Method for preparing compound simultaneously containing benzisothiazolinone skeleton and benzothiazine-4-ketone skeleton

Abstract

The invention relates to the technical field of organic synthesis, in particular to a method for preparing a compound simultaneously containing a benzisothiazolinone skeleton and a benzothiazine-4-ketone skeleton. Derivatives containing a benzisothiazolinone skeleton and a benzothiazine-4-ketone skeleton at the same time have not been reported yet. In order to solve the problems, the invention provides the method for preparing the compound simultaneously containing the benzisothiazolinone skeleton and the benzothiazine-4-one skeleton, 1, 2-benzisothiazolin-3-one and Selectfluor are used as reaction raw materials, acetonitrile is used as a reaction solvent, and the compound simultaneously containing the benzisothiazolinone skeleton and the benzothiazine-4-one skeleton is prepared through a one-pot method. The preparation method comprises the following steps: sequentially carrying out dimerization reaction and selective ring expansion reaction under the catalytic action of iodic acid and iodized salt, and after the reaction is finished, carrying out separation and purification to obtain a compound-N-(benzothiazinone methylene) benzoisothiazolinone which simultaneously contains a benzisothiazolinone skeleton and a benzothiazine-4-one skeleton, the method provides a new synthesis thought for preparing a derivative containing a benzisothiazolinone skeleton and a benzothiazine-4-ketone skeleton at the same time.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing a compound containing both a benzisothiazolinone skeleton and a benzothiazine-4-one skeleton. Background Art

[0002] Benzisothiazolinone and its derivatives and benzothiazin-4-one and its derivatives are important sulfur-containing heterocyclic compounds, showing unique activity and application value in many fields. Benzisothiazolinone and its derivatives have a broad-spectrum bactericidal effect, and have good killing ability against bacteria, molds, common Gram-negative bacteria such as Escherichia coli and Gram-positive bacteria such as Bacillus. In addition, they also show good inhibitory activity against strains such as Bacillus subtilis, Staphylococcus aureus, Mango stem rot and Candida albicans. As the core skeleton of a series of pharmaceutical preparations and bioactive molecules, benzothiazin-4-one and its derivatives have multiple pharmacological activities such as anti-HIV, antibacterial, antiviral, anti-tuberculosis, and anti-arrhythmic. These activities make benzothiazin-4-one an important compound in drug research and development.

[0003] At present, benzisothiazolinone and its derivatives or benzothiazin-4-one and its derivatives are added separately to products such as food or medicine for application, and the pharmaceutical activity of the corresponding products obtained is relatively single. Derivatives containing both benzisothiazolinone skeleton and benzothiazin-4-one skeleton have not been reported. Summary of the invention

[0004] The problem in the prior art is that no derivatives containing both a benzisothiazolinone skeleton and a benzothiazin-4-one skeleton have been reported. In view of the above problem, the present invention provides a method for preparing a compound containing both a benzisothiazolinone skeleton and a benzothiazin-4-one skeleton, characterized in that the method comprises the following steps:

[0005] 1,2-Benzisothiazoline-3-one and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (Selectfluor) are used as reaction raw materials, acetonitrile is used as reaction solvent, and a reaction is carried out under the catalytic action of iodic acid and iodine salt. After the reaction is completed, the reaction solution is concentrated and purified to obtain N-(benzothiazinone methylene)benzisothiazolinone. The chemical structure of the N-(benzothiazinone methylene)benzisothiazolinone is as follows:

[0006]

[0007] Preferably, during the reaction, the ratio of 1,2-benzisothiazolin-3-one to 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate), acetonitrile, iodic acid, and iodine salt is 0.2-0.4 mmol: 0.2 mmol: 2-4 mL: 0.2-0.6 mmol: 0.3-0.9 mmol.

[0008] Preferably, the iodic acid comprises one of HI, HBr, HCl, and HOAc.

[0009] Preferably, the iodic acid is HI.

[0010] Preferably, the iodine salt comprises one of NH4I, KI, NaI and LiI.

[0011] Preferably, the iodine salt is NaI.

[0012] Preferably, the reaction temperature is 100°C.

[0013] Preferably, the reaction time is 6-24 hours.

[0014] Preferably, the reaction time is 12 h.

