A preparation method of 2,3-dihydro-4H-1,3-benzothiazin-4-one

Abstract

The present invention belongs to the field of fine chemicals and relates to a method for preparing 2,3-dihydro-4H-1,3-benzothiazine-4-one. It includes: adding 1,2-benzisothiazolin-3-one, Selectfluor, ammonium iodide and hydroiodic acid to a sealed tube containing a reaction solvent acetonitrile or 1,4-Dioxane and reacting, and purifying after the reaction to obtain 2,3-dihydro-4H-1,3-benzothiazine-4-one. The present invention uses cheap and readily available 1,2-benzisothiazolin-3-one and Selectfluor as raw materials, ammonium iodide and hydroiodic acid as additives to construct 2,3-dihydro-4H-1,3-benzothiazine-4-one. Wherein Selectfluor can provide a methylene source, which is inserted into the five-membered heterocyclic ring of the raw material 1,2-benzisothiazolin-3-one, and 2,3-dihydro-4H-1,3-benzothiazine-4-one is constructed in one step.

Description

Technical Field

[0001] The invention belongs to the field of fine chemicals and relates to a method for preparing 2,3-dihydro-4H-1,3-benzothiazine-4-one. Background Art

[0002] 2,3-Dihydro-4H-1,3-benzothiazin-4-one is an important class of sulfur-nitrogen-containing six-membered heterocyclic compounds, which are widely present in various natural products, drugs, foods and materials with pharmaceutical activity.

[0003] At present, there is only one method reported in the literature for synthesizing 2,3-dihydro-4H-1,3-benzothiazin-4-one: using 2-methylthiophenol and polyformaldehyde as raw materials, ammonium acetate as an additive, and refluxing in toluene for 15 hours, 50% yield of 2,3-dihydro-4H-1,3-benzothiazin-4-one can be obtained. The main defects of this type of reaction are: (1) using toxic reagents 2-methylthiophenol and polyformaldehyde; (2) the yield is relatively low. The specific synthesis method can be found in the supporting materials in (Chem. Commun., 2011, 47, 2137).

[0004] In previous work, we found that the fluorination reagent Selectfluor can be used to synthesize various 1,3-benzothiazin-4-one derivatives, but this strategy has some limitations: it can only synthesize 1,3-benzothiazin-4-one derivatives with alkyl substituents on N. When the substituent on N is H or aromatic, the reaction cannot proceed (China Patent Authorization Number: ZL201811245251.0; ZL202111461347.2; ZL202111461346.8). Summary of the invention

[0005] The purpose of the present invention is to provide a novel preparation method of 2,3-dihydro-4H-1,3-benzothiazin-4-one, which avoids the use of toxic reagents such as 2-methylthiophenol and paraformaldehyde.

[0006] The preparation method of 2,3-dihydro-4H-1,3-benzothiazine-4-one involved in the present invention comprises the following steps: adding 1,2-benzisothiazolin-3-one, Selectfluor, ammonium iodide and hydroiodic acid into a sealed tube containing a reaction solvent of acetonitrile or 1,4-Dioxane and reacting, and purifying after the reaction to obtain 2,3-dihydro-4H-1,3-benzothiazine-4-one.

[0007] Furthermore, the purification method includes sequentially concentrating and separating the reaction solution by column chromatography.

[0008] In order to ensure the efficiency of obtaining the target product, the concentration of 1,2-benzisothiazolin-3-one in the reaction system of the present invention is 0.075-0.3 mol / L, preferably 0.1 mol / L.

[0009] In order to improve the yield, further, the molar ratio of NH4I to 1,2-benzisothiazolin-3-one is 1-5:1.

[0010] In order to improve the yield, further, the molar ratio of HI to 1,2-benzisothiazolin-3-one is 1-5:1.

[0011] In order to improve the construction efficiency of 2,3-dihydro-4H-1,3-benzothiazin-4-one and increase the yield, preferably, the reaction solvent is MeCN, and the molar ratio of 1,2-benzisothiazolin-3-one, Selectfluor, ammonium iodide and hydroiodic acid is 1:1:3-5:3-5.

[0012] More preferably, the reaction solvent is MeCN, and the molar ratio of 1,2-benzisothiazolin-3-one, Selectfluor, ammonium iodide and hydroiodic acid is 1.0:1.0:4.0:4.0.

[0013] In order to ensure the efficiency of obtaining the target product, the reaction temperature described in the present invention is 130-150 degrees Celsius, preferably 140 degrees Celsius.

