Preparation method of 1, 2, 4-benzothiadiazine-1, 1-dioxide derivative

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a 1, 2, 4-benzothiadiazine-1, 1-dioxide derivative. The method comprises the following steps: by taking a 2-aminobenzenesulfonamide compound as shown in a formula (I) and an aldehyde compound as shown in a formula (II) as raw materials, carrying out reflux reaction in absolute ethyl alcohol to obtain an imine intermediate as shown in a formula (III); the preparation method comprises the following steps: by taking 1, 2, 4-benzothiadiazine-1, 1-dioxide as a raw material, evaporating to remove a solvent ethanol, and reacting by taking DMSO as a solvent under the action of iodine and potassium carbonate to obtain the 1, 2, 4-benzothiadiazine-1, 1-dioxide derivative compound as shown in a formula (IV) which is described in the specification.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing a 1,2,4-benzothiadiazine-1,1-dioxide derivative. This type of compound is an important pharmacologically active molecular skeleton and can be used in areas such as hypertension treatment and potassium channel modulators. Background Technology

[0002] 1,2,4-Benzothiazine-1,1-dioxide derivatives are a class of heterocyclic compounds with significant biological activities (such as antibacterial, antihypertensive, antitumor, and antiviral effects). For example, diazine (chloromethlothiazine), represented by formula A, is a typical representative and was one of the earliest non-selective potassium channel openers used clinically. It exerts its antihypertensive effect by activating KATP channels and is mainly used for the emergency treatment of hypertensive crises, idiopathic hypoglycemia in infants, and the treatment of severe hypoglycemia caused by pancreatic beta-cell tumors. Hydrochlorothiazide, represented by formula B, has a mild antihypertensive effect and is a basic drug for treating hypertension. It can also be used for various types of edema and is the first-line drug for treating moderate edema. In addition, these compounds also have anti-inflammatory, hair growth stimulating, and AMPA receptor inhibitory effects.

[0003]

[0004] Currently, the main method for synthesizing 1,2,4-benzothiadiazine-1,1-dioxide derivatives uses o-aminobenzenesulfonamide and aldehydes as starting materials. The target product is obtained through condensation and oxidative cyclization reactions in the presence of various oxidants, such as the metal catalyst copper acetate, tert-butyl hydroperoxide (TBHP), and the functionalized iridium complex [Cp*Ir(H2O)3][OTf]2. However, copper acetate is a heavy metal catalyst, expensive and environmentally polluting. TBHP is a peroxide that may explode upon heating, friction, or impact, posing a significant safety risk. The functionalized iridium complex [Cp*Ir(H2O)3][OTf]2 is complex and costly to prepare. In addition, methods using photocatalysts (such as 4CzIPN) and electrochemical catalysis also exist, but these methods suffer from high cost, low selectivity, demanding reaction conditions, and the need for specialized equipment. Therefore, researching and developing simple, green, and efficient synthetic methods for 1,2,4-benzothiadiazine-1,1-dioxide derivatives has important application value and significance. Summary of the Invention

[0005] The purpose of this invention is to provide a low-cost, simple, green, and efficient method for preparing 1,2,4-benzothiadiazine-1,1-dioxide derivatives. This method uses 2-aminobenzenesulfonamide and aldehyde compounds as starting materials. First, an imine key intermediate is obtained by condensation in ethanol. After solvent drying, iodine is added as an oxidant, potassium carbonate as a co-reactant, and dimethyl sulfoxide as a solvent to prepare the 1,2,4-benzothiadiazine-1,1-dioxide derivative in one step. This method not only avoids the disadvantages of metal residue and environmental pollution caused by the use of metal catalysts, but also simplifies operation and post-processing. It does not require oxygen supply devices or strong oxidants such as tert-butyl hydroperoxide to assist the reaction. Furthermore, iodine is a low-cost, green oxidant. Therefore, this new route conforms to the concept of green chemistry, and the yields are all no less than 60%, with some compounds achieving yields of over 80%.

[0006] To achieve the objectives of this invention, the following technical solutions are provided:

[0007] Using 2-aminobenzenesulfonamide compounds of formula (I) and aldehyde compounds of formula (II) as starting materials, the mixture was refluxed in anhydrous ethanol to obtain an imine intermediate of formula (III); after removing the solvent ethanol, the mixture was reacted with DMSO in the presence of iodine and potassium carbonate to obtain 1,2,4-benzothiadiazine-1,1-dioxide derivative compounds of formula (IV). The reaction equation is as follows:

[0008]

[0009] In formulas (I), (II), (III) and (IV), R1 is selected from hydrogen or halogen; R2 is selected from alkyl, cycloalkyl, aryl or heteroaryl.

[0010] In some specific implementation schemes, in formulas (I), (II), (III), and (IV), R1 is selected from hydrogen, fluorine, chlorine, bromine, or iodine; R2 is selected from C. 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, phenyl substituted with alkyl, haloalkyl, nitro, halogen, alkoxy, naphthyl, furanyl, thiophene, pyridyl, styryl.

[0011] In some specific implementation schemes, in formulas (I), (II), (III), and (IV), R1 is selected from hydrogen, fluorine, chlorine, bromine, or iodine; R2 is selected from C. 1-6 Alkyl, C 3-6Cycloalkyl, phenyl, 4-trifluoromethylphenyl, 4-nitrophenyl, 4-halophenyl, 3-halophenyl, 2,4-dichlorophenyl, 4-methylphenyl, 3-methylphenyl, 2,4-dimethylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2,4-dimethoxyphenyl, thienyl, furanyl, naphthyl, pyridyl.

