A method for preparing deuterated benzoxathiie-4-one

Abstract

The present application relates to the technical field of organic synthesis, in particular to a method for preparing deuterated benzoxathiie-4-ketone. At present, there is no report on the method for preparing deuterated benzoxathiie-4-ketone. In view of the above problems, the present application provides a method for preparing deuterated benzoxathiie-4-ketone. The method uses thiosalicylic acid, DABCO·CD2Cl2, a solvent, water and HI as reaction raw materials, and successfully synthesizes deuterated benzoxathiie-4-ketone by one-pot method. The method provides a new idea for the preparation of deuterated benzoxathiie-4-ketone derivatives, and has good application prospect.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for preparing deuterated benzothioheterocyclohexane-4-one. Background Art

[0002] Benzothiophene-4-one and its derivatives are an important class of sulfur-containing oxygen heterocyclic compounds with broad application prospects and important research value in many fields such as medicinal chemistry, materials science, chemical synthesis, and optoelectronic materials.

[0003] Studies have shown that deuteration of benzothiophene-4-one and its derivatives can significantly improve the stability of the target product, change the interaction of the product, optimize the product kinetics, reduce the product toxicity and other properties.

[0004] Currently, benzothiophene-4-one usually requires the use of transition metal catalysts such as iron or silver to participate in the reaction. After the reaction is completed, the problem of transition metal residues in the reaction product is obtained. Studies have shown that using 1,2-bis(diphenylphosphine)ethane as a key reagent to catalyze the reaction of benzodithiophene-3-one with paraformaldehyde can successfully prepare benzothiophene-4-one (Org. Chem. Front., 2024, 11, 4979). However, there are currently no reports on methods for deuterated benzothiophene-4-one. Summary of the Invention

[0005] The problem in the prior art is how to prepare deuterated benzothioxan-4-one. To address this problem, the present invention provides a method for preparing deuterated benzothioxan-4-one, which comprises the following steps:

[0006] Thiosalicylic acid, 1-(chlorodideuteromethyl)-1,4-diazabicyclo[2.2.2]octane-1-ammonium chloride (DABCO·CD2Cl2), a solvent, water, and hydroiodic acid (HI) are sequentially added to a reactor, the temperature of the reaction system is raised to the reaction temperature, and the reaction is stirred until deuterated benzothiin-4-one is generated in the reaction system;

[0007] The chemical structural formula of the deuterated benzothiol-4-one is as follows:

[0008]

[0009] Preferably, the solvent comprises acetonitrile or toluene.

[0010] Preferably, the reaction temperature is not lower than 120°C.

[0011] Preferably, the reaction temperature is 120-160°C.

[0012] Preferably, the reaction temperature is 140-160℃.

[0013] Preferably, the reaction temperature is 140℃.

[0014] Preferably, the reaction time is 6-12h.

[0015] Preferably, the reaction time is 12h.

[0016] Preferably, the dosage ratio between thiosalicylic acid and DABCO·CD2Cl2, solvent, water, HI is 0.2mmol:0.2-0.6mmol:075-1.5mL:0.5-1.5mL:0.4-0.8mmol.

[0017] Preferably, the dosage ratio between thiosalicylic acid and DABCO·CD2Cl2, solvent, water, HI is 0.2mmol:0.4mmol:1mL:1mL:0.6mmol.

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

[0019] The present application uses thiosalicylic acid and DABCO·CD2Cl2, solvent, water, HI as reaction raw materials, and successfully synthesizes deuterated benzoxathiie-4-one by one-pot method, and the method provides a new idea for the preparation of deuterated benzoxathiie-4-one derivative, and has good application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figure 1 : is the hydrogen spectrum of deuterated benzoxathiie-4-ketone obtained in Example 1 of the present application.

[0021] Figure 2 : is the hydrogen spectrum of benzoxathiie-4-ketone. DETAILED DESCRIPTION

[0022] The present application will be described in detail below in combination with examples. However, it should be understood that the following examples are only illustrative of the embodiments of the present application, and are not a limitation on the scope of the present application.