[0014] In order to ensure the efficiency of obtaining the target object, the reaction time described in the present invention is 8-16 hours, preferably 12 hours.

[0015] Compared with the prior art, the present invention uses cheap and readily available 1,2-benzisothiazolin-3-one and Selectfluor as raw materials, and ammonium iodide and hydroiodic acid as additives to construct 2,3-dihydro-4H-1,3-benzothiazin-4-one. Among them, Selectfluor can provide a methylene source, which is inserted into the five-membered heterocyclic ring of the raw material 1,2-benzisothiazolin-3-one to construct 2,3-dihydro-4H-1,3-benzothiazin-4-one in one step. DETAILED DESCRIPTION

[0016] The present invention is further described in detail below in conjunction with embodiments:

[0017] Example 1

[0018] Synthesis method of 2,3-dihydro-4H-1,3-benzothiazin-4-one: acetonitrile (3mL), 1,2-benzisothiazolin-3-one (0.3mmol), Selectfluor (0.3mmol), NH4I (1.2mmol) and HI (1.2mmol) were added to a 25mL sealed tube in sequence, the temperature was controlled at 140 degrees Celsius, and the reaction was stirred vigorously for 12 hours. After the reaction, the reaction solution was concentrated and separated by column chromatography in sequence to obtain 2,3-dihydro-4H-1,3-benzothiazin-4-one, and the separation yield was 80%.

[0019]

[0020] NMR data and mass spectrometry data of target product:

[0021] 1 H NMR (300MHz, CDCl3) δ8.81(br,1H),7.98(d,J=7.6Hz,1H),7.29–7.13(m,3H),4.46(d,J=3.0Hz,2H). 13 C NMR (75MHz, CDCl3) δ165.42,136.80,131.06,128.96,127.58,126.38,125.00,41.45.MS(EI)=165.0[M] + .

[0022] Example 2 (Screening of the dosage of NH4I)

[0023] Referring to the method of Example 1, only the amount of NH4I was adjusted. The specific method was as follows: acetonitrile (3 mL), 1,2-benzisothiazolin-3-one (0.3 mmol), Selectfluor (0.3 mmol), NH4I and HI (1.2 mmol) were added to a 25 mL sealed tube in sequence, the temperature was controlled at 140 degrees Celsius, and the reaction was stirred vigorously for 12 hours. After the reaction was completed, the reaction solution was concentrated and separated by column chromatography in sequence, and the specific situation was as follows:

[0024] (1) The dosage of NH4I was 0, and the yield of the target product was 29%;

[0025] (2) The dosage of NH4I was 0.3 mmol, and the yield of the target product was 36%;

[0026] (3) The dosage of NH4I was 0.6 mmol, and the yield of the target product was 50%;

[0027] (4) The dosage of NH4I was 0.9 mmol, and the yield of the target product was 65%;

[0028] (5) The dosage of NH4I was 1.2 mmol, and the yield of the target product was 80%;

[0029] (6) The amount of NH4I used was 1.5 mmol, and the yield of the target product was 77%.

[0030] Example 3 (screening of HI dosage)

[0031] Referring to the method of Example 1, only the amount of HI was adjusted. The specific method was as follows: acetonitrile (2 mL), 1,2-benzisothiazolin-3-one (0.3 mmol), Selectfluor (0.3 mmol), NH4I (1.2 mmol) and HI were added to a 25 mL sealed tube in sequence, the temperature was controlled at 140 degrees Celsius, and the reaction was stirred vigorously for 12 hours. After the reaction was completed, the reaction solution was concentrated and separated by column chromatography in sequence, and the specific situation was as follows:

[0032] (1) The dosage of HI is 0, and the yield of the target product is 0%;

[0033] (2) The dosage of HI was 0.3 mmol, and the yield of the target product was 30%;

[0034] (3) The dosage of HI was 0.6 mmol, and the yield of the target product was 43%;

[0035] (4) The dosage of HI was 0.9 mmol, and the yield of the target product was 60%;

[0036] (5) The dosage of HI was 1.2 mmol, and the yield of the target product was 80%;

[0037] (6) The dosage of HI was 1.5 mmol, and the yield of the target product was 70%.

