Method for synthesizing N-(acetamidomethyl) benzothiazine-4-ketone

Abstract

The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing N-(acetamidomethyl) benzothiazine-4-ketone. At present, N-chloromethylacetamide is used in a synthetic method of N-(acetamidomethyl) benzothiazine-4-ketone, the synthetic route of the N-chloromethylacetamide is complex, and toxic raw materials such as CO gas also need to be used in the synthetic process of the N-chloromethylacetamide. In order to solve the problems, the invention provides the method for synthesizing the N-(acetamidomethyl) benzothiazine-4-ketone, the N-(acetamidomethyl) benzothiazine-4-ketone is successfully prepared by taking benzothiazine-4-ketone, DABCO.DCM, hydroiodic acid, acetonitrile and the like as reaction raw materials through a one-pot method, the use of N-halogenated methylacetamide is avoided in the reaction, and the reaction yield is high. The reaction is more efficient, and the reaction process is more environment-friendly.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing N-(acetamidomethyl)benzothiazine-4-one. Background Art

[0002] N-substituted benzothiazin-4-one derivatives, as an important class of sulfur-nitrogen heterocyclic compounds, are widely present in various drugs and natural products. Generally, alkyl halides or acyl chlorides are used under alkaline conditions to prepare N-substituted benzothiazin-4-one derivatives using benzothiazin-4-one as a reaction raw material (Journal of Shenyang Pharmaceutical University, 2012, 29, 834).

[0003] At present, the synthesis method of N-chloromethylacetamide used in the synthesis method of N-(acetamidomethyl)benzothiazin-4-one is quite complicated, and toxic CO gas, phosphorus oxychloride and phosphorus pentachloride reagents are required in the synthesis process, resulting in low production efficiency of N-(acetamidomethyl)benzothiazin-4-one.

[0004] In view of the above problems, the present invention designs a new synthesis route for the synthesis of N-(acetamidomethyl)benzothiazin-4-one. The method uses benzothiazin-4-one, DABCO·DCM, hydroiodic acid, acetonitrile and the like as reaction raw materials, and successfully prepares N-(acetamidomethyl)benzothiazin-4-one through a one-pot method. The use of N-halomethylacetamide is avoided in the reaction, and the reaction is more efficient. Summary of the invention

[0005] The problem in the prior art is that: currently, N-chloromethylacetamide is used in the synthesis method of N-(acetamidomethyl)benzothiazin-4-one, and the synthesis route of N-chloromethylacetamide is complicated. Toxic raw materials such as CO gas are also required in the synthesis process of N-chloromethylacetamide. In view of the above problems, the present invention provides a method for synthesizing N-(acetamidomethyl)benzothiazin-4-one, and the preparation method thereof comprises the following steps:

[0006] Add acetonitrile, benzothiazin-4-one, 1-(chloromethyl)-1,4-diazabicyclo[2.2.2]octane-1-chloride (DABCO·DCM), HI, NH4I and / or water to the reactor in sequence, heat the reaction system to the reaction temperature, and stir vigorously until N-(acetamidomethyl)benzothiazin-4-one is generated in the reaction system;

[0007] The chemical structural formula of the N-(acetamidomethyl)benzothiazin-4-one is as follows:

[0008]

[0009] Preferably, the ratio of acetonitrile to benzothiazin-4-one, DABCO·DCM, HI, NH4I and water in the reaction raw materials is 1-3 mL: 0.2 mmol: 0.4 mmol: 0.4-0.8 mmol: 0.4-0.8 mmol: 0.2-0.6 mmol.

[0010] Preferably, the ratio of acetonitrile to benzothiazin-4-one, DABCO·DCM, HI, NH4I and water in the reaction raw materials is 2 mL: 0.2 mmol: 0.4 mmol: 0.6 mmol: 0.6 mmol: 0.4 mmol.

[0011] Preferably, the reaction temperature is 100-140°C.

[0012] Preferably, the reaction temperature is 120-140°C.

[0013] Preferably, the reaction temperature is 120°C.

[0014] Preferably, the reaction time is at least 6 h.

[0015] Preferably, the reaction time is 6-24h.

[0016] Preferably, the reaction time is 6-12 hours.

[0017] Preferably, the reaction time is 12 h.

[0018] The present invention has the following beneficial effects:

[0019] The invention designs a new synthesis route for the synthesis of N-(acetamidomethyl)benzothiazin-4-one. The method adopts benzothiazin-4-one, DABCO·DCM, hydroiodic acid, acetonitrile and the like as reaction raw materials, successfully prepares N-(acetamidomethyl)benzothiazin-4-one through a one-pot method, avoids the use of N-halogenated methylacetamide in the reaction, has higher reaction efficiency, is more environmentally friendly in the reaction process, and has good application prospects. DETAILED DESCRIPTION

[0020] 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.

[0021] The DABCO·DCM in the following examples of the present invention has a CAS number of 36273-11-7.

[0022] Example 1

[0023] Acetonitrile (2 mL), benzothiazin-4-one (0.2 mmol), DABCO·DCM (0.4 mmol), HI (0.6 mmol), NH4I (0.6 mmol) and water (0.4 mmol) were added in sequence to a 25 mL sealed tube, and then the temperature of the reaction system was raised to 120°C, and the reaction was vigorously stirred for 12 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and separated by column chromatography to obtain N-(acetamidomethyl)benzothiazin-4-one in a yield of 67%.

