A preparation method of 2-acetyl-3,3-dimethylindole

Abstract

The present invention discloses an industrial preparation method for 2-acetyl-3,3-dimethylindole. The structure of the compound is shown in the figure below: #imgabs0#; this compound is formed by oxidation of 2-ethyl-3,3-dimethylindole with corresponding substituents via an oxide. The synthesis method is simple, separation and purification are convenient, and the purity is 97.84%, with a yield of up to 99.1%, making it suitable for industrial production. The method of the present invention utilizes inexpensive and readily available raw materials, a rationally designed process flow, and a short process step, thus addressing a gap in domestic methods for preparing this compound. It can overcome the limitations of laboratory testing and enable large-scale industrial production.

Description

Technical Field

[0001] The present invention relates to the field of fine chemicals, and more specifically to an industrial preparation method of 2-acetyl-3,3-dimethylindole. Background Art

[0002] Indole products have various unique chemical properties and biological activities. Therefore, the research and development of indole products has always been highly valued in the pharmaceutical, chemical and pesticide fields. In particular, in recent years, domestic and foreign journals and patent literature have frequently reported on indole products and their preparation methods.

[0003] 2-Acetyl-3,3-dimethylindole can serve as a lead compound for the development of new drugs. Through structural modification and optimization, potential drug candidates with antibacterial, anti-inflammatory, and anti-tumor activities can be obtained. These new drugs have broad application prospects in the treatment of infectious diseases, inflammatory diseases, and tumors. Furthermore, this indole compound and its derivatives exhibit insecticidal and fungicidal bioactivities and can be used as pesticide raw materials, potentially developing into novel environmentally friendly pesticides. However, this compound has currently received relatively little attention in domestic academia and industry. In contrast, some international research institutions and companies have conducted in-depth research and development, and a small number of derivatives are now available on the international market. However, the generally high prices of these foreign products have limited their promotion and application in China.

[0004] In response to the above problems, the present invention discloses an industrial preparation method for 2-acetyl-3,3-dimethylindole, which can break through the limitation of laboratory test stage and can be smoothly scaled up in pilot and industrial production. Summary of the Invention

[0005] The main purpose of the present invention is to invent an industrial preparation method of 2-acetyl-3,3-dimethylindole. The technical solution of the present invention is as follows:

[0006] An industrial preparation method of 2-acetyl-3,3-dimethylindole, wherein the chemical structural formula of the compound is:

[0007]

[0008] An industrial preparation method for synthesizing the 2-acetyl-3,3-dimethylindole comprises the following synthesis path:

[0009]

[0010] R1=H, Br, or OCH3

[0011] R2=H, or Br;

[0012] The method comprises the following steps:

[0013] (1) Add compound S, m-chloroperoxybenzoic acid, 30% hydrogen peroxide, acetyl peroxide, or peracetic acid as a catalyst to a reaction flask at room temperature, add an appropriate amount of solvent, dissolve under magnetic stirring, and heat to obtain a reaction solution;

[0014] (2) The reaction solution in step (1) is concentrated, added to an ethanol solution, and ultrasonically allowed to stand. After the product precipitates, it is filtered to obtain product I, i.e., 2-acetyl-3,3-dimethylindole.

[0015] In the step (1), the feed ratio of compound S to catalyst is 5-20:1.

[0016] In the step (1), the solvent used is any one of cyclohexane, n-hexane, and cyclopentane, or a mixed solvent of two of them.

[0017] The order of feeding in step (1) is compound S, m-chloroperoxybenzoic acid, 30% hydrogen peroxide, acetyl peroxide, or peracetic acid as a catalyst, an appropriate amount of solvent, and finally, pure oxygen is introduced or stored in dry air.

[0018] The heating reflux reaction temperature of step (1) is 25-85°C, and the reaction time is 9-240 hours.

[0019] The beneficial effects of the present invention are as follows:

[0020] (1) In the preparation method of 2-acetyl-3,3-dimethylindole of the present invention, the raw materials are readily available and inexpensive, the preparation method is simple, and no special instruments are required, which greatly saves production costs. The preparation method can complete the reaction in a one-step process, without the need for cumbersome multi-step operations. The entire synthesis process is more environmentally friendly and has higher atom economy. The preparation method has excellent reproducibility and scalability, which is conducive to smooth scale-up in pilot and industrial production. In addition, the purity of the products obtained by this method is generally high, and the subsequent separation and purification process is relatively simple, which is also conducive to its large-scale production.