[0038] Example 4 (Screening of different reaction solvents)

[0039] Referring to the method of Example 1, only the type of solvent was adjusted. The specific method was as follows: different reaction solvents (3 mL), 1,2-benzisothiazolin-3-one (0.3 mmol), Selectfluor (0.3 mmol), NH4I (1.2 mmol) and HI (1.2 mmol) were added to a 25 mL sealed tube in sequence, the temperature was controlled at 140 degrees Celsius, and the reaction was stirred vigorously for 12 hours. After the reaction was completed, the reaction solution was concentrated and separated by column chromatography in sequence, and the specific situation was as follows:

[0040] (1) Using MeCN as solvent, the yield of the target product is 80%;

[0041] (2) Using THF as solvent, the yield of the target product was 48%;

[0042] (3) Using DCM as solvent, the yield of the target product was 19%;

[0043] (4) Using 1,4-Dioxane as solvent, the yield of the target product was 54%;

[0044] (5) The yield of the target product using DCE as solvent was 21%.

[0045] (6) In addition, the target product could not be isolated using DMF, DMSO, toluene, methanol, and acetone as solvents.

[0046] In addition, based on the above Example 1, the concentration of 1,2-benzisothiazolin-3-one in the reaction system is controlled to be 0.075-0.3 mol / L; and / or, the reaction temperature is 130-150 degrees Celsius; and / or, the reaction time is 8-16h, and the yield can be achieved. More than 50% has a high reaction efficiency. When the concentration of 1,2-benzisothiazolin-3-one in the reaction system is 0.075-0.15 mol / L; and / or, the reaction temperature is 130-150 degrees Celsius; and / or, the reaction time is 10-16h, the yield can be achieved. More than 60%; when the concentration of 1,2-benzisothiazolin-3-one in the reaction system is 0.075-0.1 mol / L; and / or, the reaction temperature is 140-150 degrees Celsius; and / or, the reaction time is 10-14h, the yield can be achieved. More than 70% of the yield.

[0047] The above describes the optional embodiments of the present invention to teach those skilled in the art how to implement and reproduce the present invention. In order to teach the present invention, some conventional technical aspects have been simplified and omitted. Those skilled in the art should understand that variations derived from this aspect are all within the scope of protection of the present invention.

Claims

1. A method for preparing 2,3-dihydro-4H-1,3-benzothiazin-4-one, characterized in that: The method comprises the following steps: adding 1,2-benzisothiazolin-3-one, 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate), ammonium iodide and hydroiodic acid into a sealed tube containing a reaction solvent of acetonitrile or 1,4-dioxane and reacting, and purifying after the reaction to obtain 2,3-dihydro-4H-1,3-benzothiazine-4-one.

2. The method for preparing 2,3-dihydro-4H-1,3-benzothiazin-4-one according to claim 1, characterized in that: The purification method comprises sequentially concentrating the reaction solution and separating it by column chromatography.

3. The method for preparing 2,3-dihydro-4H-1,3-benzothiazin-4-one according to claim 1, characterized in that: The concentration of 1,2-benzisothiazolin-3-one in the reaction system is 0.075-0.3 mol / L; and / or, the reaction temperature is 130-150 degrees Celsius; and / or, the reaction time is 8-16 hours.

4. The method for preparing 2,3-dihydro-4H-1,3-benzothiazin-4-one according to claim 1, characterized in that: The concentration of 1,2-benzisothiazolin-3-one in the reaction system was 0.1 mol / L.

5. The method for preparing 2,3-dihydro-4H-1,3-benzothiazin-4-one according to claim 1, characterized in that: The molar ratio of NH4I to 1,2-benzisothiazolin-3-one is 1-5:

1.

6. The method for preparing 2,3-dihydro-4H-1,3-benzothiazin-4-one according to claim 1, characterized in that: The molar ratio of HI to 1,2-benzisothiazolin-3-one is 1-5:

1.

7. The method for preparing 2,3-dihydro-4H-1,3-benzothiazin-4-one according to claim 1, characterized in that: The reaction solvent is MeCN, and the molar ratio of 1,2-benzisothiazolin-3-one, 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt, ammonium iodide and hydroiodic acid is 1:1:3-5:3-5.

8. The method for preparing 2,3-dihydro-4H-1,3-benzothiazin-4-one according to claim 1, characterized in that: The reaction solvent is MeCN, and the molar ratio of 1,2-benzisothiazolin-3-one, 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate), ammonium iodide and hydroiodic acid is 1.0:1.0:4.0:4.

0.

9. The method for preparing 2,3-dihydro-4H-1,3-benzothiazin-4-one according to claim 1, characterized in that: The reaction temperature is 140 degrees Celsius.

10. The method for preparing 2,3-dihydro-4H-1,3-benzothiazin-4-one according to claim 1, characterized in that: The reaction time is 12 hours.

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