[0012] According to the synthesis method of the present invention, the 2-aminobenzenesulfonamide compound represented by formula (I) and the aldehyde compound represented by formula (II) are reacted in anhydrous ethanol for 2-10 hours; preferably, the reaction time is 2-6 hours, and more preferably, the reaction time is 2-3 hours.

[0013] According to the synthesis method of the present invention, the feed ratio of the 2-aminobenzenesulfonamide compound represented by formula (I) and the aldehyde compound represented by formula (II) is 1:1 to 1:2; preferably, the feed ratio of the 2-aminobenzenesulfonamide compound represented by formula (I) and the aldehyde compound represented by formula (II) is 1:1.

[0014] The inventors have discovered that the solvent and temperature of the reaction between the 2-aminobenzenesulfonamide compound shown in formula (I) and the aldehyde compound shown in formula (II) have a significant impact on the yield of the compound in formula (III). When dichloromethane and ethyl acetate are used as solvents, the yield is low. When anhydrous ethanol is used as solvent and the reaction is refluxed for 2 hours, the yield can reach 99%. In particular, when the feed ratio of the 2-aminobenzenesulfonamide compound shown in formula (I) and the aldehyde compound shown in formula (II) is 1:1, not only is the yield of the compound in formula (III) high, but the product of the compound in formula (IV) generated under the action of iodine and potassium carbonate has high purity and few by-products, which greatly reduces the difficulty of subsequent purification.

[0015] According to the synthesis method of the present invention, the imine intermediate represented by formula (III) is reacted in DMSO at a temperature of 100℃-150℃; preferably, the imine intermediate represented by formula (III) is reacted in DMSO at a temperature of 110℃-130℃; more preferably, the imine intermediate represented by formula (III) is reacted in DMSO at a temperature of 110℃.

[0016] According to the synthesis method of the present invention, the molar ratio of the 2-aminobenzenesulfonamide compound represented by formula (I) to iodine is 1:1 to 1:1.5; preferably, the molar ratio of the 2-aminobenzenesulfonamide compound represented by formula (I) to iodine is 1:1.

[0017] According to the synthesis method of the present invention, the molar ratio of the 2-aminobenzenesulfonamide compound represented by formula (I) to potassium carbonate is 1:3-1:5; preferably, the molar ratio of the 2-aminobenzenesulfonamide compound represented by formula (I) to potassium carbonate is 1:3.

[0018] According to the synthesis method of the present invention, the imine intermediate represented by formula (III) is reacted in DMSO for 2-4 hours; preferably, the imine intermediate represented by formula (III) is reacted in DMSO for 2-3 hours; more preferably, the imine intermediate represented by formula (III) is reacted in DMSO for 2 hours.

[0019] The inventors discovered that the reaction of the 2-aminobenzenesulfonamide compound shown in formula (I) and the aldehyde compound shown in formula (II), regardless of increasing the temperature, extending the reaction time, or changing the solvent, only yields the imine intermediate shown in formula (III), and does not produce the 1,2,4-benzothiadiazine-1,1-dioxide derivative shown in formula (IV). This was presumably due to insufficient reaction temperature. After removing ethanol, toluene was added as a solvent, and iodine was used as an oxidant. Reacting at 110°C, no 1,2,4-benzothiadiazine-1,1-dioxide derivative shown in formula (IV) was generated. However, when using DMF as a solvent and reacting at 110°C, the yield of the 1,2,4-benzothiadiazine-1,1-dioxide derivative shown in formula (IV) was less than 10%. When using DMSO as a solvent and reacting at 110°C for 2 hours, the yield of the 1,2,4-benzothiadiazine-1,1-dioxide derivative shown in formula (IV) was 20%. Furthermore, the inventors unexpectedly discovered that by using DMSO as a solvent, iodine as an oxidant, and adding potassium carbonate, and reacting at 110°C for 2 hours, the yield of the 1,2,4-benzothiadiazine-1,1-dioxide derivative shown in (IV) can be increased to over 60%, and some compounds can reach over 80%.

[0020] Existing methods for synthesizing 1,2,4-benzothiadiazine-1,1-dioxide derivatives utilize transition metal catalysts or peroxides, which are either expensive, pose a risk of metal residue, or have poor safety. If photocatalysts are used, they are either unstable, prone to deactivation, highly energy-dependent, or subject to significant light source limitations. Electrochemical synthesis may also require specialized equipment. The method described in this invention uses elemental iodine as an oxidant, which not only possesses unique physicochemical properties but is also inexpensive, readily available, easy to store, low in toxicity, and environmentally friendly. In particular, the addition of potassium carbonate significantly improves the yield, resulting in high economic value. Furthermore, the method provided by this invention is applicable to the synthesis of 1,2,4-benzothiadiazine-1,1-dioxide derivatives with various substituents. The method has broad applicability, high reaction yields and purity, and is of significant value for both laboratory preparation and industrial production. Specific Implementation

