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

Abstract

The invention belongs to the field of fine chemicals and relates to a preparation method of N-phenyl-2,3-dihydro-4H-1,3-benzothiazine-4-one. N-phenyl-1,2-benzisothiazolin-3-one and 1-(chloromethyl)-1,4-diazabicyclo[2.2.2]octane-1-ium chloride are used as raw materials, potassium iodide and hydroiodic acid are used as important additives, and a target product N-phenyl-2,3-dihydro-4H-1,3-benzothiazine-4-one is obtained by one-step reaction in acetonitrile. The method is simple to operate, avoids the use of a transition metal catalyst, and can synthesize N-phenyl-2,3-dihydro-4H-1,3-benzothiazine-4-one in one step, and has potential application value.

Description

Technical Field

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

[0002] N-Phenyl-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 N-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one: using N-phenyl-o-iodobenzamide, elemental sulfur and dichloromethane as raw materials, copper bromide as catalyst, 1,10-phenanthroline as ligand, triethylamine as base, and reacting in DMSO at 120 degrees Celsius for 12 hours, a 56% yield of N-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one can be obtained. The main defects of this type of reaction are: (1) using copper bromide as a catalyst easily leads to transition metal residues; (2) the yield is relatively low. For the specific synthesis method, see the supporting materials in (Adv.Synth.Catal.2019,361,550).

[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 phenyl, 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 overcome the metal residue problem in the prior art and provide a preparation method of N-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one. The method uses N-phenyl-1,2-benzisothiazolin-3-one and 1-(chloromethyl)-1,4-diazabicyclo[2.2.2]octan-1-ium chloride (DABCO·DCM) as raw materials, potassium iodide and hydroiodic acid as additives to construct N-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one. DABCO·DCM can provide a methylene source, which is inserted into the five-membered heterocyclic ring of the raw material N-phenyl-1,2-benzisothiazolin-3-one to construct N-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one in one step.

[0006] In order to achieve the purpose of the present invention, the technical scheme adopted is: a preparation method of N-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one, comprising the following steps: adding N-phenyl-1,2-benzisothiazolin-3-one, 1-(chloromethyl)-1,4-diazabicyclo[2.2.2]octan-1-ium chloride (DABCO·DCM), potassium iodide and hydroiodic acid into a reaction container containing acetonitrile as a reaction solvent, reacting at a reaction temperature, and obtaining the target product N-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one through separation and purification after the reaction is completed.

[0007] Preferably, the separation and purification method comprises sequentially concentrating the reaction solution and performing column chromatography separation after the reaction is completed.

[0008] In order to improve the yield of the target product, the reaction solvent of the system in the present invention is acetonitrile.

[0009] In order to improve the yield of the target product, the concentration of N-phenyl-1,2-benzisothiazolin-3-one in the reaction system of the present invention is 0.07-0.2 mol / L; more preferably, 0.1 mol / L.

[0010] In order to improve the yield of the target product, the molar ratio of KI to N-phenyl-1,2-benzisothiazolin-3-one of the present invention is 2-5:1;

[0011] And / or, the molar ratio of HI to N-phenyl-1,2-benzisothiazolin-3-one of the present invention is 1-5:1, more preferably 2-5:1.

[0012] In order to improve the yield of the target product, it is more preferred that the molar ratio of N-phenyl-1,2-benzisothiazolin-3-one, N-phenyl-1,2-benzisothiazolin-3-one, 1-(chloromethyl)-1,4-diazabicyclo[2.2.2]octan-1-ium chloride (DABCO·DCM), potassium iodide and hydroiodic acid in the present invention is 1.0:2.0:4.0:4.0

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

[0014] In order to improve the yield of the target product, preferably, the reaction time in the present invention is at least 3 hours, preferably at least 6 hours, and more preferably 6-12 hours.

[0015] Compared with the prior art, the present invention uses N-phenyl-1,2-benzisothiazolin-3-one and 1-(chloromethyl)-1,4-diazabicyclo[2.2.2]octan-1-ium chloride as raw materials, potassium iodide and hydroiodic acid as important additives, and obtains the target product N-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one in a one-step reaction in acetonitrile. The method is simple to operate, avoids the use of a transition metal catalyst, and can synthesize N-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one in one step, which has potential application value. DETAILED DESCRIPTION

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

[0017] Example 1

[0018] Synthesis method of N-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one: acetonitrile (2mL), N-phenyl-1,2-benzisothiazolin-3-one (0.2mmol), 1-(chloromethyl)-1,4-diazabicyclo[2.2.2]octan-1-ium chloride (DABCO·DCM) (0.4mmol), KI (0.8mmol) and HI (0.8mmol) were added to a 25mL sealed tube in sequence, the temperature was controlled at 140 degrees Celsius, and the reaction was vigorously stirred for 12 hours. After the reaction was completed, the reaction solution was concentrated and separated by column chromatography in sequence to obtain N-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one, and the separation yield was 75%.

[0019]

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

[0021] H NMR (300 MHz, CDCl 3 )δ8.11(d,J=7.7Hz,1H),7.45–7.12(m,8H),4.91(s,2H). 13 CNMR (75MHz, CDCl 3 )δ163.58,142.23,137.35,132.01,131.21,129.61,129.33,127.32,127.15,126.33,125.82,51.66.MS(EI)=241.0[M] + .

