A method for the metal-free photocatalytic oxidation synthesis of benzothiadiazine-1,1-dioxide derivatives
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- HUAIYIN INSTITUTE OF TECHNOLOGY
- Filing Date
- 2024-04-15
- Publication Date
- 2026-08-07
AI Technical Summary
[0004]近年来关于苯并噻二嗪-1,1-二氧化合物的合成方法已有许多报道，传统的合成方法大多以邻氨基苯磺酰胺、邻溴苯磺酰胺、原甲酸三乙酯、醛类、苯乙烯类等化合物为原料，需要在过渡金属如铁、铜、钯、钐等催化下进行，且反应条件苛刻，操作繁琐，造成产品收率较低(Heterocyclic Communications,2006,12(5):341–346；RSC Advances,2013,3(47):24863–24867；Tetrahedron,2018,74(51):7237–7241；Advanced SynthesisCatalysis,2018,360(24):4764–4773；Tetrahedron Lett，2019,13(60),891-894；OrganicChemistry Frontiers,2018,5,2734-2738)
[0023]本发明以廉价易得的醛类化合物和邻氨基苯磺酰胺和为起始原料，无金属蓝光照射(450-460nm)室温条件下，合成苯并噻二嗪-1,1-二氧化物衍生物，反应简单高效，具有较高的研究价值与广阔的工业应用前景。
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic synthesis technology and relates to the synthesis of benzothiadiazine-1,1-dioxide derivatives of pharmaceutically active compounds. Specifically, it relates to a method for the metal-free photocatalytic oxidation synthesis of benzothiadiazine-1,1-dioxide derivatives. Background Technology
[0002] Nitrogen-containing heterocyclic compounds are widely found in pharmaceuticals, pesticides, natural products, and various functional materials, occupying a prominent position in biochemistry and medicinal chemistry. Their synthesis has always been a hot topic for organic synthetic chemists. Benzothiazine-1,1-dioxane, as a classic drug molecule skeleton, is an important component of nitrogen-containing heterocyclic compounds. Its derivatives exhibit good biological and pharmacological activities in medicine, such as antiviral, anticancer, hypoglycemic, hypotensive, and diuretic effects, as shown in the following examples of pharmaceutically active compounds containing the benzothiadiazine-1,1-dioxane structural unit.
[0003]
[0004] In recent years, there have been many reports on the synthesis methods of benzothiadiazine-1,1-dioxane compounds. Traditional synthesis methods mostly use compounds such as o-aminobenzenesulfonamide, o-bromobenzenesulfonamide, triethyl orthoformate, aldehydes, and styrene as raw materials. These methods require the catalysis of transition metals such as iron, copper, palladium, and samarium, and the reaction conditions are harsh and the operation is cumbersome, resulting in low product yields (Heterocyclic Communications, 2006, 12(5):341–346; RSC Advances, 2013, 3(47):24863–24867; Tetrahedron, 2018, 74(51):7237–7241; Advanced Synthesis Catalysis, 2018, 360(24):4764–4773; Tetrahedron Lett, 2019, 13(60), 891-894; Organic Chemistry). (Frontiers, 2018, 5, 2734-2738). More importantly, the use of metal catalysts means that even after rigorous post-processing, trace amounts of metal residues can still be detected in the product, significantly impacting its application in biopharmaceuticals and active pharmaceutical ingredients. Therefore, developing a new, simple, and efficient method for the synthesis of benzothiadiazine-1,1-dioxane derivatives under mild conditions without metal catalysis is of great significance. Summary of the Invention
[0005] To address the shortcomings of existing technologies, the present invention aims to provide a metal-free photocatalytic oxidation method for synthesizing benzothiadiazine-1,1-dioxide derivatives. This invention uses readily available aldehydes and o-aminobenzenesulfonamide as starting materials, 4CzIPN as a photocatalyst, and DMSO as a solvent. The reaction conditions are mild, and the post-processing is simple, achieving high yields of benzothiadiazine-1,1-dioxide compounds and their derivatives, thus providing a new strategy for the synthesis of these compounds.
[0006] This invention is achieved through the following technical solution:
[0007] A method for synthesizing benzothiadiazine-1,1-dioxide derivatives by metal-free photocatalytic oxidation includes the following steps:
[0008] The o-aminobenzenesulfonamide shown in Formula I and the aldehyde compound shown in Formula II are dissolved in an organic solvent and react at a certain temperature under the combined action of a catalyst, light, and solvent to generate the benzothiadiazine-1,1-dioxide derivative shown in Formula III.