[0021] (2) The indole compounds described in the present invention can be used as lead compounds for the development of new drugs. Through structural modification and optimization, potential drug candidate compounds with antibacterial, anti-inflammatory, and anti-tumor biological activities can be obtained. In addition, the compounds are indole compounds, and their indole skeletons have unique conjugated structures and color properties. 2-acetyl-3,3-dimethylindole and its derivatives are expected to be used in dyes, pigments and other fields to meet people's demand for a variety of bright colors. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is the hydrogen spectrum of compound I obtained in Example 2.

[0023] Figure 2 This is the high-resolution mass spectrum of compound 1 obtained in Example 2.

[0024] Figure 3 This is a single crystal image of Compound I obtained in Example 2.

[0025] Figure 4 is a high performance liquid chromatogram of compound I obtained in Example 2. DETAILED DESCRIPTION

[0026] The present invention is further described below with reference to the following examples. However, the scope of protection claimed in the present invention is not limited to the scope described in the examples.

[0027] The preparation method of this application is as follows:

[0028] ;

[0029] Among them, S-1: R1=H, R2=H; S-2: R1=Br, R2=H; S-3: R1=H, R2=Br; S-4: R1=OCH3, R2=H.

[0030] Example 1

[0031]

[0032] Weigh compound S-1 (173 mg, 1 mmol) and m-chloroperbenzoic acid (17.26 mg, 0.1 mmol) and dissolve them in 10 mL of cyclohexane. Then, introduce pure oxygen and stir at room temperature (25°C). The reaction is complete after 24 hours, with a yield of 65.1%. The molecular formula is C 12 H 13 NO, the structure is: .

[0033] Example 2

[0034]

[0035] Weigh compound S-1 (173 mg, 1 mmol) and m-chloroperbenzoic acid (17.26 mg, 0.1 mmol) and dissolve them in 10 mL of cyclohexane. Then, introduce pure oxygen and stir in an oil bath while heating to 85°C. The reaction is complete after 10 hours, with a yield of 96.7%. The molecular formula is C 12 H 13 NO, the structure is: When the temperature was increased by 60°C relative to Example 1, the yield increased by 31.6% and the reaction time was shortened by 14 hours.

[0036] Example 3

[0037]

[0038] Compound S-1 (173 mg, 1 mmol) and 30% hydrogen peroxide (10.21 μL, 0.1 mmol) were weighed and dissolved in 10 mL of cyclohexane. Pure oxygen was then introduced, and the mixture was stirred in an oil bath and heated to 85°C. The reaction was complete after 10 hours, with a yield of 96.3%. The molecular formula is C 12 H 13 NO, the structure is: When the catalyst was replaced with 30% hydrogen peroxide relative to Example 2, the yield was not significantly affected.

[0039] Example 4

[0040]

[0041] Weigh compound S-1 (173 mg, 1 mmol) and acetyl peroxide (11.81 mg, 0.1 mmol) and dissolve them in 10 mL of cyclohexane. Then, introduce pure oxygen and stir in an oil bath while heating to 85°C. The reaction is complete after 10 hours, with a yield of 95.4%. The molecular formula is C 12 H 13 NO, the structure is: When the catalyst was replaced with acetyl peroxide relative to Example 2, the yield was not significantly affected.

[0042] Example 5

[0043]

[0044] Compound S-1 (173 mg, 1 mmol) and peracetic acid (7.6 mg, 0.1 mmol) were weighed and dissolved in 10 mL of cyclohexane. Pure oxygen was then introduced, and the mixture was stirred in an oil bath and heated to 85°C. The reaction was complete after 10 hours, with a yield of 92.4%. The molecular formula is C 12 H 13 NO, the structure is: When the catalyst was replaced with peracetic acid relative to Example 2, the yield was not significantly affected.

[0045] Example 6

[0046]

[0047] Compound S-1 (173 mg, 1 mmol) and 30% hydrogen peroxide (20.42 μL, 0.2 mmol) were weighed and dissolved in 10 mL of cyclohexane. Pure oxygen was then introduced, and the mixture was stirred in an oil bath and heated to 85°C. The reaction was complete after 9 hours, with a yield of 97.0%. The molecular formula is C 12 H 13 NO, the structure is: When the amount of 30% hydrogen peroxide was doubled relative to Example 3, the yield did not change much and the reaction time was slightly shortened.

[0048] Example 7

[0049]

[0050] Compound S-1 (173 mg, 1 mmol) and 30% hydrogen peroxide (5.11 μL, 0.05 mmol) were weighed and dissolved in 10 mL of cyclohexane. Pure oxygen was then introduced, and the mixture was stirred in an oil bath and heated to 85°C. The reaction was complete after 26 hours, with a yield of 96.2%. The molecular formula is C 12 H 13 NO, the structure is: When the amount of 30% hydrogen peroxide was reduced by half relative to that in Example 3, the reaction time was extended by 16 hours.