[0021] Example 1: Preparation of 3-phenyl-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0022] Add 2-aminobenzenesulfonamide (0.2 g, 1.2 mmol), benzaldehyde (0.12 g, 1.2 mmol), and 5 mL of anhydrous ethanol to a 50 mL round-bottom flask. Heat to 80 °C and stir at this reflux temperature for 2 h. After the reaction is complete, cool to room temperature, concentrate under reduced pressure to remove anhydrous ethanol, add I2 (0.29 g, 1.2 mmol), K2CO3 (0.48 g, 3.6 mmol), and 5 mL of DMSO, heat to 110 °C and stir at this temperature for 2 h. After the reaction is complete, cool to room temperature, add 10 mL of water, and adjust the pH to 3–4 with 4 mol / L hydrochloric acid. Then filter, purify by slurrying with ethyl acetate, to give 0.25 g of white solid, yield 84%, Mp 309–310 °C (lit. Mp 308–310 °C). 1 H NMR(400MHz, DMSO-d6)(δ,ppm):12.17(s,1H),8.07-7.94(m,2H),7.86-7.79(m,1H),7.74-7.64(m,2H),7.64-7.53(m,3H),7.51-7.43(m,1H); 13 C NMR(100MHz,DMSO-d6)(δ,ppm):155.34,136.01,133.71,133.41,132.35,129.43,128.82,127.30,123.89,121.98,119.00.HRMS(ESI):m / z[M+Na] + Calcd.for C 13 H 10 N2O2SNa:281.0361; Found:281.0363.

[0023] Example 2 Preparation of 3-(4-nitrophenyl)-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0024] Using 2-aminobenzenesulfonamide and anhydrous ethanol as raw materials, the same procedure as in Example 1 was followed to obtain 0.30 g of a yellow solid, with a yield of 86% and an Mp of 209-212℃ (lit. Mp 210-212℃). 1 H NMR (400MHz, DMSO-d6) (δ, ppm): 12.45 (s, 1H), 8.41 (d, J = 8.0Hz, 2H), 8.26 (d, J = 8.0Hz, 2H) ,7.86(d,J=8.0Hz,1H),7.72(t,J=7.6Hz,1H),7.59(d,J=8.2Hz,1H),7.52(t,J=7.6Hz,1H); 13C NMR(100MHz,DMSO-d6)(δ,ppm):153.64,150.31,138.22,136.05,133.85,130. 45,127.65,124.40,123.95,121.96,119.28.HRMS(ESI):m / z[M+H]+Calcd.for C 13 H 10 N3O4S:304.0392; Found:304.0394.

[0025] Example 3 Preparation of 3-(4-trifluoromethylphenyl)-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0026] Using 2-aminobenzenesulfonamide and anhydrous ethanol as raw materials, the same procedure as in Example 1 was followed to obtain 0.30 g of a grayish-white solid with a yield of 80% and an Mp of 320-323℃ (lit. Mp 318-320℃). 1 H NMR (400MHz, DMSO-d6) (δ, ppm): 12.37 (s, 1H), 8.22 (d, J = 8.2Hz, 2H), 7.98 (d, J = 8.4Hz, 2H) ,7.85(d,J=8.1Hz,1H),7.76-7.69(m,1H),7.59(d,J=8.3Hz,1H),7.49(t,J=7.6Hz,1H); 13C NMR(100MHz,DMSO-d6)(δ,ppm): 13 CNMR(100MHz,DMSO-d6)δ154.09,136.29,135.88,133.84,132.99,129.83,127 .58,126.35,124.3,123.96,121.95,119.10; HRMS(ESI):m / z[M+Na]+Calcd.for C 14 H9F3N2O2SNa:349.0235; Found:349.0236.

[0027] Example 4 Preparation of 3-(4-fluorophenyl)-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0028] Using 2-aminobenzenesulfonamide and anhydrous ethanol as raw materials, the same procedure as in Example 1 was followed to obtain 0.24 g of white solid, yield 76%, Mp 347-351℃; 1H NMR(400MHz, DMSO-d6)(δ,ppm):12.17(s,1H),8.14-8.05(m,2H),7.84-7.80(m,1H),7.73-7.67(m,1H),7.58-7.50(m,1H),7.50-7.40(m,3H); 13 C NMR (100MHz, DMSO-d6) (δ, ppm): 165.31, 154.32, 136.01, 133.72, 131.69, 128. 82,127.30,123.87,121.97,119.03,116.55; HRMS(ESI):m / z[M+Na]+Calcd.for C 13 H9FN2O2SNa:299.0266; Found:299.0270.

[0029] Example 5 Preparation of 3-(4-chlorophenyl)-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0030] Using 2-aminobenzenesulfonamide and anhydrous ethanol as raw materials, the same procedure as in Example 1 was followed to obtain 0.25 g of white solid, yield 73%, Mp 342-345℃ (lit. Mp 343-345℃); 1 H NMR (400MHz, DMSO-d6) (δ, ppm): 12.23 (s, 1H), 8.07-8.02 (m, 2H), 7.85-7.80 (m, 1H), 7.73-7.65 (m, 3H), 7.60 (d, J = 8.5Hz, 1H), 7.47 (t, J = 7.5Hz, 1H); 13 C NMR (100MHz, DMSO-d6) (δ, ppm): 154.27, 138.28, 136.04, 133.73, 131.17, 130.74, 129.51, 127.36, 123.88, 121.99, 119.11; HRMS (ESI): m / z [M+Na] + Calcd.for C 13 H9ClN2O2SNa:314.9971; Found:314.9973.