[0015] The present invention has the following beneficial effects:

[0016] (1) The present invention uses 1,2-benzisothiazolin-3-one and Selectfluor as reaction raw materials and acetonitrile as reaction solvent. Under the catalytic action of iodic acid and iodine salt, a dimerization reaction and a selective ring expansion reaction are carried out in sequence. After the reaction is completed, a compound containing both a benzisothiazolinone skeleton and a benzothiazin-4-one skeleton, N-(benzothiazinone methylene)benzisothiazolinone, is obtained by separation and purification. This method provides a new synthetic idea for preparing derivatives containing both a benzisothiazolinone skeleton and a benzothiazin-4-one skeleton.

[0017] (2) The method of the present invention is simple, the raw materials are easily available, the reaction conditions are relatively mild, and it has high potential activity and application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 : Schematic diagram of two possible reaction pathways involved in the chemical reaction process for preparing N-(benzothiazinone methylene)benzisothiazolinone in Example 1 of the present invention. DETAILED DESCRIPTION

[0019] The present invention is described in detail below with reference to the examples. However, it should be understood that the following examples are only illustrative of the embodiments of the present invention, and are not intended to limit the scope of the present invention.

[0020] Example 1

[0021] The synthesis method of N-(benzothiazinone methylene)benzisothiazolinone is as follows:

[0022] Acetonitrile (3 mL), 1,2-benzisothiazolin-3-one (0.3 mmol), Selectfluor (0.2 mmol), HI (0.4 mmol) and NaI (0.6 mmol) were added to a 25 mL sealed tube in sequence. The reaction temperature was controlled at 100 ° C. The reaction was stirred for 12 hours. After the reaction was completed, the reaction solution was concentrated and separated by column chromatography in sequence to obtain the target product N-(benzothiazinone methylene)benzisothiazolinone, and the product yield was 60%. The chemical reaction process involved is as follows:

[0023]

[0024] The hydrogen spectrum and mass spectrum data of N-(benzothiazinone methylene)benzisothiazolinone are as follows:

[0025] 1 H NMR (300MHz, CDCl3) δ8.09 (dd, J=8.2, 1.6Hz, 1H), 7.97 (d, J=7.9Hz, 1H), 7.62-7.54 (m, 1H ),7.47(d,J=8.1Hz,1H),7.39-7.28(m,2H),7.27-7.16(m,2H),5.62(s,2H),4.81(s,2H).

[0026] 13 C NMR (75MHz, CDCl3) δ166.62,164.94,141.70,137.78,132.56,132.37,130.98,128.19,1 27.44,126.85,126.23,125.61,123.19,120.56,54.77,48.50.LC-MS(ESI)=329.0[M+H] + .

[0027] Example 2 is the same as Example 1, except that the amount of 1,2-benzisothiazolin-3-one used in Example 2 is 0.2 mmol, and the yield of the target product N-(benzothiazinone methylene)benzisothiazolinone is 51%.

[0028] Example 3 is the same as Example 1, except that the amount of 1,2-benzisothiazolin-3-one used in Example 3 is 0.4 mmol, and the yield of the target product N-(benzothiazinone methylene)benzisothiazolinone is 55%.

[0029] Example 4 is the same as Example 1, except that the reaction temperature in Example 4 is 80° C., and the yield of the target product N-(benzothiazinone methylene)benzisothiazolinone is 0.

[0030] Example 5 is the same as Example 1, except that the reaction temperature in Example 5 is 120° C., and the yield of the target product N-(benzothiazinone methylene)benzisothiazolinone is 37%.

[0031] Example 6 is the same as Example 1, except that the amount of HI used in Example 6 is 0, and the yield of the target product N-(benzothiazinone methylene)benzisothiazolinone is 0%.

[0032] Example 7 is the same as Example 1, except that the amount of HI used in Example 7 is 0.2 mmol, and the yield of the target product N-(benzothiazinone methylene)benzisothiazolinone is 50%.

[0033] Example 8 is the same as Example 1, except that the amount of HI used in Example 8 is 0.6 mmol, and the yield of the target product N-(benzothiazinone methylene)benzisothiazolinone is 15%.

[0034] Example 9 is the same as Example 1, except that an equal molar amount of HBr is used in Example 9, and the yield of the target product N-(benzothiazinone methylene)benzisothiazolinone is 30%.

[0035] Example 10 is the same as Example 1, except that an equal molar amount of HCl is used in Example 10, and the yield of the target product N-(benzothiazinone methylene)benzisothiazolinone is 13%.

[0036] Example 11 is the same as Example 1, except that an equal molar amount of HOAc is used in Example 11, and the yield of the target product N-(benzothiazinone methylene)benzisothiazolinone is 0%.

[0037] Example 12 is the same as Example 1, except that Example 12 uses the same molar amount of NH4I, and the yield of the target product N-(benzothiazinone methylene)benzisothiazolinone is 42%.