[0009]
[0010] Wherein, R is hydrogen, methyl, ethyl, n-propyl, n-butyl, n-octyl, phenyl, 4-methylphenyl, 3-methylphenyl, 4-methoxyphenyl, 4-tert-butylphenyl, 4-isopropylphenyl, 4-methylthiophenyl, 3,4-dimethylphenyl, 4-nitrophenyl, 4-halogen (F, Cl, Br)phenyl, 4-trifluoromethylphenyl, 4-cyanophenyl, styryl, 2-thienyl-, 2-pyridyl or 2-furanyl;
[0011] The photocatalysts are: 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (4CzIPN), 2,4,5,6-tetra(diphenylamino)-isophthalonitrile (4DPAIPN), 2,4,6-tris(diphenylamino)-5-fluoroisophthalonitrile (3DPAFIPN), 2,4,5,7-tetrabromofluorescein (Eosin Y), Rhodamine B, and 9-trimethylmethyl-10-methylacrimidine perchlorate (Acr-Mes-Me). + ClO4 - It may be one or a mixture of two or more of the following: ruthenium chloride (Ru(bpy)3Cl2) or terpyridine.
[0012] Preferably, the photocatalyst is 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile.
[0013] A further improvement to the present invention is as follows:
[0014] The molar ratio of o-aminobenzamide to the photocatalyst is 1:0.01 to 0.06.
[0015] Furthermore, the molar ratio of the o-aminobenzenesulfonamide compound to the aldehyde compound is 1:1.2 to 2.0.
[0016] Furthermore, the illumination is one or a mixture of two or more of the following: sunlight, red light, blue light, green light, violet light, infrared light, and ultraviolet light.
[0017] Preferably, the illumination condition is blue light with a wavelength range of 450-460nm.
[0018] Furthermore, the solvent is one or a mixture of two or more of the following: 1,4-dioxane, chlorobenzene, dimethyl sulfoxide, DMF, tert-butanol, tert-amyl alcohol, 1,2-dichloroethane, water, and toluene.
[0019] Preferably, the solvent is dimethyl sulfoxide.
[0020] Furthermore, the reaction temperature is room temperature, and the reaction time is 6–12 hours.
[0021] Furthermore, after the reaction is completed, the product is separated and purified. The separation process includes washing with water, extraction, separation, drying, and removal of the organic phase to obtain a crude product. The purification method is column chromatography or recrystallization, wherein the column chromatography eluent is dichloromethane and ethyl acetate, and the mixing ratio is dichloromethane:ethyl acetate = 8:1 to 2:1; the recrystallization solvent is methanol or ethanol.
[0022] Compared with the prior art, the beneficial effects of the present invention are as follows:
[0023] This invention uses inexpensive and readily available aldehydes and o-aminobenzenesulfonamides as starting materials to synthesize benzothiadiazine-1,1-dioxide derivatives at room temperature without metal blue light irradiation (450-460nm). The reaction is simple and efficient, and has high research value and broad industrial application prospects. Detailed Implementation
[0024] The present invention will now be described in detail with reference to specific embodiments.
[0025] Example 1: 3-Phenyl-2H-benzothiadiazine-1,1-dioxane
[0026]
[0027] 0.5 mmol of o-aminobenzenesulfonamide, 0.6 mmol of benzaldehyde, 3 mol% of photocatalyst 4CzIPN, and 2 mL of dimethyl sulfoxide were added sequentially to a 10 mL reaction tube. The mixture was reacted at room temperature (25 °C) under blue LED (450-460 nm) irradiation for 12 h. The mixture was then extracted with dichloromethane, washed three times with water, and the organic phase was separated. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (dichloromethane: ethyl acetate = 2:1) to obtain a white solid pure product with a yield of 89%.
[0028] Example 2: 3-(3-methylphenyl)-2H-benzothiadiazine-1,1-dioxane
[0029]
[0030] 0.5 mmol of o-aminobenzenesulfonamide, 0.6 mmol of 4-methylbenzaldehyde, 3 mol% of photocatalyst 4CzIPN, and 2 mL of dimethyl sulfoxide were added sequentially to a 10 mL reaction tube. The mixture was reacted at room temperature (25 °C) under blue LED (450-460 nm) irradiation for 12 h. The mixture was then extracted with dichloromethane, washed three times with water, and the organic phase was separated. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (dichloromethane: ethyl acetate = 2:1) to obtain a white solid pure product with a yield of 90%.
[0031] Example 3: 3-(4-methoxyphenyl)-2H-benzothiadiazine-1,1-dioxane
[0032]
[0033] 0.5 mmol of o-aminobenzenesulfonamide, 0.6 mmol of 4-methylbenzaldehyde, 3 mol% of photocatalyst 4CzIPN, and 2 mL of dimethyl sulfoxide were added sequentially to a 10 mL reaction tube. The mixture was reacted at room temperature (25 °C) under blue LED (450-460 nm) irradiation for 12 h. The mixture was then extracted with dichloromethane, washed three times with water, and the organic phase was separated. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (dichloromethane: ethyl acetate = 2:1) to obtain a white solid pure product with a yield of 92%.