[0031] Example 6 Preparation of 3-(4-bromophenyl)-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0032] Using 2-aminobenzenesulfonamide and anhydrous ethanol as raw materials, the same procedure as in Example 1 was followed to obtain 0.27 g of white solid, yield 71%, Mp 289-292℃ (lit. Mp 288-290℃); 1 H NMR (400MHz, DMSO-d6) (δ, ppm): 12.22 (s, 1H), 7.99-7.94 (m, 2H), 7.86-7.77 (m, 3H), 7.73-7.66 (m, 1H), 7.59 (d, J = 8.6Hz, 1H), 7.47 (t, J = 7.6Hz, 1H); 13 C NMR (100MHz, DMSO-d6) (δ, ppm): 154.39, 135.99, 133.75, 132.46, 131.52, 130.85, 127.39, 127.33, 123.89, 121.98, 119.08; HRMS (ESI): m / z [M+Na] + Calcd.for C 13 H9BrN2O2SNa:358.9466; Found:358.9461.

[0033] Example 7 Preparation of 3-(4-methylphenyl)-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0034] Using 2-aminobenzenesulfonamide and anhydrous ethanol as raw materials, the same procedure as in Example 1 was followed to obtain 0.21 g of white solid, yield 68%, Mp 335-337℃ (lit. Mp 334-336℃); 1 H NMR (400MHz, DMSO-d6) (δ, ppm): 12.05 (s, 1H), 7.95 (d, J = 8.3Hz, 2H), 7.82 (d, J = 7. 9Hz,1H),7.72-7.66(m,1H),7.60(d,J=8.4Hz,1H),7.48-7.36(m,3H),2.39(s,3H); 13 C NMR(100MHz,DMSO-d6)(δ,ppm):155.19,143.83,136.12,133.64,129.96,129 .45,128.79,127.14,123.84,122.05,119.00,21.64.;HRMS(ESI):m / z[M+Na] + Calcd.for C 14 H 12 N2O2SNa:295.0517; Found:295.0518.

[0035] Example 8 Preparation of 3-(4-methoxyphenyl)-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0036] Using 2-aminobenzenesulfonamide and anhydrous ethanol as raw materials, the same procedure as in Example 1 was followed to obtain 0.24 g of white solid, yield 73%, Mp 325-326℃ (lit. Mp 323-325℃); 1 H NMR (400MHz, DMSO-d6) (δ, ppm): 11.98 (s, 1H), 8.02 (d, J = 9.0Hz, 2H), 7.80 (d, J = 8.0Hz, 1H), 7.7 1-7.66(m,1H),7.60(d,J=8.4Hz,1H),7.45(t,J=7.6Hz,1H),7.14(d,J=9.0Hz,2H),3.84(s,3H); 13 C NMR(100MHz,DMSO-d6)(δ,ppm): 13 C NMR(100MHz,DMSO-d6)(δ,ppm):163.56,154.81,136.14,133.58,130.85,12 7.00,124.08,123.79,122.09,118.92,114.78,56.19; HRMS(ESI):m / z[M+Na] + Calcd forC 14 H 12 N2O3SNa:311.0466; Found:311.0468.

[0037] Example 9 Preparation of 3-(3-fluorophenyl)-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0038] Using 2-aminobenzenesulfonamide and anhydrous ethanol as raw materials, the same procedure as in Example 1 was followed to obtain 0.24 g of white solid, yield 75%, Mp 274-276℃ (lit. Mp 272-274℃); 1 H NMR(400MHz, DMSO-d6)(δ,ppm):12.21(s,1H),7.88-7.82(m,3H),7.74-7.68(m,1H),7.69-7.62(m,1H),7.60-7.57(m,1H),7.56-7.45(m,2H); 13C NMR(100MHz,DMSO-d6)(δ,ppm):162.39,154.02,135.88,134.61,133.79,131.70 ,127.48,125.11,123.91,121.97,120.28,119.09,115.68; HRMS(ESI):m / z[M+Na] + Calcd.for C 13 H9FN2O2SNa:299.0266; Found:299.0270

[0039] Example 10 Preparation of 3-(3-chlorophenyl)-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0040] Using 2-aminobenzenesulfonamide and anhydrous ethanol as raw materials, the same procedure as in Example 1 was followed to obtain 0.24 g of white solid, yield 71%, Mp 268-271℃ (lit. Mp 268-270℃); 1 H NMR(400MHz,DMSO-d6)(δ,ppm):12.26(s,1H),8.10-8.04(m,1H),8.00-7.94(m,1H),7.8 6-7.80(dd,J=8.0,1.4Hz,1H),7.78-7.67(m,2H),7.62-7.59(m,2H),7.51-7.44(m,1H); 13 CNMR(100MHz,DMSO-d6)(δ,ppm):153.97,136.08,134.49,134.04,133.74,133.07 ,131.38,128.45,127.65,127.42,123.89,122.02,119.20; HRMS(ESI):m / z[M+Na] + Calcd.for C 13 H9ClN2O2SNa:314.9971; Found:314.9973.

[0041] Example 11 Preparation of 3-(3-bromophenyl)-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0042] Using 2-aminobenzenesulfonamide and anhydrous ethanol as raw materials, the same procedure as in Example 1 was followed to obtain 0.24 g of white solid, yield 67%, Mp 243-246℃; 1HNMR(400MHz,DMSO-d6)(δ,ppm):12.23(s,1H),8.21-8.15(m,1H),8.04-7.98(m,1 H),7.88-7.80(m,2H),7.73-7.67(m,1H),7.61-7.52(m,2H),7.48(t,J=7.6Hz,1H); 13 C NMR(100MHz,DMSO-d6)(δ,ppm):153.91,136.19,135.93,134.74,133.71,131.58 ,131.25,128.00,127.38,123.88,122.42,122.04,119.27; HRMS(ESI):m / z[M+Na] + Calcd.for C 13 H9BrN2O2SNa:358.9466; Found:358.9464.

