滴下した。
反応容器内の液温を２０℃に維持して３０分間撹拌した後、液温を５℃に降温して２時間撹拌した。撹拌終了後、吸引ろ過により固形分を分取し、水２４０ｍＬにて洗浄を行なって、一般式（３）で表される化合物である下記例示化合物－１の黄色結晶を８７．８ｇ得た。
反応率は７７％であり、収率は７１％であつた。
<Synthesis of compound represented by general formula (3): Step II>
After putting 200 mL of acetonitrile into the reaction container and further adding 170 mL of 25% by mass aqueous ammonia, the liquid temperature in the reaction container was brought to 0° C. to 5° C. and stirring was performed to obtain a mixed solvent. The entire amount of the solid content containing Compound B obtained in Step I above was added into the reaction vessel while maintaining the liquid temperature in the reaction vessel at 0°C to 5°C. The mixture was stirred for 30 minutes while maintaining the temperature of the liquid in the reaction vessel at 0°C to 5°C, and then the temperature of the liquid in the reaction vessel was raised to 20°C, and stirring was continued for an additional hour.
Next, in order to adjust the pH of the reaction system to pH 7 to 8, 80 mL of concentrated hydrochloric acid was added dropwise while maintaining the liquid temperature in the reaction vessel at 20° C. or lower, and then 520 mL of water was further added dropwise at the same temperature.
After stirring for 30 minutes while maintaining the liquid temperature in the reaction vessel at 20°C, the liquid temperature was lowered to 5°C and stirred for 2 hours. After the 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 Exemplified Compound-1, which is a compound represented by general formula (3).
The reaction rate was 77% and the yield was 71%.
＜例示化合物－１の確認＞
得られた黄色結晶の核磁気共鳴装置（ＮＭＲ）により得たスペクトル：１Ｈ－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スペクトルにより、得られた化合物は、３－アミノベンゾ［ｃ］イソチアゾール－５－スルホンアミドの構造を有することを確認した。
<Confirmation of Exemplary Compound-1>
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)
The NMR spectrum confirmed that the obtained compound had a structure of 3-aminobenzo[c]isothiazole-5-sulfonamide.
〔実施例２〕
＜一般式（２）で表される化合物の合成：工程Ｉ＞
実施例１の工程Ｉと同様にして、一般式（２）で表される化合物である上記化合物Ｂを含む固形分を得た。化合物Ｂの結晶を含む固形分は乾燥することなく、以下の工程ＩＩにおいて、一般式（３）で表される化合物の合成に使用した。
[Example 2]
<Synthesis of compound represented by general formula (2): Step I>
In the same manner as in Step I of Example 1, a solid content containing the above compound B, which is a compound represented by general formula (2), was obtained. The solid content containing crystals of Compound B was used in the following Step II to synthesize a compound represented by general formula (3) without drying.
＜一般式（３）で表される化合物の合成：工程ＩＩ＞
アンモニアを２ｍｏｌ／Ｌ含む２－プロパノール溶液１１３０ｍＬを、反応容器内に投入し、反応容器内の液温を０℃～５℃に維持しながら撹拌を行い、上記で得た化合物Ｂを含む固形分の全量を、反応容器内の液温を０℃～５℃に維持しながら添加した。液温を０℃～５℃として、３０分間撹拌を行い、その後、液温を２０℃に昇温して１時間撹拌を行った。
次いで、反応系のｐＨをｐＨ７～８に調整するため濃塩酸８０ｍＬを、反応容器内の液温を２０℃以下に保持して滴下し、その後、さらに、水５２０ｍＬを同温度で滴下した。
反応容器内の液温を２０℃に維持して３０分間撹拌した後、液温を５℃に降温して２時間撹拌した。撹拌終了後、吸引ろ過により固形分を分取し、水２４０ｍＬにて洗浄を行なって、一般式（３）で表される化合物の黄色結晶を６１．８ｇ得た。
反応率は７６％であり、収率は５０％であった。
実施例１と同様の条件にてＮＭＲスペクトルを得たところ、得られた化合物は、例示化合物－１の構造を有することを確認した。
<Synthesis of compound represented by general formula (3): Step II>
Pour 1130 mL of a 2-propanol solution containing 2 mol/L of ammonia into a reaction container, stir while maintaining the liquid temperature in the reaction container at 0°C to 5°C, and solid content containing compound B obtained above. was added while maintaining the liquid temperature in the reaction vessel at 0°C to 5°C. The liquid temperature was set at 0°C to 5°C, and stirring was performed for 30 minutes, and then the liquid temperature was raised to 20°C, and stirring was performed for 1 hour.
Next, in order to adjust the pH of the reaction system to pH 7 to 8, 80 mL of concentrated hydrochloric acid was added dropwise while maintaining the liquid temperature in the reaction vessel at 20° C. or lower, and then 520 mL of water was further added dropwise at the same temperature.
