A method for preparing N-methyl-2,3-dihydrobenzothiazin-4-one

Abstract

This invention relates to the field of fine chemical technology and discloses a method for preparing N-methyl-2,3-dihydrobenzothiazin-4-one. Specifically, the method involves using 2-mercapto-N-methylbenzamide and 1-(chloromethyl)-1,4-diazabicyclo[2.2.2]octane-1-ammonium chloride (DABCO•DCM) as raw materials, with hydroiodic acid (HI) as an important additive. A one-step reaction is carried out in acetonitrile at 100-120°C. After purification, the target product, N-methyl-2,3-dihydrobenzothiazin-4-one, is obtained. This method is simple to operate, has a high yield, and does not require the use of formaldehyde, a carcinogen, as a reactant, making it potentially applicable.

Description

Technical Field

[0001] The invention belongs to the technical field of fine chemicals, and particularly relates to a method for preparing N-methyl-2,3-dihydrobenzothiazin-4-one. Background Art

[0002] 2,3-Dihydrobenzothiazin-4-one derivatives are an important class of organic sulfur-containing heterocyclic compounds. Their structural skeletons are widely present in various natural products and drugs. They can serve as auxiliary groups for antitumor activity and play an important role in structure-activity relationships. They have antimalarial and antitumor activities. In addition, the 2,3-dihydrobenzothiazin-4-one skeleton also has strong antibacterial activity against two Gram-positive B strains. The synthesis method we reported previously uses N-methyl-2-(ethylthio)benzamide and selective fluorine as raw materials, 1 equivalent of HI and 3 equivalents of NaI as additives, and after reaction in acetonitrile, the product is concentrated and separated by column chromatography with a yield of 74%. During the condition screening, it was found that if no additional NaI was added, the product yield would drop significantly ( Org. Chem. Front., 2022, 9 , 4016-4022). Based on this, we designed and synthesized a method for synthesizing N-methyl-2,3-dihydrobenzothiazin-4-one by the one-step reaction of 2-mercapto-N-methylbenzamide with 1-(chloromethyl)-1,4-diazabicyclo[2.2.2]octane-1-ammonium chloride (DABCO•DCM) using only hydroiodic acid (HI). Summary of the Invention

[0003] The present invention aims to provide a simpler and more efficient method for synthesizing 2,3-dihydrobenzothiazin-4-one derivatives. Specifically, it provides a method for preparing N-methyl-2,3-dihydrobenzothiazin-4-one using hydroiodic acid. The preparation method of the compound of the present invention is simple and provides a method for synthesizing N-methyl-2,3-dihydrobenzothiazin-4-one by a one-step reaction of hydroiodic acid with 2-mercapto-N-methylbenzamide and 1-(chloromethyl)-1,4-diazabicyclo[2.2.2]octane-1-ammonium chloride (DABCO•DCM, CAS No. 36273-11-7). This method is simple and efficient.

[0004] The present invention provides a method for synthesizing N-methyl-2,3-dihydrobenzothiazin-4-one with the participation of hydroiodic acid. The method comprises the following steps: in acetonitrile, in the presence of hydroiodic acid (HI), reacting 2-mercapto-N-methylbenzamide with 1-(chloromethyl)-1,4-diazabicyclo[2.2.2]octane-1-ammonium chloride (DABCO•DCM) in one step to obtain N-methyl-2,3-dihydrobenzothiazin-4-one.

[0005] The parameters of the preparation method of N-methyl-2,3-dihydrobenzothiazin-4-one are particularly preferably as follows:

[0006] In some exemplary embodiments of the present invention, the effect of solvent was investigated. Synthesis was conducted in reaction systems containing acetonitrile, N,N-dimethylformamide, 1,2-dichloroethane, dichloromethane, water, dimethyl sulfoxide, anhydrous methanol, and toluene. The results showed that the target product could not be obtained in any of the test solvents except acetonitrile. Acetonitrile is preferably the organic solvent of the present invention.

[0007] In some exemplary embodiments of the present invention, the reaction systems of different methylene sources, DABCO·DCM, and 1-chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octane bis(tetrafluoroborate) (selective fluorine) were compared. Adding only HI to the selective fluorine reaction system failed to produce the target product. Therefore, DABCO·DCM was used as the methylene source in the present invention.

[0008] The volume-to-mass ratio of the acetonitrile to the compound 2-mercapto-N-methylbenzamide can be a conventional volume-to-mass ratio for this type of reaction in the art. In the present invention, a ratio of 0.067-0.2 mol / L is particularly preferred. 0.1 mol / L is most preferred.

[0009] The molar ratio of the hydroiodic acid (HI) to the 2-mercapto-N-methylbenzamide can be a conventional molar ratio for this type of reaction in the art. In the present invention, a molar ratio of 0.5-3:1 is particularly preferred. 1:1 is most preferred.

[0010] The molar ratio of 1-(chloromethyl)-1,4-diazabicyclo[2.2.2]octane-1-ammonium chloride (DABCO•DCM) to 2-mercapto-N-methylbenzamide can be any conventional molar ratio for this type of reaction in the art. In the present invention, a ratio of 1 to 3:1 is particularly preferred. A ratio of 2:1 is most preferred.

[0011] The reaction temperature can be a conventional temperature for this type of reaction in the art. In the present invention, 100-120°C is particularly preferred. More preferably, the reaction temperature is 100°C.

[0012] The reaction time can be any conventional time for such reactions in the art. In the present invention, 12-24 hours is particularly preferred. More preferably, the reaction time is 12 hours.