[0038] Example 13 is the same as Example 1, except that Example 13 uses the same molar amount of KI, and the yield of the target product N-(benzothiazinone methylene)benzisothiazolinone is 57%.

[0039] Example 14 is the same as Example 1, except that Example 14 uses the same molar amount of LiI, and the yield of the target product N-(benzothiazinone methylene)benzisothiazolinone is 31%.

[0040] Example 15 is the same as Example 12, except that the amount of NH4I used in Example 15 is 0, and the yield of the target product N-(benzothiazinone methylene)benzisothiazolinone is 0%.

[0041] Example 16 is the same as Example 12, except that the amount of NH4I used in Example 16 is 0.3 mmol, and the yield of the target product N-(benzothiazinone methylene)benzisothiazolinone is 45%.

[0042] Example 17 is the same as Example 12, except that the amount of NH4I used in Example 17 is 0.6 mmol, and the yield of the target product N-(benzothiazinone methylene)benzisothiazolinone is 60%.

[0043] Example 18 is the same as Example 12, except that the amount of NH4I used in Example 18 is 0.9 mmol, and the yield of the target product N-(benzothiazinone methylene)benzisothiazolinone is 60%.

[0044] Example 19 is the same as Example 1, except that the amount of acetonitrile used in Example 19 is 2 mL, and the yield of the target product N-(benzothiazinone methylene)benzisothiazolinone is 33%.

[0045] Example 20 is the same as Example 1, except that the amount of acetonitrile used in Example 20 is 4 mL, and the yield of the target product N-(benzothiazinone methylene)benzisothiazolinone is 53%.

[0046] Example 21 is the same as Example 1, except that the reaction time in Example 21 is 6 hours, and the yield of the target product N-(benzothiazinone methylene)benzisothiazolinone is 15%.

[0047] Example 22 is the same as Example 1, except that the reaction time in Example 22 is 24 hours, and the yield of the target product N-(benzothiazinone methylene)benzisothiazolinone is 29%.

[0048] Based on the above ideal embodiments of the present invention, the relevant staff can make various changes and modifications without departing from the technical concept of the present invention through the above description. The technical scope of the present invention is not limited to the contents of the specification, and its technical scope must be determined according to the scope of the claims.

Claims

1. A method for preparing a compound containing both a benzisothiazolinone skeleton and a benzothiazin-4-one skeleton, characterized in that: The following steps are involved: 1,2-Benzisothiazoline-3-one and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt are used as reaction raw materials, acetonitrile is used as reaction solvent, and a reaction is carried out under the catalytic action of iodic acid and iodine salt. After the reaction is completed, the reaction solution is concentrated and purified to obtain N-(benzothiazinone methylene)benzisothiazolinone. The chemical structure of the N-(benzothiazinone methylene)benzisothiazolinone is as follows:

2. A method for preparing a compound containing both a benzisothiazolinone skeleton and a benzothiazin-4-one skeleton according to claim 1, characterized in that: During the reaction, the dosage ratio of 1,2-benzisothiazolin-3-one to 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate), acetonitrile, iodic acid, and iodine salt is 0.2-0.4 mmol: 0.2 mmol: 2-4 mL: 0.2-0.6 mmol: 0.3-0.9 mmol.

3. A method for preparing a compound containing both a benzisothiazolinone skeleton and a benzothiazin-4-one skeleton according to claim 1, characterized in that: The iodic acid includes one of HI, HBr, HCl, and HOAc.

4. A method for preparing a compound containing both a benzisothiazolinone skeleton and a benzothiazin-4-one skeleton according to claim 3, characterized in that: The iodic acid is HI.

5. The method for preparing a compound containing both a benzisothiazolinone skeleton and a benzothiazin-4-one skeleton according to claim 1, characterized in that: The iodine salt includes one of NH4I, KI, NaI and LiI.

6. A method for preparing a compound containing both a benzisothiazolinone skeleton and a benzothiazin-4-one skeleton according to claim 5, characterized in that: The iodized salt is NaI.

7. A method for preparing a compound containing both a benzisothiazolinone skeleton and a benzothiazin-4-one skeleton according to claim 1, characterized in that: The reaction temperature was 100°C.

8. The method for preparing a compound containing both a benzisothiazolinone skeleton and a benzothiazin-4-one skeleton according to claim 1, characterized in that: The reaction time is 6-24h.

9. A method for preparing a compound containing both a benzisothiazolinone skeleton and a benzothiazin-4-one skeleton according to claim 8, characterized in that: The reaction time is 12h.

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