[0023] The benzoxathiie-4-ketone in the present application is prepared by the following method:

[0024] Thiosalicylic acid (0.2 mmol, 30 mg), DABCO·CH2Cl2 (0.4 mmol, 79.8 mg), acetonitrile (1.0 mL), H2O (1.0 mL), and HI (0.6 mmol, 71 μL) were added sequentially to a 25 mL sealed tube and stirred at 140°C for 12 h. After the reaction, the reaction solution was concentrated under reduced pressure and separated by column chromatography to obtain benzoxamethasone-4-one in a yield of 75%. The hydrogen spectrum of the obtained benzoxamethasone-4-one is shown in the attached instructions. Figure 2 shown.

[0025] The DABCO·CD2Cl2 in the present invention can be prepared according to the literature (Guangke He, Yuan Li, Zilun Yu, Zhaoqiang Chen, et al. Selectfluor TM -catalyzed oxidative cyclization of ynamidesenables facile synthesis of oxazolidine-2,4-diones[J].Organic ChemistryFrontiers,2019,6,3644.DOI:10.1039 / c9qo00845d.) was used to prepare the product, and the steps were as follows:

[0026] 1 g of 1,4-diazabicyclo[2.2.2]octane (DABCO) and 1 mL of deuterated dichloromethane (CD2Cl2) were stirred and reacted at room temperature for 12 h. After filtration, a white solid product DABCO·CD2Cl2 was obtained.

[0027] The preparation method of DABCO·CH2Cl2 in the present invention is as follows:

[0028] 1 g of 1,4-diazabicyclo[2.2.2]octane (DABCO) and 1 mL of dichloromethane (CH2Cl2) were stirred and reacted at room temperature for 12 h. After filtration, a solid product DABCO·CH2Cl2 was obtained.

[0029] Example 1

[0030] Thiosalicylic acid (0.2 mmol, 30 mg), DABCO·CD2Cl2 (0.4 mmol, 79.8 mg), acetonitrile (1.0 mL), H2O (1.0 mL), and HI (0.6 mmol, 71 μL) were added sequentially to a 25 mL sealed tube and stirred at 140°C for 12 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure and separated by column chromatography to obtain deuterated benzothiin-4-one in a yield of 70%. The reaction process is as follows:

[0031]

[0032] The hydrogen spectrum of the obtained deuterated benzothiophene-4-one is shown in the attached instructions. Figure 1 The hydrogen spectrum data and mass spectrum data are as follows:

[0033] 1 H NMR (300MHz, CDCl3) δ8.20-8.15(m,1H),7.52-7.46(m,1H),7.37-7.30(m,2H).

[0034] MS(EI)=168.0[M] + .

[0035] Example 2 is the same as Example 1, except that the amount of DABCO·CD2Cl2 used in Example 2 is 0.2 mmol. The yield of deuterated benzothiin-4-one obtained is 62%.

[0036] Example 3 is the same as Example 1, except that the amount of DABCO·CD2Cl2 used in Example 3 is 0.6 mmol. The yield of deuterated benzothiin-4-one obtained is 51%.

[0037] Example 4 is the same as Example 1, except that the amount of HI used in Example 4 is 0. The yield of deuterated benzothiin-4-one obtained is 0.

[0038] Example 5 is the same as Example 1, except that the amount of HI used in Example 5 is 0.4 mmol. The yield of deuterated benzothiin-4-one is 40%.

[0039] Example 6 is the same as Example 1, except that the amount of HI used in Example 6 is 0.8 mmol. The yield of deuterated benzothiin-4-one is 55%.

[0040] Example 7 is the same as Example 1, except that the reaction time in Example 7 is 1 hour. The yield of deuterated benzothiin-4-one is 15%.

[0041] Example 8 is the same as Example 1, except that the reaction time in Example 8 is 6 hours. The yield of deuterated benzothiin-4-one is 60%.

[0042] Example 9 is the same as Example 1, except that the reaction time in Example 9 is 24 hours. The yield of deuterated benzothiin-4-one is 32%.

[0043] Example 10 is the same as Example 1, except that an equal amount of ethyl acetate is used in place of acetonitrile in Example 1. The yield of deuterated benzothiin-4-one is 0%.