[0043] Example 12 Preparation of 3-(3-methylphenyl)-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0044] Using 2-aminobenzenesulfonamide and anhydrous ethanol as raw materials, the same procedure as in Example 1 was followed to obtain 0.24 g of white solid, yield 62%, Mp 273-276℃; 1 HNMR (400MHz, DMSO-d6) (δ, ppm): 12.13 (s, 1H), 7.86-7.76 (m, 3H), 7.72-7.67 (m, 1H), 7.60 (d, J = 8.4Hz, 1H), 7.52-7.43 (m, 3H), 2.40 (s, 3H); 13 C NMR(100MHz,DMSO-d6)(δ,ppm):155.42,138.91,136.04,134.03,133.68,132.33,12 9.33,129.16,127.25,125.98,123.88,122.00,118.98,21.45; HRMS(ESI):m / z[M+Na] + Calcd.forC 14 H 12 N2O2SNa:295.0517; Found:295.0516.

[0045] Example 13 Preparation of 3-(3-methoxyphenyl)-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0046] Using 2-aminobenzenesulfonamide and anhydrous ethanol as raw materials, the same procedure as in Example 1 was followed to obtain 0.24 g of white solid, yield 64%, Mp 314-316℃ (lit. Mp 312-314℃); 1 H NMR (400MHz, DMSO-d6) (δ, ppm): 12.13 (s, 1H), 7.83 (d, J = 7.9Hz, 1H), 7.73-7.6 7(m,1H),7.62-7.56(m,2H),7.54-7.44(m,3H),7.26-7.21(m,1H),3.84(s,3H); 13 C NMR(100MHz,DMSO-d6)(δ,ppm):159.87,155.11,136.01,133.73,133.70,130.66,12 7.30,123.88,121.99,121.01,119.11,119.06,113.88,56.06; HRMS(ESI):m / z[M+Na] + Calcd.for C 14 H 12 N2O3SNa:311.0466; Found:311.0470.

[0047] Example 14 Preparation of 3-(2,4-dichlorophenyl)-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0048] Using 2-aminobenzenesulfonamide and anhydrous ethanol as raw materials, the same procedure as in Example 1 was followed to obtain 0.24 g of white solid, yield 75%, Mp 249-252℃; 1 HNMR (400MHz, DMSO-d6) (δ, ppm): 12.60 (s, 1H), 7.91-7.83 (m, 2H), 7.78-7.67 (m, 2H), 7.65-7.60 (m, 1H), 7.52-7.46 (m, 1H), 7.36 (d, J = 8.4Hz, 1H); 13 C NMR(100MHz,DMSO-d6)(δ,ppm):153.72,136.98,135.69,133.96,132.98,132.29 ,132.03,130.14,128.38,127.64,124.11,121.88,118.59; HRMS(ESI):m / z[M+Na] + Calcd forC 13 H8Cl2N2O3SNa:348.9581; Found:384.9584.

[0049] Example 15 Preparation of 3-(2,4-dimethylphenyl)-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0050] Using 2-aminobenzenesulfonamide and anhydrous ethanol as raw materials, the same procedure as in Example 1 was followed to obtain 0.24 g of white solid, yield 67%, Mp 239-242℃; 1 H NMR (400MHz, DMSO-d6) (δ, ppm): 12.26 (s, 1H), 7.84-7.81 (dd, J = 8.0, 1.6Hz, 1H), 7 .71-7.65(m,1H),7.51-7.37(m,3H),7.21-7.13(m,2H),2.35(s,3H),2.32(s,3H); 13 C NMR(100MHz,DMSO-d6)(δ,ppm):157.09,141.47,136.84,135.97,133.70,132.06,130.7 2,129.16,127.23,127.03,123.94,121.75,118.54,21.42,19.57; HRMS(ESI):m / z[M+Na] + Calcd.for C 15 H 14 N2O2SNa:309.0674; Found:309.0677.

[0051] Example 16 Preparation of 3-(2,4-dimethoxyphenyl)-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0052] Using 2-aminobenzenesulfonamide and anhydrous ethanol as raw materials, the same procedure as in Example 1 was followed to obtain 0.24 g of white solid, yield 68%, Mp 268-271℃; 1 H NMR (400MHz, DMSO-d6) (δ, ppm): 11.83 (s, 1H), 7.82-7.75 (dd, J = 8.0, 1.2Hz 1H),7.71-7.57(m,2H),7.49-7.39(m,2H),6.76-6.64(m,2H),3.88(s,3H),3.83(s,3H); 13C NMR(100MHz,DMSO-d6)δ164.35,159.61,154.44,135.81,133.54,132.71,127.01,1 23.79,121.89,118.74,114.02,106.50,99.27,56.77,56.28; HRMS(ESI):m / z[M+Na] + Calcd.for C 15 H 14 N2O4SNa:341.0572; Found:341.0574.

[0053] Example 17 Preparation of 3-(2-naphthyl)-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0054] Using 2-aminobenzenesulfonamide and anhydrous ethanol as raw materials, the same procedure as in Example 1 was followed to obtain 0.26 g of a grayish-white solid, with a yield of 74% and an Mp of 219-221℃. 1 H NMR (400MHz, DMSO-d6) (δ, ppm): 12.61 (s, 1H), 8.18 (t, J = 8.1Hz, 2H), 8.06 (d, J = 8.0Hz, 1H ),7.89(t,J=9.2Hz,2H),7.75-7.58(m,4H),7.52(t,J=7.8Hz,1H),7.45(d,J=8.3Hz,1H); 13 C NMR(100MHz,DMSO-d6)(δ,ppm):156.44,136.10,133.82,133.65,132.17,130.80,130.32,129.16 ,128.26,128.02,127.47,127.35,125.61,124.76,124.01,121.91,118.77.HRMS(ESI):m / z[M+Na] + Calcd for C 17 H 12 N2O2SNa:331.0517; Found:331.0519.

