A process for the preparation of 2-substituted-2,3-dihydro-4H-benzothiazine-4-ones
By preparing 2-substituted -2,3-dihydro-4H-benzothiazine-4-one compounds through reaction in organic solvents, the problems of high synthesis cost and difficulty in obtaining raw materials in existing technologies are solved, and efficient and simple compound preparation is achieved.
Patent Information
- Application Number
- CN202311719188.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-12-14
- Publication Date
- 2025-11-25
- Estimated Expiration
- 2043-12-14
AI Technical Summary
The existing methods for synthesizing 2,2-dimethyl-2,3-dihydro-4H-benzothiazine-4-one are costly, difficult to prepare raw materials, and have few literature reports.
2-substituted -2,3-dihydro-4H-benzothiazine-4-one compounds are prepared by reacting 1,2-benzisothiazolin-3-one with carbonyl compounds in the presence of hydrogen iodide and ammonium iodide in an organic solvent. Acetonitrile or 1,4-dioxane is used as the solvent, the reaction temperature is 40-120℃, and the time is 2-24h.
A simple method for preparing 2-substituted -2,3-dihydro-4H-benzothiazine-4-one compounds has been achieved. The raw materials are readily available, the operation is simple, the equipment requirements are low, the post-processing is simple, and the yield is high.
Smart Images
Figure SMS_1 
Figure SMS_2 
Figure SMS_3
Abstract
Description
Technical Field
[0001] This invention belongs to the field of medicinal chemistry, and specifically relates to a method for preparing 2-substituted -2,3-dihydro-4H-benzothiazin-4-one. Background Technology
[0002] Fungal infections are a common and difficult-to-treat condition. In recent years, fungal infections have become increasingly serious, but the available drugs for treating fungal diseases are currently very limited. While azole antifungal drugs have some efficacy, their significant toxic side effects limit their clinical application. Therefore, developing highly effective, low-toxicity antifungal drugs with novel mechanisms of action remains a very meaningful endeavor. 2-Substituted-2,3-dihydro-4H-benzothiazine-4-one compounds have strong bactericidal effects against common pathogenic fungi (Journal of Shenyang Pharmaceutical University, 2012, 29, 834; Furthermore, 2-Substituted-2,3-dihydro-4H-benzothiazine-4-one compounds have also been reported as potential selective cyclooxygenase-2 inhibitors, and as drugs for relieving pain, reducing inflammation, and lowering fever (Bioorganic & Medicinal Chemistry, 2009, 17, 5369).
[0003] Currently, most literature focuses on the synthesis of 2-monosubstituted or unsubstituted 2,3-dihydro-4H-benzothiazin-4-one derivatives, while no method for synthesizing 2,2-dimethyl-2,3-dihydro-4H-benzothiazin-4-one has been reported. There is only one method for synthesizing its analogs: in the presence of p-toluenesulfonic acid, 2-mercaptobenzamide is reacted with methyl ethyl ketone to obtain 2-methyl-2-ethyl-2,3-dihydro-4H-benzothiazin-4-one. This method has the disadvantages of high cost and difficult raw material preparation (Chemical & Pharmaceutical Bulletin, 1984, 32, 2571). Summary of the Invention
[0004] Based on the problems pointed out in the background art, the purpose of this invention is to provide a method for preparing 2-substituted -2,3-dihydro-4H-benzothiazine-4-one compounds. The preparation method of the compounds of this invention is simple and overcomes the shortcomings of the above-mentioned expensive reaction raw materials and difficult preparation.
[0005] This invention provides a method for preparing 2-substituted -2,3-dihydro-4H-benzothiazine-4-one compounds, characterized by comprising the following steps: reacting 1,2-benzisothiazolin-3-one with a carbonyl compound in an organic solvent in the presence of hydrogen iodide and ammonium iodide to obtain the 2-substituted -2,3-dihydro-4H-benzothiazine-4-one compounds; wherein the organic solvent is acetonitrile or a 1,4-dioxane solvent; and the carbonyl compound is selected from any one of acetone, methyl ethyl ketone, benzaldehyde, and propionaldehyde.
[0006] In the reaction system, the molar concentration of 1,2-benzisothiazolin-3-one in the organic solvent is 0.075-0.3 mol / L; preferably, the molar concentration is 0.1 mol / L.
[0007] In the reaction system, the molar ratio of 1,2-benzisothiazolin-3-one, the carbonyl compound, hydrogen iodide, and ammonium iodide is 1:2-4:1-4:1-7; more preferably, the molar ratio is 1:3-4:2-4:3-7.
[0008] The above reaction system can react at 40-120℃; to further improve the yield, the preferred reaction temperature is 100℃.
[0009] The target product can be obtained by reacting the above reaction system in the reaction temperature range of 40-120℃ for 2-24 hours; in order to further improve the yield, the preferred reaction time is 12 hours.
[0010] Furthermore, by controlling the reaction temperature at 100℃ and the reaction time at 12h, the yield of the target product was satisfactory.
[0011] Compared with the prior art, the synthesis method of the present invention has readily available raw materials, simple operation, low equipment requirements, and simple post-processing. It can obtain 2-substituted -2,3-dihydro-4H-benzothiazine-4-one compounds in one step. Detailed Implementation
[0012] Example 1
[0013] 1,2-Benzisothiazolin-3-one (0.3 mmol), acetonitrile (3 mL), acetone (1.5 mmol), HI (0.9 mmol), and NH4I (0.9 mmol) were added sequentially to a 25 mL sealed tube. The mixture was stirred at 100 °C for 12 hours until the reaction was complete. After the reaction was complete, the reaction solution was concentrated and separated by column chromatography to obtain 2,2-dimethyl-2,3-dihydro-4H-benzothiazin-4-one, with a yield of 86%.