After stirring for 30 minutes while maintaining the liquid temperature in the reaction vessel at 20°C, the liquid temperature was lowered to 5°C and stirred for 2 hours. After the 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.
〔実施例３〕
＜一般式（２）で表される化合物の合成：工程Ｉ＞
実施例１の工程Ｉと同様にして、一般式（２）で表される化合物である上記化合物Ｂを含む固形分を得た。化合物Ｂの結晶を含む固形分は乾燥することなく、以下の工程ＩＩにおいて、一般式（３）で表される化合物の合成に使用した。
[Example 3]
<Synthesis of compound represented by general formula (2): Step I>
In the same manner as in Step I of Example 1, a solid content containing the above compound B, which is a compound represented by general formula (2), was obtained. The solid content containing crystals of Compound B was used in the following Step II to synthesize a compound represented by general formula (3) without drying.
＜一般式（３）で表される化合物の合成：工程ＩＩ＞
イソプロピルアルコール２００ｍＬ中に２５質量％アンモニア水１７０ｍＬを反応容器内に投入し、反応容器内の液温を０℃～５℃に維持しながら撹拌を行い、上記で得た化合物Ｂを含む固形分の全量を、液温を０℃～５℃に維持しながら添加した。液温を０℃～５℃として、３０分間撹拌を行い、その後、反応容器内の液温を２０℃に昇温して１時間撹拌を行った。
次いで、反応系のｐＨをｐＨ７～８に調整するため濃塩酸８０ｍＬを、反応容器内の液温を２０℃以下に保持して滴下し、その後、さらに、水５２０ｍＬを同温度で滴下した。
反応容器内の液温を２０℃に維持して３０分間撹拌した後、液温を５℃に降温して２時間撹拌した。撹拌終了後、吸引ろ過により固形分を分取し、水２４０ｍＬにて洗浄を行なって、一般式（３）で表される化合物の黄色結晶を６８．０ｇ得た。
反応率は６７％であり、収率は５５％であった。
実施例１と同様の条件にてＮＭＲスペクトルを得たところ、得られた化合物は、例示化合物－１の構造を有することを確認した。
<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 into a reaction vessel, and the mixture was stirred while maintaining the liquid temperature in the reaction vessel at 0°C to 5°C to remove the solid content containing the compound B obtained above. The entire amount was added while maintaining the liquid temperature at 0°C to 5°C. The liquid temperature was set at 0°C to 5°C, and stirring was performed for 30 minutes, and then the liquid temperature in the reaction vessel was raised to 20°C, and stirring was performed for 1 hour.
Next, in order to adjust the pH of the reaction system to pH 7 to 8, 80 mL of concentrated hydrochloric acid was added dropwise while maintaining the liquid temperature in the reaction vessel at 20° C. or lower, and then 520 mL of water was further added dropwise at the same temperature.
After stirring for 30 minutes while maintaining the liquid temperature in the reaction vessel at 20°C, the liquid temperature was lowered to 5°C and stirred for 2 hours. After the 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.
〔実施例４〕
＜一般式（２）で表される化合物の合成：工程Ｉ＞
実施例１の工程Ｉと同様にして、一般式（２）で表される化合物である上記化合物Ｂを含む固形分を得た。化合物Ｂの結晶を含む固形分は乾燥することなく、以下の工程ＩＩにおいて、一般式（３）で表される化合物の合成に使用した。
[Example 4]
<Synthesis of compound represented by general formula (2): Step I>
In the same manner as in Step I of Example 1, a solid content containing the above compound B, which is a compound represented by general formula (2), was obtained. The solid content containing crystals of Compound B was used in the following Step II to synthesize a compound represented by general formula (3) without drying.
＜一般式（３）で表される化合物の合成：工程ＩＩ＞
テトラヒドロフラン２００ｍＬに２５質量％アンモニア水１７０ｍＬを混合して得た混合溶媒を反応容器内に投入し、反応容器の液温を０℃～５℃に維持しながら撹拌を行い、上記で得た化合物Ｂの全量を、液温を０℃～５℃に維持しながら添加した。液温を０℃～５℃として、３０分間撹拌を行い、その後、液温を２０℃に昇温して１時間撹拌を行った。
次いで、反応系のｐＨをｐＨ７～８に調整するため濃塩酸８０ｍＬを、反応容器内の液温を２０℃以下に保持して滴下し、その後、さらに、水５２０ｍＬを同温度で滴下した。
反応容器内の液温を２０℃に維持して３０分間撹拌した後、液温を５℃に降温して２時間撹拌した。撹拌終了後、吸引ろ過により固形分を分取し、水２４０ｍＬにて洗浄を行なって、一般式（３）で表される化合物の黄色結晶９２．７ｇを得た。
反応率は８６％であり、収率は７５％であった。
実施例１と同様の条件にてＮＭＲスペクトルを得たところ、得られた化合物は、例示化合物－１の構造を有することを確認した。
<Synthesis of compound represented by general formula (3): Step II>
A mixed solvent obtained by mixing 200 mL of tetrahydrofuran and 170 mL of 25% by mass aqueous ammonia was poured into a reaction container, and stirring was performed while maintaining the liquid temperature in the reaction container at 0 ° C. to 5 ° C. to form the compound B obtained above. was added while maintaining the liquid temperature at 0°C to 5°C. The liquid temperature was set at 0°C to 5°C, and stirring was performed for 30 minutes, and then the liquid temperature was raised to 20°C, and stirring was performed for 1 hour.