[0055] Example 18 Preparation of 3-(2-furanyl)-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0056] Using 2-aminobenzenesulfonamide and anhydrous ethanol as raw materials, the same procedure as in Example 1 was followed to obtain 0.21 g of a pale yellow solid, with a yield of 72% and an Mp of 282-285℃ (lit. Mp 282-284℃). 1H NMR(400MHz,DMSO-d6)(δ,ppm):11.89(s,1H),8.57(s,1H),7.91-7.86(m,1H ),7.79(d,J=8.1Hz,1H),7.72-7.65(m,1H),7.53-7.41(m,2H),7.07(s,1H); 13 C NMR(100MHz,DMSO-d6)(δ,ppm):150.06,147.63,145.76,135.84,133.71,127.08,123.90,122.22,121.05,118.50,109.51.HRMS(ESI):m / z[M+Na] + Calcdfor C 11 H8N2O3SNa:271.0153; Found:271.0155.

[0057] Example 19 Preparation of 3-(2-thienyl)-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0058] Using 2-aminobenzenesulfonamide and anhydrous ethanol as raw materials, the same procedure as in Example 1 was followed to obtain 0.22 g of a grayish-white solid, with a yield of 71% and an Mp of 338-341℃ (lit. Mp 338-340℃). 1 H NMR(400MHz, DMSO-d6)(δ,ppm):12.14(s,1H),8.21-8.16(m,1H),8.01-7.98(m,1H),7.82-7. 78(m,1H),7.73-7.67(m,1H),7.57(d,J=8.4Hz,1H),7.45(t,J=7.6Hz,1H),7.32-7.27(m,1H); 13 C NMR(100MHz,DMSO-d6)(δ,ppm):150.12,136.09,135.91,134.85,133.80,132.33,129.36,127.08,123.85,122.26,118.77.HRMS(ESI):m / z[M+Na] + Calcd.for C 11 H8N2O2S2Na:286.9925; Found:286.9926.

[0059] Example 20 Preparation of 3-(2-pyridyl)-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0060] Using 2-aminobenzenesulfonamide and anhydrous ethanol as raw materials, the same procedure as in Example 1 was followed to obtain 0.20 g of a grayish-white solid, with a yield of 70% and an Mp of 287-290℃. 1 H NMR (400MHz, DMSO-d6) (δ, ppm): 12.57 (s, 1H), 8.86-8.82 (m, 1H), 8.28 (d, J = 8.0Hz, 1H), 8.13-8. 07(m,1H),7.92(d,J=8.4Hz,1H),7.84(d,J=8.0Hz,1H),7.76-7.67(m,2H),7.48(t,J=7.6Hz,1H); 13 C NMR (100MHz, DMSO-d6) (δ, ppm): 152.26, 149.71, 139.10, 133.75, 128.38, 127.45, 123.87, 123.62, 122.18, 119.71; HRMS (ESI): m / z [M+Na] + Calcd for C 12 H9N3O2SNa:282.0313; Found:282.0317.

[0061] Example 21: Preparation of (E)3-styryl-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0062] Using 2-aminobenzenesulfonamide and anhydrous ethanol as raw materials, the same procedure as in Example 1 was followed to obtain 0.22 g of white solid, yield 67%, Mp 226-229℃; 1 H NMR (400MHz, DMSO-d6) (δ, ppm): 12.25 (s, 1H), 7.84-7.80 (m, 1H), 7.80-7.68 (dd, J = 8.0, 1 .2Hz,1H),7.70-7.64(m,3H),7.47-7.40(m,4H),7.37(d,J=8.0Hz,1H),6.80-6.85(m,1H); 13 C NMR(100MHz,DMSO-d6)(δ,ppm):153.77,142.41,135.76,134.65,133.67,131.17 ,129.73,128.78,127.11,123.98,122.55,119.92,118.34; HRMS(ESI):m / z[M+Na] + Calcd.for C 15 H 12 N2O2SNa:307.0517; Found:307.0519.

[0063] Example 22 Preparation of 3-isopropyl-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0064] Using 2-aminobenzenesulfonamide and anhydrous ethanol as raw materials, the same procedure as in Example 1 was followed to obtain 0.20 g of white solid, yield 78%, Mp 195-198℃; 1 H NMR (400MHz, DMSO-d6) (δ, ppm): 11.85 (s, 1H), 7.74 (d, J = 8.0Hz, 1H), 7.63 (t, J = 7.6Hz, 1H ),7.39(t,J=7.6Hz,1H),7.31(d,J=8.4Hz,1H),2.82-2.73(m,1H),1.17(d,J=6.8Hz,6H); 13 C NMR (100MHz, DMSO-d6) (δ, ppm): 164.89, 135.75, 133.57, 126.74, 123.99, 121.85, 117.97, 34.87, 20.42; HRMS (ESI): m / z [M+Na] + Calcd.forC8H7ClN2O2SNa:252.9814; Found:252.9813.