[0024] The above reaction process is as follows:

[0025]

[0026] The NMR data and mass spectrometry data of the obtained N-(acetamidomethyl)benzothiazin-4-one are as follows:

[0027] 1 H NMR (400MHz, CDCl3) δ8.06 (dd, J=7.8, 1.5Hz, 1H), 7.40-7.36 (m, 1H), 7.30-7.24 (m, 2H), 7.10 (t, J = 6.8Hz, 1H), 4.96 (d, J = 6.7Hz, 2H), 4.85 (s, 2H), 2.03 (s, 3H).

[0028] 13 C NMR (101MHz, CDCl3) δ171.59,164.97,137.92,132.12,130.45,128.62,127.41,126.06,52.97,49.44,23.07.

[0029] LC-MS (ESI) = 237.0 [M+H] + .

[0030] Example 2 is the same as Example 1, except that the amount of water used in Example 2 is 0. The yield of N-(acetamidomethyl)benzothiazin-4-one obtained is 50%.

[0031] Example 3 is the same as Example 1, except that the amount of water used in Example 3 is 0.2 mmol. The yield of N-(acetamidomethyl)benzothiazin-4-one obtained is 60%.

[0032] Example 4 is the same as Example 1, except that the amount of water used in Example 4 is 0.6 mmol. The yield of N-(acetamidomethyl)benzothiazin-4-one obtained is 61%.

[0033] Example 5 is the same as Example 1, except that the reaction temperature in Example 5 is 100° C. The yield of N-(acetamidomethyl)benzothiazin-4-one obtained is 50%.

[0034] Example 6 is the same as Example 1, except that the reaction temperature in Example 6 is 140° C. The yield of N-(acetamidomethyl)benzothiazin-4-one obtained is 55%.

[0035] The difference between Example 7 and Example 1 is that the amount of acetonitrile used in Example 7 is 1 mL. The yield of N-(acetamidomethyl)benzothiazin-4-one obtained is 43%.

[0036] The difference between Example 8 and Example 1 is that the amount of acetonitrile used in Example 8 is 3 mL. The yield of N-(acetamidomethyl)benzothiazin-4-one obtained is 60%.

[0037] Example 9 is the same as Example 1, except that the reaction time in Example 9 is 6 hours. The yield of N-(acetamidomethyl)benzothiazin-4-one obtained is 51%.

[0038] Example 10 is the same as Example 1, except that the reaction time in Example 10 is 24 hours. The yield of N-(acetamidomethyl)benzothiazin-4-one is 40%.

[0039] Example 11 is the same as Example 1, except that the amount of HI used in Example 11 is 0. The yield of N-(acetamidomethyl)benzothiazin-4-one obtained is 0%.

[0040] Example 12 is the same as Example 1, except that the amount of HI used in Example 12 is 0.4 mmol. The yield of N-(acetamidomethyl)benzothiazin-4-one obtained is 52%.

[0041] Example 13 is the same as Example 1, except that the amount of HI used in Example 13 is 0.8 mmol. The yield of N-(acetamidomethyl)benzothiazin-4-one obtained is 65%.

[0042] Example 14 is the same as Example 1, except that the amount of NH4I used in Example 14 is 0. The yield of N-(acetamidomethyl)benzothiazin-4-one obtained is 17%.

[0043] Example 15 is the same as Example 1, except that the amount of NH4I used in Example 15 is 0.4 mmol. The yield of N-(acetamidomethyl)benzothiazin-4-one obtained is 50%.

[0044] Example 16 is the same as Example 1, except that the amount of NH4I used in Example 16 is 0.8 mmol. The yield of N-(acetamidomethyl)benzothiazin-4-one obtained is 61%.

[0045] 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 synthesizing N-(acetamidomethyl)benzothiazin-4-one, characterized in that: The preparation method comprises the following steps: Add acetonitrile, benzothiazin-4-one, DABCO·DCM, HI, NH4I and / or water to the reactor in sequence, heat the reaction system to the reaction temperature, and stir vigorously until N-(acetamidomethyl)benzothiazin-4-one is generated in the reaction system; The chemical structural formula of the N-(acetamidomethyl)benzothiazin-4-one is as follows:

2. A method for synthesizing N-(acetamidomethyl)benzothiazin-4-one according to claim 1, characterized in that: The dosage ratio of acetonitrile to benzothiazin-4-one, DABCO·DCM, HI, NH4I and water in the reaction raw materials is 1-3mL:0.2mmol:0.4mmol:0.4-0.8mmol:0.4-0.8mmol:0.2-0.6mmol.

3. A method for synthesizing N-(acetamidomethyl)benzothiazin-4-one according to claim 2, characterized in that: The dosage ratio of acetonitrile to benzothiazin-4-one, DABCO·DCM, HI, NH4I and water in the reaction raw materials is 2mL:0.2mmol:0.4mmol:0.6mmol:0.6mmol:0.4mmol.

4. A method for synthesizing N-(acetamidomethyl)benzothiazin-4-one according to claim 1, characterized in that: The reaction temperature is 100-140°C.

5. A method for synthesizing N-(acetamidomethyl)benzothiazin-4-one according to claim 4, characterized in that: The reaction temperature is 120-140°C.

6. A method for synthesizing N-(acetamidomethyl)benzothiazin-4-one according to claim 5, characterized in that: The reaction temperature is 120°C.

7. A method for synthesizing N-(acetamidomethyl)benzothiazin-4-one according to claim 1, characterized in that: The reaction time is at least 6 hours.

8. A method for synthesizing N-(acetamidomethyl)benzothiazin-4-one according to claim 7, characterized in that: The reaction time is 6-24h.

9. A method for synthesizing N-(acetamidomethyl)benzothiazin-4-one according to claim 8, characterized in that: The reaction time is 6-12h.

10. A method for synthesizing N-(acetamidomethyl)benzothiazin-4-one according to claim 9, characterized in that: The reaction time is 12h.

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