Next, in order to adjust the pH of the reaction system to pH 7 to 8, 80 mL of concentrated hydrochloric acid was added dropwise while maintaining the liquid temperature in the reaction vessel at 20° C. or lower, and then 520 mL of water was further added dropwise at the same temperature.
After stirring for 30 minutes while maintaining the liquid temperature in the reaction vessel at 20°C, the liquid temperature was lowered to 5°C and stirred for 2 hours. After the 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.
実施例１～実施例４に明らかな如く、各実施例の製造方法により、新規化合物である一般式（３）で表される化合物、及び、その中間体である一般式（２）で表される化合物を得ることができた。
また、各実施例の対比より、一般式（２）で示される化合物から一般式（３）で表される化合物を合成する工程ＩＩでは、アンモニア水とアセトニトリルとの混合溶媒を用いた実施例１、及び、アンモニア水とテトラヒドロフランとの混合溶媒を用いた実施例４は、収率がより良好であることが分かる。
As is clear from Examples 1 to 4, the production method of each Example produced a novel compound represented by the general formula (3) and an intermediate thereof represented by the general formula (2). We were able to obtain a compound.
In addition, from the comparison of each example, in step II of synthesizing the compound represented by general formula (3) from the compound represented by general formula (2), Example 1 using a mixed solvent of aqueous ammonia and acetonitrile It can be seen that Example 4 using a mixed solvent of aqueous ammonia and tetrahydrofuran had a better yield.
Claims (6)
一般式（３）中、Ｒ１、Ｒ２、及びＲ３はそれぞれ独立に、水素原子、炭素数１～４のアルキル基、ハロゲン原子、又は、ハロアルキル基を表す。 A 3-aminobenzo[c]isothiazole-5-sulfonamide derivative represented by the following general formula (3).
In general formula (3), R 1 , R 2 and R 3 each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a halogen atom, or a haloalkyl group.
一般式（２）中、Ｒ１、Ｒ２、及びＲ３はそれぞれ独立に、水素原子、炭素数１～４のアルキル基、ハロゲン原子、又は、ハロアルキル基を表す。 A 3-aminobenzo[c]isothiazole-5-chlorosulfonyl derivative represented by the following general formula (2).
In general formula (2), R 1 , R 2 and R 3 each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a halogen atom, or a haloalkyl group.
前記反応溶媒全量に対するハロゲン化スルホン酸以外の溶媒の含有量が１質量％未満である、下記一般式（３）で表される３－アミノベンゾ［ｃ］イソチアゾール－５－スルホンアミド誘導体の製造方法。
一般式（１）中、Ｒ１、Ｒ２、及びＲ３はそれぞれ独立に、水素原子、炭素数１～４のアルキル基、ハロゲン原子、又は、ハロアルキル基を表す。
一般式（２－２）中、Ｒ１、Ｒ２、及びＲ３はそれぞれ独立に、水素原子、炭素数１～４のアルキル基、ハロゲン原子、又は、ハロアルキル基を表し、Ｒ４はハロゲン原子を表す。
一般式（３）中、Ｒ１、Ｒ２、及びＲ３はそれぞれ独立に、水素原子、炭素数１～４のアルキル基、ハロゲン原子、又は、ハロアルキル基を表す。 A benzisothiazole derivative represented by the following general formula (1) is reacted with a reaction solvent containing a halogenated sulfonic acid to produce 3-aminobenzo[c]isothiazole represented by the following general formula (2-2). - Obtaining a 5-halogenated sulfonyl derivative,
A method for producing a 3-aminobenzo[c]isothiazole-5-sulfonamide derivative represented by the following general formula (3), wherein the content of a solvent other than the halogenated sulfonic acid with respect to the total amount of the reaction solvent is less than 1% by mass. .
In general formula (1), R 1 , R 2 and R 3 each independently represent 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 represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a halogen atom, or a haloalkyl group, and R 4 is a halogen atom. represents.
In general formula (3), R 1 , R 2 and R 3 each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a halogen atom, or a haloalkyl group.
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