[0022] Example 2 (screening of dosage of KI)

[0023] Referring to the method of Example 1, only the amount of KI was adjusted. The specific method was as follows: acetonitrile (2 mL), N-phenyl-1,2-benzisothiazolin-3-one (0.2 mmol), 1-(chloromethyl)-1,4-diazabicyclo[2.2.2]octan-1-ium chloride (DABCO·DCM) (0.4 mmol), KI (0-1.0 mmol) and HI (0.8 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 KI was 0, and the yield of the target product was 16%;

[0025] (2) The dosage of KI was 0.2 mmol, and the yield of the target product was 22%;

[0026] (3) The dosage of KI was 0.4 mmol, and the yield of the target product was 51%;

[0027] (4) The dosage of KI was 0.3 mmol, and the yield of the target product was 68%;

[0028] (5) The dosage of KI was 0.8 mmol, and the yield of the target product was 75%;

[0029] (6) The dosage of KI was 1.0 mmol, and the yield of the target product was 70%;

[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), N-phenyl-1,2-benzisothiazolin-3-one (0.2 mmol), 1-(chloromethyl)-1,4-diazabicyclo[2.2.2]octan-1-ium chloride (DABCO·DCM) (0.4 mmol), KI (0.8 mmol) and HI (0-1.0 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:

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

[0033] (2) The dosage of HI was 0.2 mmol, and the yield of the target product was 40%;

[0034] (3) The dosage of HI was 0.4 mmol, and the yield of the target product was 62%;

[0035] (4) The dosage of HI was 0.6 mmol, and the yield of the target product was 70%;

[0036] (5) The dosage of HI was 0.8 mmol, and the yield of the target product was 75%;

[0037] (6) The dosage of HI was 1.0 mmol, and the yield of the target product was 72%.

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

[0039] Referring to the method of Example 1, only the reaction solvent was adjusted. The specific method was as follows: different reaction solvents (2 mL), N-phenyl-1,2-benzisothiazolin-3-one (0.2 mmol), 1-(chloromethyl)-1,4-diazabicyclo[2.2.2]octan-1-ium chloride (DABCO·DCM) (0.4 mmol), KI (0.8 mmol) and HI (0.8 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 was 75%;

[0041] (2) Using DCM as solvent, the yield of the target product was 15%;

[0042] (3) Using DCE as solvent, the yield of the target product is 10%.

[0043] (4) In addition, the target product could not be isolated using THF, 1,4-Dioxane, DMF, DMSO, toluene, and methanol as solvents.

[0044] Example 5 (Using Selectfluor instead of DABCO·DCM)

[0045] Referring to the method of Example 1, Selectfluor was used instead of DABCO·DCM. The specific method was as follows: acetonitrile (2mL), N-phenyl-1,2-benzisothiazolin-3-one (0.2mmol), Selectfluor (0.4mmol), KI (0.8mmol) and HI (0.8mmol) 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 was completed, the reaction solution was concentrated and separated by column chromatography in sequence, but the target product could not be isolated.

[0046] In addition, based on the above experimental verification 1, the reaction temperature was controlled at 130 degrees Celsius and 150 degrees Celsius, and the corresponding yields were 70% and 75%, respectively; the reaction time was controlled at 3h, 6h, and 24h, and the yields were 40%, 68%, and 70%, respectively.

[0047] On the basis of the above-mentioned Example 1, the concentration of N-phenyl-1,2-benzisothiazolin-3-one in the reaction system was controlled to be 0.075-0.2 mol / L, at which a yield of more than 60% could be achieved, wherein when the acetonitrile concentration was 0.067 mol / L, the yield was 70%.

[0048] 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 N-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one, characterized in that: Adding N-phenyl-1,2-benzisothiazolin-3-one, 1-(chloromethyl)-1,4-diazabicyclo[2.2.2]octan-1-ium chloride, potassium iodide and hydroiodic acid into a reactor containing a reaction solvent, acetonitrile, and reacting at a reaction temperature. After the reaction is completed, separating and purifying to obtain the N-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one; The molar ratio of HI to N-phenyl-1,2-benzisothiazolin-3-one is 1-5:1; The molar ratio of KI to N-phenyl-1,2-benzisothiazolin-3-one is 2-5:1; The reaction temperature is 130-150 degrees Celsius.

2. The method for preparing N-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one according to claim 1, characterized in that: The separation and purification method includes vacuum distillation after the reaction, column chromatography separation and collection of the target product.

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

1.

4. The method for preparing N-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one according to claim 1, characterized in that: The molar ratio of N-phenyl-1,2-benzisothiazolin-3-one, 1-(chloromethyl)-1,4-diazabicyclo[2.2.2]octan-1-ium chloride, potassium iodide and hydroiodic acid is 1.0:2.0:4.0:4.

0.

5. The method according to claim 1, characterized in that: The reaction time is at least 3 hours; and / or the concentration of N-phenyl-1,2-benzisothiazolin-3-one in the reaction system is 0.07-0.2 mol / L.

6. The method according to claim 1, characterized in that: The reaction temperature is 140 degrees Celsius.

7. The method according to claim 1, characterized in that: The reaction time is at least 6 hours.

8. The method according to claim 1, characterized in that: The reaction time is 6-12 hours.

9. The method according to claim 1, characterized in that: The concentration of N-phenyl-1,2-benzisothiazolin-3-one in the reaction system was 0.1 mol / L.

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