[0044] Example 11 is the same as Example 1, except that an equal amount of tetrahydrofuran is used in Example 11 to replace the acetonitrile in Example 1. The yield of deuterated benzothiin-4-one is 0%.

[0045] Example 12 is the same as Example 1, except that an equal amount of toluene is used in Example 12 to replace the acetonitrile in Example 1. The yield of deuterated benzothiin-4-one is 54%.

[0046] Example 13 is the same as Example 1, except that an equal amount of N,N-dimethylformamide is used in place of acetonitrile in Example 1. The yield of deuterated benzothiin-4-one is 0%.

[0047] Example 14 is the same as Example 1, except that an equal amount of dimethyl sulfoxide is used in place of acetonitrile in Example 1. The yield of deuterated benzothiin-4-one is 0%.

[0048] Example 15 is the same as Example 1, except that an equal amount of methanol is used in place of acetonitrile in Example 1. The yield of deuterated benzothiin-4-one is 0%.

[0049] Example 16 is the same as Example 1, except that an equal amount of dichloromethane is used in place of acetonitrile in Example 1. The yield of deuterated benzothiin-4-one is 0%.

[0050] Example 17 is the same as Example 1, except that the amount of acetonitrile used in Example 17 is 0.5 mL and the amount of water used is 1.5 mL. The yield of deuterated benzothiin-4-one obtained is 0%.

[0051] Example 18 is the same as Example 1, except that the amount of acetonitrile used in Example 18 is 0.75 mL and the amount of water used is 1.25 mL. The yield of deuterated benzothiin-4-one obtained is 39%.

[0052] Example 19 is the same as Example 1, except that the amount of acetonitrile used in Example 19 is 1.5 mL and the amount of water used is 0.5 mL. The yield of deuterated benzothiin-4-one obtained is 60%.

[0053] Example 20 is the same as Example 1, except that the reaction temperature in Example 20 is 100° C. The yield of deuterated benzothiin-4-one is 0%.

[0054] Example 21 is the same as Example 1, except that the reaction temperature in Example 21 is 120° C. The yield of deuterated benzothiin-4-one is 54%.

[0055] Example 22 is the same as Example 1, except that the reaction temperature in Example 22 is 160° C. The yield of deuterated benzothiin-4-one is 60%.

[0056] With the above-described preferred embodiments of the present invention as a guide, and with reference to the above description, relevant personnel are fully capable of making various changes and modifications without departing from the technical scope of this invention. The technical scope of this invention is not limited to the contents of the specification and must be determined according to the scope of the claims.

Claims

1. A method for preparing deuterated benzothiin-4-one, characterized in that: The preparation method comprises the following steps: Adding thiosalicylic acid, DABCO•CD2Cl2, solvent, water and HI in sequence into the reactor, raising the temperature of the reaction system to the reaction temperature, and stirring the reaction until deuterated benzothiin-4-one is generated in the reaction system; The chemical structural formula of the deuterated benzothiol-4-one is as follows: ， The solvent is acetonitrile or toluene; The reaction temperature is not less than 120°C; The usage ratio of thiosalicylic acid to DABCO•CD2Cl2, solvent, water and HI is 0.2mmol:0.2-0.6mmol:0.75-1.5mL:0.5-1.5mL:0.4-0.8mmol.

2. The method for preparing deuterated benzothiin-4-one according to claim 1, wherein: The reaction temperature is 140-160°C.

3. The method for preparing deuterated benzothiin-4-one according to claim 2, wherein: The reaction temperature was 140°C.

4. The method for preparing deuterated benzothiin-4-one according to claim 1, wherein: The reaction time is 6-12h.

5. The method for preparing deuterated benzothioxadiene-4-one according to claim 4, wherein: The reaction time is 12h.

6. The method for preparing deuterated benzothiin-4-one according to claim 1, wherein: The usage ratio of thiosalicylic acid to DABCO•CD2Cl2, solvent, water and HI is 0.2mmol:0.4mmol:1mL:1mL:0.6mmol.

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