[0034] Example 4: 3-(4-isopropylphenyl)-2H-benzothiadiazine-1,1-dioxane
[0035]
[0036] 0.5 mmol of o-aminobenzenesulfonamide, 0.6 mmol of 4-isopropylbenzaldehyde, 3 mol% of photocatalyst 4CzIPN, and 2 mL of dimethyl sulfoxide were added sequentially to a 10 mL reaction tube. The mixture was reacted at room temperature (25 °C) under blue LED (450-460 nm) irradiation for 12 h. The mixture was then extracted with dichloromethane, washed three times with water, and the organic phase was separated. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (dichloromethane: ethyl acetate = 2:1) to obtain a white solid pure product with a yield of 86%.
[0037] Example 5: 3-(4-cyanophenyl)-2H-benzothiadiazine-1,1-dioxane
[0038]
[0039] 0.5 mmol of o-aminobenzenesulfonamide, 0.6 mmol of 4-cyanobenzaldehyde, 3 mol% of photocatalyst 4CzIPN, and 2 mL of dimethyl sulfoxide were added sequentially to a 10 mL reaction tube. The mixture was reacted at room temperature (25 °C) under blue LED (450-460 nm) irradiation for 12 h. The mixture was then extracted with dichloromethane, washed three times with water, and the organic phase was separated. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (dichloromethane: ethyl acetate = 4:1) to obtain a white solid pure product with a yield of 80%.
[0040] Example 6: 3-(4-bromophenyl)-2H-benzothiadiazine-1,1-dioxane
[0041]
[0042] 0.5 mmol of o-aminobenzenesulfonamide, 0.6 mmol of 4-bromobenzaldehyde, 3 mol% of photocatalyst 4CzIPN, and 2 mL of dimethyl sulfoxide were added sequentially to a 10 mL reaction tube. The mixture was reacted at room temperature (25 °C) under blue LED (450-460 nm) irradiation for 12 h. The mixture was then extracted with dichloromethane, washed three times with water, and the organic phase was separated. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (dichloromethane: ethyl acetate = 4:1) to obtain a white solid pure product with a yield of 78%.
[0043] Example 7: 3-(4-bromophenyl)-2H-benzothiadiazine-1,1-dioxane
[0044]
[0045] 0.5 mmol of o-aminobenzenesulfonamide, 0.6 mmol of 4-bromobenzaldehyde, 3 mol% of photocatalyst 4CzIPN, and 2 mL of dimethyl sulfoxide were added sequentially to a 10 mL reaction tube. The mixture was reacted at room temperature (25 °C) under blue LED (450-460 nm) irradiation for 12 h. The mixture was then extracted with dichloromethane, washed three times with water, and the organic phase was separated. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (dichloromethane: ethyl acetate = 8:1) to obtain a white solid pure product with a yield of 70%.
[0046] Example 8: 2H-benzothiadiazine-1,1-dioxane
[0047]
[0048] 0.5 mmol of o-aminobenzenesulfonamide, 0.6 mmol of formaldehyde, 3 mol% of photocatalyst 4CzIPN, and 2 mL of dimethyl sulfoxide were added sequentially to a 10 mL reaction tube. The mixture was reacted at room temperature (25 °C) under blue LED (450-460 nm) irradiation for 12 h. The mixture was then extracted with dichloromethane, washed three times with water, and the organic phase was separated. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (dichloromethane: ethyl acetate = 2:1) to obtain a white solid pure product with a yield of 54%.
[0049] Example 9: 3-Methyl-2H-benzothiadiazine-1,1-dioxane
[0050]
[0051] 0.5 mmol of o-aminobenzenesulfonamide, 0.6 mmol of acetaldehyde, 3 mol% of photocatalyst 4CzIPN, and 2 mL of dimethyl sulfoxide were added sequentially to a 10 mL reaction tube. The mixture was reacted at room temperature (25 °C) under blue LED (450-460 nm) irradiation for 12 h. The mixture was then extracted with dichloromethane, washed three times with water, and the organic phase was separated. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (dichloromethane: ethyl acetate = 2:1) to obtain a white solid pure product with a yield of 60%.
[0052] Example 10: 3-n-Heptyl-2H-benzothiadiazine-1,1-dioxane
[0053]
[0054] 0.5 mmol of o-aminobenzenesulfonamide, 0.6 mmol of n-octanal, 3 mol% of photocatalyst 4CzIPN, and 2 mL of dimethyl sulfoxide were added sequentially to a 10 mL reaction tube. The mixture was reacted at room temperature (25 °C) under blue LED (450-460 nm) irradiation for 12 h. The mixture was then extracted with dichloromethane, washed three times with water, and the organic phase was separated. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (dichloromethane: ethyl acetate = 2:1) to obtain a white solid pure product with a yield of 67%.