[0065] Example 23 Preparation of 3-cyclopentyl-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0066] Using 2-aminobenzenesulfonamide and anhydrous ethanol as raw materials, the same procedure as in Example 1 was followed to obtain 0.21 g of white solid, yield 73%, Mp 230-233℃; 1 H NMR (400MHz, DMSO-d6) (δ, ppm): 11.89 (s, 1H), 7.75-7.72 (dd, J = 8.0, 1.2Hz, 1H), 7.65-7.60 (m, 1H) ,7.41-7.36(m,1H),7.30(d,J=8.4Hz,1H),2.98-2.89(m,1H),1.99-1.85(m,2H),1.81-1.52(m,6H); 13 C NMR (100MHz, DMSO-d6) (δ, ppm): 163.99, 135.77, 133.55, 126.68, 123.98, 121.86, 117.92, 45.07, 31.32, 25.95; HRMS (ESI): m / z [M+Na] + Calcd.for C 12 H14 N2O2SNa:273.0674; Found:273.0680.

[0067] Example 24 Preparation of 3-cyclohexyl-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0068] Using 2-aminobenzenesulfonamide and anhydrous ethanol as raw materials, the same procedure as in Example 1 was followed to obtain 0.23 g of white solid, yield 74%, Mp 280-283℃; 1 H NMR(400MHz, DMSO-d6)(δ,ppm):11.84(s,1H),7.75-7.71(dd,J=8.0,1.6Hz,1H),7.65-7.59(m,1H),7.41-7.35(m,1H) ,7.30(d,J=8.4Hz,1H),2.51-2.42(m,1H),1.89-1.71(m,4H),1.67-1.60(m,1H),1.49-1.36(m,2H),1.33-1.12(m,3H); 13 C NMR (100MHz, DMSO-d6) (δ, ppm): 163.84, 135.78, 133.55, 133.53, 126.64, 123.98, 121.83, 117.96, 44.28, 30.19, 25.65; HRMS (ESI): m / z [M+Na] + Calcd.for C 13 H 16 N2O2SNa:287.0830; Found:287.0832.

[0069] Example 25 Preparation of 3-cyclopropyl-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0070] Using 2-aminobenzenesulfonamide and anhydrous ethanol as raw materials, the same procedure as in Example 1 was followed to obtain 0.18 g of white solid, yield 70%, Mp 222-225℃; 1 H NMR (400MHz, DMSO-d6) (δ, ppm): 12.33 (s, 1H), 7.74-7.69 (dd, J = 8.0, 1.6Hz, 1H), 7.65-7. 59(m,1H),7.40-7.34(m,1H),7.31(d,J=8.0Hz,1H),1.94-1.84(m,1H),1.08-0.96(m,4H); 13C NMR (100MHz, DMSO-d6) (δ, ppm): 162.70, 135.80, 133.47, 126.77, 123.96, 122.34, 117.56, 14.56, 9.58; HRMS (ESI): m / z [M+Na] + Calcd.forC 10 H 10 N2O2SNa:245.0361; Found:245.0365.

[0071] Example 26 Preparation of 3-(2-methylpropenyl)-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0072] Using 2-aminobenzenesulfonamide and anhydrous ethanol as raw materials, the same procedure as in Example 1 was followed to obtain 0.18 g of white solid, yield 66%, Mp 315-318℃; 1 H NMR(400MHz,DMSO-d6)(δ,ppm): 1 H NMR(400MHz, DMSO-d6)11.84(s,1H),7.73(d,J=8.0Hz,1H),7.62(t,J=7.2Hz,1H),7 .39(t,J=8.0Hz,1H),7.27(d,J=8.4Hz,1H),5.93(s,1H),2.19(s,3H),1.93(s,3H); 13 C NMR (100MHz, DMSO-d6) (δ, ppm): 155.60, 153.94, 135.86, 133.53, 123.85, 121.64, 118.08, 117.02, 28.27, 21.02, 21.00; HRMS (ESI): m / z [M+Na] + Calcd.for C 11 H 12 N2O2SNa:259.0517; Found:259.0521.

[0073] Example 27 Preparation of 7-chloro-3-methyl-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0074] Add 0.24 g (1.2 mmol) of 5-chloro-2-aminobenzenesulfonamide, 0.05 g (1.2 mmol) of acetaldehyde, and 5 mL of anhydrous ethanol to a 50 mL round-bottom flask, and stir at room temperature for 2 h. After the reaction is complete, concentrate under reduced pressure to remove the anhydrous ethanol, add 0.29 g (1.2 mmol) of I2, 0.48 g (3.6 mmol) of K2CO3, and 5 mL of DMSO, heat to 110 °C, and stir at this temperature for 2 h. Post-treatment is the same as in Example 1, yielding 0.16 g of a grayish-white solid, yield 63%, Mp 330-332 °C; 1 H NMR (400MHz, DMSO-d6) (δ, ppm): 12.34 (s, 1H), 7.80 (s, 1H), 7.69 (d, J = 8.8Hz, 1H), 7.29 (d, J = 8.8Hz, 1H), 2.27 (s, 3H); 13 C NMR (100MHz, DMSO-d6) (δ, ppm): 158.17, 134.68, 133.75, 130.02, 123.31, 122.57, 120.22, 23.08; HRMS (ESI): m / z [M+Na] + Calcd.for C8H7ClN2O2SNa:252.9814; Found:252.9813.