[0013] Compared with the prior art, the reaction mechanism and beneficial effects of the present invention are as follows:

[0014] In the present invention, HI is used for activation with DABCO•DCM to obtain intermediate A. Secondly, the SH group in the substrate can directly react with intermediate A to obtain intermediate B and intermediate C containing a SCH2Cl group. Finally, intermediate B undergoes a ring-closure reaction under heating conditions to obtain the target product.

[0015]

[0016] This invention designs a more efficient method for synthesizing N-methyl-2,3-dihydrobenzothiazin-4-one. By adding only HI to the reaction system of 2-mercapto-N-methylbenzamide, DABCO•DCM, and acetonitrile, N-methyl-2,3-dihydrobenzothiazin-4-one can be synthesized in a single step. This method features readily available raw materials and additives, is simple to operate, requires minimal equipment, simplifies post-processing, and produces high yields. Furthermore, the use of DABCO•DCM as a methylene source avoids the use of carcinogen formaldehyde as a reactant, making it more environmentally friendly and safe. This invention provides a more efficient preparation method for the synthesis of this class of active compounds and has potential application value. DETAILED DESCRIPTION Example 1

[0017] In a 25 mL sealed tube, 2-mercapto-N-methylbenzamide (0.2 mmol, 33.45 mg), 1-(chloromethyl)-1,4-diazabicyclo[2.2.2]octane-1-ammonium chloride DABCO•DCM (0.4 mmol, 78.8 mg), acetonitrile (2.0 mL), and HI (0.2 mmol, 24 μL) were added in sequence. The mixture was stirred at 100°C. The reaction was completed after 12 hours. After the reaction, the reaction solution was concentrated and separated by column chromatography to obtain N-methyl-2,3-dihydrobenzothiazin-4-one in a yield of 95%.

[0018]

[0019] NMR data of target product: 1 H NMR (400 MHz, CDCl3) δ 8.16 – 8.10 (m, 1H), 7.39 –7.33 (m, 1H), 7.30 – 7.26 (m, 2H), 4.59 (s, 2H), 3.24 (s, 3H). 13 C NMR (75MHz, CDCl3) δ 164.15, 136.85, 131.56, 130.60, 129.28, 127.10, 126.16, 50.09,35.73. Example 2

[0020] The difference between this example and Example 1 is that the amount of HI used is 0.1 mmol, and the yield of the target product is 70%. Example 3

[0021] The difference between this example and Example 1 is that the amount of HI used is 0.6 mmol, and the yield of the target product is 95%. Example 4

[0022] The difference between this example and Example 1 is that the amount of acetonitrile used is 1.0 mL, and the yield of the target product is 83%. Example 5

[0023] The difference between this example and Example 1 is that the amount of acetonitrile used is 3.0 mL, and the yield of the target product is 92%. Example 6

[0024] The difference between this example and Example 1 is that the amount of DABCO•DCM used is 0.2 mmol, and the yield of the target product is 70%. Example 7

[0025] The difference between this example and Example 1 is that the amount of DABCO•DCM used is 0.6 mmol, and the yield of the target product is 90%. Example 8

[0026] The reaction system of Example 1 was stirred at 100°C for 1 hour, 6 hours, and 24 hours, respectively. After completion of the reaction, the reaction solution was concentrated and separated by column chromatography to collect the target product. The target product was not obtained after 1 hour or 6 hours of reaction. After 24 hours of reaction, the yield of the target product was 90%. Example 9

[0027] The reaction system of Example 1 was stirred at 25°C, 60°C, 80°C, and 120°C, respectively, and reacted vigorously with stirring for 12 hours. After the reaction, the reaction solution was concentrated and separated by column chromatography to collect the target product. The target product could not be obtained at reaction temperatures between 25°C and 80°C. The target product yield was 90% when the reaction was carried out at 120°C for 12 hours. Comparative Example 1

[0028] The solvent acetonitrile in the reaction system of Example 1 was replaced by dichloromethane, 1,2-dichloroethane, toluene, N,N-dimethylformamide, dimethyl sulfoxide, methanol, and water, but no target product was obtained. Comparative Example 2

[0029] When DABCO•DCM in the reaction system of Example 1 was replaced with an equivalent amount of selective fluorine, no target product was obtained.

[0030] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing N-methyl-2,3-dihydrobenzothiazin-4-one, characterized in that: The method comprises the following steps: sequentially adding 2-mercapto-N-methylbenzamide, 1-(chloromethyl)-1,4-diazabicyclo[2.2.2]octane-1-ammonium chloride, acetonitrile and hydroiodic acid into a sealed tube, heating and stirring the system to allow the system to react vigorously, and purifying the system after the reaction to obtain N-methyl-2,3-dihydrobenzothiazin-4-one; wherein the molar ratio of hydroiodic acid to 2-mercapto-N-methylbenzamide is 0.5-3:1; and the reaction temperature is 100-120°C.

2. The method for preparing N-methyl-2,3-dihydrobenzothiazin-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 N-methyl-2,3-dihydrobenzothiazin-4-one according to claim 1, characterized in that: The concentration of 2-mercapto-N-methylbenzamide in the reaction system is 0.067-0.2 mol / L.

4. The method for preparing N-methyl-2,3-dihydrobenzothiazin-4-one from hydrogen according to claim 1, characterized in that: The molar ratio of 1-(chloromethyl)-1,4-diazabicyclo[2.2.2]octane-1-ammonium chloride to 2-mercapto-N-methylbenzamide is 1-3:

1.

5. The method for preparing N-methyl-2,3-dihydrobenzothiazin-4-one according to claim 1, characterized in that: The reaction time is 12-24 hours.

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