[0055] Comparative Example 1
[0056] In this comparative example, the photocatalyst is EosinY, and other operations are the same as in Example 1.
[0057] 0.5 mmol of o-aminobenzenesulfonamide, 0.6 mmol of benzaldehyde, 3 mol% of photocatalyst EosinY, and 2 mL of toluene were added sequentially to a 10 mL reaction tube. The mixture was reacted at room temperature (25 °C) under blue LED (450-460 nm) irradiation for 12 h. The mixture was then extracted with dichloromethane, washed three times with water, and the organic phase was separated. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (dichloromethane: ethyl acetate = 2:1) to obtain a white solid pure product with a yield of 35%.
[0058] Comparative Example 2
[0059] In this comparative example, the solvent is toluene, and other operations are the same as in Example 1.
[0060] 0.5 mmol of o-aminobenzenesulfonamide, 0.6 mmol of benzaldehyde, 3 mol% of photocatalyst 4CzIPN, and 2 mL of toluene were added sequentially to a 10 mL reaction tube. The mixture was reacted at room temperature (25 °C) under blue LED (450-460 nm) irradiation for 12 h. The mixture was then extracted with dichloromethane, washed three times with water, and the organic phase was separated. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (dichloromethane: ethyl acetate = 2:1) to obtain a white solid pure product with a yield of 59%.
[0061] Comparative Example 3
[0062] In this comparative example, the blue LED wavelength range is 440-450nm, and other operations are the same as in Example 1.
[0063] 0.5 mmol of o-aminobenzenesulfonamide, 0.6 mmol of benzaldehyde, 3 mol% of photocatalyst 4CzIPN, and 2 mL of dimethyl sulfoxide were added sequentially to a 10 mL reaction tube. The mixture was reacted at room temperature (25 °C) under blue LED (440-450 nm) irradiation for 12 h. The mixture was then extracted with dichloromethane, washed three times with water, and the organic phase was separated. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (dichloromethane: ethyl acetate = 2:1) to obtain a white solid pure product with a yield of 65%.
[0064] The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent transformations or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.
Claims
1. A method for the metal-free photocatalytic oxidation synthesis of benzothiadiazine-1,1-dioxide derivatives, characterized in that, Includes the following steps: The o-aminobenzenesulfonamide shown in Formula I and the aldehyde compound shown in Formula II are dissolved in a solvent and react at a certain temperature under the combined action of a catalyst, light, and solvent to generate the benzothiadiazine-1,1-dioxide derivative shown in Formula III. ； Wherein, R is hydrogen, methyl, ethyl, n-propyl, n-butyl, n-octyl, phenyl, 4-methylphenyl, 3-methylphenyl, 4-methoxyphenyl, 4-tert-butylphenyl, 4-isopropylphenyl, 4-methylthiophenyl, 3,4-dimethylphenyl, 4-nitrophenyl, 4-halogenphenyl, 4-trifluoromethylphenyl, 4-cyanophenyl, 2-thienyl-, 2-pyridyl or 2-furanyl; The photocatalyst is 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile; The illumination condition is blue light with a wavelength range of 450-460nm; The solvent is dimethyl sulfoxide.
2. The method for synthesizing benzothiadiazine-1,1-dioxide derivatives by metal-free photocatalytic oxidation according to claim 1, characterized in that: The molar ratio of o-aminobenzenesulfonamide to the photocatalyst is 1:0.01~0.
06.
3. The method for synthesizing benzothiadiazine-1,1-dioxide derivatives by metal-free photocatalytic oxidation according to claim 1, characterized in that: The molar ratio of o-aminobenzenesulfonamide to aldehyde compound is 1:1.2~2.
0.
4. The method for synthesizing benzothiadiazine-1,1-dioxide derivatives by metal-free photocatalytic oxidation according to claim 1, characterized in that: The reaction temperature was room temperature, and the reaction time was 6-12 h.
5. The method for synthesizing benzothiadiazine-1,1-dioxide derivatives by metal-free photocatalytic oxidation according to claim 1, characterized in that: After the reaction is completed, the product is further separated and purified. The separation process includes washing with water, extraction, separation, drying and removal of the organic phase to obtain the crude product. The purification method is column chromatography or recrystallization. The column chromatography eluent is dichloromethane and ethyl acetate, and the mixing ratio is dichloromethane:ethyl acetate = 8:1~2:
1. The recrystallization solvent is methanol or ethanol.