[0014]
[0015] NMR and mass spectrometry data of the target product:
[0016] 1 H NMR (400MHz, CDCl3) δ8.07 (dd, J = 8.1, 1.4Hz, 1H), 7.76 (br, 1H), 7.35-7.31 (m, 1H), 7.21-7.17 (m, 2H), 1.66 (s, 6H). 13 C NMR (101MHz, CDCl3) δ165.67,136.33,132.55,129.99,127.64,127.30,125.84,59.95,30.33.GC-MS(EI):193.0[M + ].
[0017] This example also investigated the effects of using 1,4-dioxane, tetrahydrofuran, methanol, toluene, 1,2-dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, and water as solvents on the reaction. Only 1,4-dioxane could be used to isolate the target product, with a yield of 45%.
[0018] Referring to the aforementioned synthesis method, the yields are shown in Table 1 below by adjusting only the amount of HI, or only the amount of NH4I, or only the amount of acetone.
[0019] Table 1
[0020] HI dosage yield [CAT] amount of NH4I yield Acetone dosage yield 0 mmol 0 0 mmol 0 0.3mmol 45％ 0.3mmol 0 0.3mmol 57％ 0.9mmol 77％ 0.6mmol 26％ 0.6mmol 74％ 2.1mmol 82％ 1.2mmol 80％ 1.2mmol 80％
[0021] This embodiment further investigated the effects of reaction temperature and reaction time on the yield.
[0022] The reaction temperatures were as follows: (1) 40℃, yield 61%; (2) 60℃, yield 77%; (3) 80℃, yield 80%; (4) 120℃, yield 70%.
[0023] The reaction time was (1) 2 h, yield 44%; (2) 6 h, yield 45%; (3) 24 h, yield 69%.
[0024] Example 2
[0025] 1,2-Benzisothiazolin-3-one (0.3 mmol), acetonitrile (3 mL), benzaldehyde (1.5 mmol), HI (0.9 mmol), and NH4I (0.9 mmol) were added sequentially to a 25 mL sealed tube. The mixture was stirred at 100 °C for 12 hours until the reaction was complete. After the reaction was complete, the reaction solution was concentrated and separated by column chromatography to obtain 2-phenyl-2,3-dihydro-4H-benzothiazin-4-one, with a yield of 90%.
[0026]
[0027] NMR and mass spectrometry data of the target product:
[0028] 1 H NMR (400MHz, CDCl3) δ8.13-8.03(m,1H),7.50-7.48(m,2H),7.36-7.32(m,4H),7.23-7.19(m,2H),6.58(br,1H),5.97(d,J=1.3Hz,1H). 13 C NMR (101MHz, CDCl3) δ165.69,136.90,136.19,132.66,130.36,129.87,129.21,127.90,127.36,127.04,126.26,59.81.GC-MS(EI):241.0[M + ].
[0029] Example 3
[0030] 1,2-Benzisothiazolin-3-one (0.3 mmol), acetonitrile (3 mL), n-propionaldehyde (1.5 mmol), HI (0.9 mmol), and NH4I (0.9 mmol) were added sequentially to a 25 mL sealed tube. The mixture was stirred at 100 °C for 12 hours until the reaction was complete. After the reaction was complete, the reaction solution was concentrated and separated by column chromatography to obtain 2-ethyl-2,3-dihydro-4H-benzothiazin-4-one, with a yield of 89%.
[0031]
[0032] NMR and mass spectrometry data of the target product:
[0033] 1 H NMR(400MHz, CDCl3)δ8.10(d,J=7.7Hz,1H),7.78(br,1H),7.41-7.37(m,1H),7 .31-7.24(m,2H),4.85-7.24(m,1H),2.05-1.93(m,2H),1.11(t,J=7.4Hz,3H). 13 C NMR (101MHz, CDCl3) δ166.14,136.90,132.29,130.08,128.36,127.60,125.92,58.15,27.81,10.26.GC-MS(EI):193.0[M + ].
Claims
1. A 2-substituted -2,3-dihydro-4 H A method for preparing benzothiazine-4-one, characterized in that: The process includes the following steps: 1,2-benzisothiazolin-3-one and an organic solvent are added to a sealed tube, followed by the addition of a carbonyl compound, hydrogen iodide, and ammonium iodide. The mixture is heated and stirred to react. After the reaction is complete, the mixture is purified to obtain 2-substituted -2,3-dihydro-4-one. H -Benzothiazine-4-one; the organic solvent is acetonitrile or 1,4-dioxane; the carbonyl compound is any one of acetone, methyl ethyl ketone, benzaldehyde, and propionaldehyde; in the reaction system, the molar ratio of 1,2-benzisothiazolin-3-one, the carbonyl compound, hydrogen iodide, and ammonium iodide is 1:3-4:2-4:3-7.
2. The 2-substituted -2,3-dihydro-4 ... H A method for preparing benzothiazine-4-one, characterized in that: The molar concentration of 1,2-benzisothiazolin-3-one in organic solvents is 0.075-0.3 mol / L.
3. The 2-substituted -2,3-dihydro-4 ... H A method for preparing benzothiazine-4-one, characterized in that: The reaction temperature is 40-120℃, and the reaction time is 2-24h.
4. The 2-substituted -2,3-dihydro-4 ... H A method for preparing benzothiazine-4-one, characterized in that: The reaction temperature was 100℃ and the reaction time was 12h.
5. The 2-substituted -2,3-dihydro-4 ... H A method for preparing benzothiazine-4-one, characterized in that: The purification method includes sequential concentration of the reaction solution and separation by column chromatography.