[0075] Example 28 Preparation of 7-chloro-3-phenyl-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0076] Using benzaldehyde and anhydrous ethanol as raw materials, the same procedure as in Example 1 was followed to obtain 0.24 g of white solid, yield 71%, MP 347-350℃; 1 H NMR(400MHz, DMSO-d6)(δ,ppm):12.31(s,1H),8.03-7.98(m,2H),7.95-7.90(m,1H),7.80-7.75(m,1H),7.71-7.66(m,1H),7.65-7.57(m,3H); 13 C NMR (100MHz, DMSO-d6) (δ, ppm): 155.44, 134.96, 133.91, 133.59, 132.09, 130.68, 129.46, 128.87, 123.24, 123.04, 121.43; HRMS (ESI): m / z [M+Na] + Calcd.for C 13 H9ClN2O2SNa:314.9971; Found:314.9973.

[0077] Example 29 Preparation of 7-bromo-3-phenyl-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0078] Using benzaldehyde and anhydrous ethanol as raw materials, the same procedure as in Example 1 was followed to obtain 0.24 g of white solid, with a yield of 60% and an MPa of 347-349℃ (lit. MPa of 348-350℃). 1 H NMR (400MHz, DMSO-d6) (δ, ppm): 12.30 (s, 1H), 8.03-7.97 (m, 3H), 7.91-7.87 (m, 1H), 7.71-7.65 (m, 1H), 7.62-7.54 (m, 3H); 13 C NMR (100MHz, DMSO-d6) (δ, ppm): 155.43, 136.66, 135.30, 133.59, 132.11, 129.46, 128.87, 126.01, 123.31, 121.58, 118.33; HRMS (ESI): m / z [M+Na] + Calcd.for C 13 H9BrN2O2SNa:358.9466; Found:358.9463.

[0079] Example 30 Preparation of 7-iodo-3-phenyl-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0080] Using benzaldehyde and anhydrous ethanol as raw materials, the same procedure as in Example 1 was followed to obtain 0.29 g of a grayish-white solid, with a yield of 66% and an MPa of 377-380℃. 1 H NMR (400MHz, DMSO-d6) (δ, ppm): 12.26 (s, 1H), 8.07 (d, J = 2.0Hz, 1H), 8.05-8.01 (dd, J = 8.8, 2.0Hz,1H),8.01-7.98(m,2H),7.70-7.65(m,1H),7.62-7.56(m,2H),7.40(d,J=8.4Hz,1H)); 13 C NMR (100MHz, DMSO-d6) (δ, ppm): 155.38, 142.12, 135.66, 133.54, 132.22, 131.51, 129.44, 128.85, 123.43, 121.37, 90.44; HRMS (ESI): m / z [M+Na] + Calcd.for C 13H9IN2O2SNa:406.9327; Found:406.9328.

[0081] Example 31 Preparation of 5,7-dibromo-3-phenyl-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide

[0082] Using benzaldehyde and anhydrous ethanol as raw materials, the same procedure as in Example 1 was followed to obtain 0.15 g of a grayish-white solid, with a yield of 32% and an MPa of 315-318℃. 1 H NMR(400MHz, DMSO-d6)(δ,ppm):11.42(s,1H),8.34(s,1H),8.05(s,1H),7.97-7.87(m,2H),7.75-7.67(m,1H),7.65-7.54(m,2H); 13 CNMR(100MHz,DMSO-d6)(δ,ppm):157.58,139.44,134.03,133.45,132.92,129.85,129.39,125.77,125.24,120.25,119.25; HRMS(ESI):m / z[M+Na] + Calcd.for C 13 H8Br2N2O2SNa:436.8571; Found:436.8567.

Claims

1. A method for preparing 1,2,4-benzothiadiazine-1,1-dioxide derivatives of formula (IV) by refluxing 2-aminobenzenesulfonamides of formula (I) and aldehydes of formula (II) in anhydrous ethanol to obtain imine intermediates of formula (III), and then removing the solvent ethanol and reacting in DMSO with the presence of iodine and potassium carbonate to obtain the 1,2,4-benzothiadiazine-1,1-dioxide derivatives of formula (IV), as shown in the following reaction equation: wherein R1 is selected from hydrogen, halogen; R2 is selected from alkyl, cycloalkyl, aryl or heteroaryl. The molar ratio of 2-aminobenzenesulfonamides of formula (I) to aldehydes of formula (II) is 1:

1.

2. The method of claim 1, wherein: In formula (I), formula (II), formula (III), and formula (IV), R1is selected from hydrogen, fluoro, chloro, bromo, or iodo; R2is selected from C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, 4-trifluoromethylphenyl, 4-nitrophenyl, 4-halophenyl, 3-halophenyl, 2,4-dichlorophenyl, 4-methylphenyl, 3-methylphenyl, 2,4-dimethylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2,4-dimethoxyphenyl, thienyl, furanyl, naphthyl, pyridyl.

3. The method of claim 1, wherein: The reaction time of 2-aminobenzenesulfonamides of formula (I) and aldehydes of formula (II) in anhydrous ethanol is 2-3 hours.

4. The method of claim 1, wherein: The reaction temperature of imine intermediates of formula (III) in DMSO is 110°C.

5. The method of claim 1, wherein: The molar ratio of 2-aminobenzenesulfonamides of formula (I) to iodine is 1:

1.

6. The method of claim 1, wherein: The molar ratio of 2-aminobenzenesulfonamides of formula (I) to potassium carbonate is 1:3 according to the synthesis method of the present application.

7. The method of claim 1, wherein: The reaction time of imine intermediates of formula (III) in DMSO is 2-4 hours.

8. The method of claim 1, wherein: ​

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