[0051] Example 8

[0052]

[0053] Compound S-1 (173 mg, 1 mmol) and 30% hydrogen peroxide (10.21 μL, 0.1 mmol) were weighed and dissolved in 10 mL of n-hexane. Pure oxygen was then introduced, and the mixture was stirred in an oil bath and heated to 85°C. The reaction was complete after 10 hours, with a yield of 91.3%. The molecular formula is C 12 H 13 NO, the structure is: When the solvent was changed to n-hexane relative to the cyclohexane in Example 3, the yield decreased by 7.4%.

[0054] Example 9

[0055]

[0056] Compound S-1 (173 mg, 1 mmol) and 30% hydrogen peroxide (10.21 μL, 0.1 mmol) were weighed and dissolved in 10 mL of cyclopentane. Pure oxygen was then introduced, and the mixture was stirred in an oil bath and heated to 85°C. The reaction was complete after 10 hours, with a yield of 96.1%. The molecular formula is C 12 H 13 NO, the structure is: When the solvent type was changed to cyclopentane relative to the cyclohexane in Example 3, the yield did not change much.

[0057] Example 10

[0058]

[0059] Compound S-1 (173 mg, 1 mmol) and 30% hydrogen peroxide (10.21 μL, 0.1 mmol) were weighed and dissolved in 10 mL of a mixed solvent of cyclopentane and cyclohexane. Pure oxygen was then introduced, and the mixture was stirred in an oil bath and heated to 85°C. The reaction was complete after 10 hours, with a yield of 96.0%. The molecular formula is C 12 H 13 NO, the structure is: When the solvent type was changed to a mixed solvent of cyclopentane and cyclohexane relative to the cyclohexane in Example 3, the yield did not change much.

[0060] Example 11

[0061]

[0062] Compound S-1 (173 mg, 1 mmol) and 30% hydrogen peroxide (10.21 μL, 0.1 mmol) were weighed and dissolved in 10 mL of a cyclopentane mixed solvent. The mixture was placed in a dry air atmosphere and heated to 85°C in an oil bath with stirring. The reaction was complete after 240 hours, with a yield of 99.1%. The molecular formula is C 12 H 13 NO, the structure is: When the reaction mixture was stored in dry air instead of pure oxygen in Example 3, the yield increased slightly, but the reaction time was prolonged.

[0063] Example 12

[0064]

[0065] Compound S-2 (265 mg, 1 mmol) and 30% hydrogen peroxide (10.21 μL, 0.1 mmol) were weighed and dissolved in 10 mL of cyclohexane. Pure oxygen was then introduced, and the mixture was stirred in an oil bath and heated to 85°C. The reaction was complete after 11 hours, with a yield of 95.3%. The molecular formula is C 12 H 12 BrNO, the structure is: .

[0066] Example 13

[0067]

[0068] Compound S-3 (265 mg, 1 mmol) and 30% hydrogen peroxide (10.21 μL, 0.1 mmol) were weighed and dissolved in 10 mL of cyclohexane. Pure oxygen was then introduced, and the mixture was stirred in an oil bath and heated to 85°C. The reaction was complete after 12 hours, with a yield of 94.0%. The molecular formula is C 12 H 12 BrNO, the structure is: .

[0069] Example 14

[0070]

[0071] Compound S-4 (217 mg, 1 mmol) and 30% hydrogen peroxide (10.21 μL, 0.1 mmol) were weighed and dissolved in 10 mL of cyclohexane. Pure oxygen was then introduced, and the mixture was stirred in an oil bath and heated to 85°C. The reaction was complete after 12 hours, with a yield of 91.2%. The molecular formula is C 13 H 15 NO2, the structure is: .

Claims

1. An industrial preparation method of 2-acetyl-3,3-dimethylindole, characterized in that: The method is through the following synthetic route: ; R1 = H, Br, or OCH3; R2 = H, or Br; (1) At room temperature, compound S, any one of m-chloroperoxybenzoic acid, 30% hydrogen peroxide, acetyl peroxide, and peracetic acid as a catalyst, and an appropriate amount of solvent are added to a reaction bottle, pure oxygen is introduced, and the mixture is dissolved by magnetic stirring. The reaction temperature is heated under reflux at 85°C to obtain a reaction solution. The feed ratio of compound S to the catalyst is 5-20:1, and the solvent used is any one of cyclohexane, n-hexane, and cyclopentane, or a mixed solvent of two of them; (2) The reaction solution in step (1) is concentrated, added to an ethanol solution, and ultrasonically allowed to stand. After the product precipitates, it is filtered to obtain product I, i.e., 2-acetyl-3,3-dimethylindole.

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