A preparation method of α-bromoacetophenone compounds

Abstract

The invention discloses a method for preparing an alpha-bromoacetophenone compound. The method comprises the following steps: using an acetophenone compound represented by formula (I) and a bromination reagent represented by formula (II) as raw materials, using an organic acid represented by formula (III) as a catalyst, using silica gel as a grinding aid, adding stainless steel grinding balls with a diameter of 6-12 mm, grinding at a grinding frequency of 10-30 Hz for 1-45 minutes, scraping out a reactant after grinding, adding an organic solvent A to dissolve the reactant, filtering and neutralizing with a saturated sodium bicarbonate aqueous solution, washing an upper organic phase with water, extracting the aqueous phase with ethyl acetate, combining the organic phases, drying the organic phases with anhydrous sodium sulfate, filtering, concentrating, and purifying by column chromatography to obtain the alpha-bromoacetophenone compound represented by formula (IV). The method is simple to operate, has mild reaction conditions, short reaction time, and little pollution, and can effectively realize the synthesis of the alpha-bromoacetophenone compound. The reaction formula is as follows:

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis and relates to a method for preparing α-bromoacetophenone compounds, specifically to solvent-free synthesis of α-bromoacetophenone compounds under the assistance of mechanical grinding. Background Art

[0002] α-Bromoacetophenone compounds are important organic compounds, which are widely used in the synthesis of functional chemicals such as medicines and pesticides. For example, α-bromo-m-chloroacetophenone is an important intermediate for the antidepressant Bupropion Hydrochloride; α-bromo-p-methoxyacetophenone is an important intermediate for the synthesis of estrogen drugs Ralxifene; α-bromoacetophenone is a drug intermediate for the aromatic ethanolamine receptor agonist Mirabegron.

[0003]

[0004] At present, many chemical synthesis methods of α-bromoacetophenone compounds have been reported. The preparation of such compounds is usually to directly brominate acetophenone compounds with liquid bromine or bromine water in different systems, or to use CuBr2, NBS, DBDMH and the like as bromination reagents for reaction (Eur. J. Med. Chem., 2015, 18-23; CN 1053151141 A, 2016.).

[0005] CN 105884601 A reports the following method: choline chloride, zinc chloride and water are mixed in a mass ratio of 5:15-20:2-4 to prepare a deep eutectic solvent, and the composite solvent, acetophenone and liquid bromine are sequentially added into a reactor for reaction.

[0006] In 2018, Yang Jingwen et al. used 1.20 equiv. NBS as bromination reagent, 0.20 equiv. p-toluenesulfonic acid as catalyst, and methanol as solvent to carry out the reaction at 30-50 °C. (Chin. J. Org. Chem., 2018, 38, 1811-1816.)

[0007] In 2020, Rodriguez et al. used 1.10 equiv. NBS as a bromination reagent and 1.50 equiv. p-toluenesulfonic acid as a catalyst to carry out bromination of acetophenone compounds by microwave method. (Journal of Heterocyclic Chemistry., 2020, 2279-2287.)

[0008] Although a variety of methods can be used to synthesize α-bromoacetophenone compounds, the practical application of the above methods is still restricted by the disadvantages of long solution reaction time, poor selectivity, difficulty in product separation, large amount of organic solvents, and environmental unfriendliness. Therefore, the green synthesis of α-bromoacetophenone compounds still needs further research.

[0009] Mechanochemistry is a hot topic in the current field of organic synthesis and has important value for the realization of green chemistry. Since the substrate needs to be fully mixed during the reaction, mechanical ball milling technology can effectively promote the introduction of heterogeneous reactions into the field of organic synthesis. So far, Aldol reaction, Michael addition reaction, Sonogashira reaction, etc. can all be carried out in a mechanochemical environment. However, there is no report on the synthesis of brominated acetophenone compounds using mechanical ball milling technology. Summary of the invention

[0010] In view of the above problems existing in the prior art, the object of the present invention is to provide a method for preparing an α-bromoacetophenone compound which is efficient and environmentally friendly.

[0011] The present invention adopts the following technical scheme: the preparation method of the α-bromoacetophenone compound, using the acetophenone compound represented by formula (I) and the bromination reagent represented by formula (II) as raw materials, using the organic acid represented by formula (III) as a catalyst, and using silica gel as a grinding aid, all the materials are added into a grinding pot, and stainless steel grinding balls are added, and the grinding is performed at a grinding frequency of 10 to 30 Hz for 1 to 45 minutes. After the grinding is completed, the α-bromoacetophenone compound is obtained by post-treatment, and the reaction formula is as follows:

[0012]

[0013] In the above formula, R represents a single or multiple substitution of H on the benzene ring, R represents a halogen, an alkyl, an alkoxy or a nitro group, and further, the substituent R represents H, 4-Br, 3-Br, 2-Br, 4-Cl, 3-Cl, 2-Cl, 3,4-F, 4-F-3-OMe, 4-F, 3-F, 2-F, 4-CH3, 3-CH3, 4-NO2 or 3-NO2.

[0014] Furthermore, the present invention also defines the ratio of the amount of the feed materials of the acetophenone compound, the bromination reagent and the organic acid as 1:0.5~1.1:0.4~1.2, preferably 1:1:1; wherein the bromination reagent is any one of N-bromosuccinimide (NBS), 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) or copper bromide (CuBr2), preferably N-bromosuccinimide (NBS) or 1,3-dibromo-5,5-dimethylhydantoin, and the best is N-bromosuccinimide; the organic acid is any one of acetic acid, formic acid, p-toluenesulfonic acid or trifluoromethanesulfonic acid, preferably p-toluenesulfonic acid or trifluoromethanesulfonic acid, and the best is trifluoromethanesulfonic acid.

[0015] Furthermore, the present invention also defines the grinding aid as any one of silica gel, sodium chloride, anhydrous sodium sulfate, and potassium chloride, preferably silica gel or anhydrous sodium sulfate, and the most preferred is silica gel; the ratio of the added mass of the grinding aid to the amount of the acetophenone compound shown in formula (I) is 0.1 to 0.8:1, preferably 0.3:1, the mass unit is g, and the amount unit is mmol.

[0016] Furthermore, the present invention also defines the grinding ball diameter as 6-12 mm; the grinding frequency as 20-30 Hz, preferably 20 Hz; and the grinding time as 10-20 min, preferably 10 min.

[0017] Furthermore, the present invention also defines the post-treatment process as follows: after the grinding is completed, the reactants are scraped out, an organic solvent is added to dissolve the reactants, the filtrate is filtered and neutralized by adding a saturated sodium bicarbonate aqueous solution, the upper organic phase is washed with water, the aqueous phase is extracted three times with ethyl acetate, the organic phases are combined and dried with anhydrous sodium sulfate, the filtrate is filtered, concentrated, and purified by column chromatography to obtain the α-bromoacetophenone compound shown in formula (IV).

[0018] Furthermore, the present invention also limits the organic solvent to be selected from the following one or a mixture of any proportions: methyl tert-butyl ether, dichloromethane, ethyl acetate, preferably ethyl acetate.

[0019] Furthermore, the present invention also defines the column chromatography eluent as a mixed solvent of dichloromethane and petroleum ether in a volume ratio of 1:1 to 20.

[0020] Furthermore, the mechanical grinding method defined in the present invention is as follows: the substrate mixture is added to a grinding jar with a volume of 25 ml, placed in a vibrating ball mill, and the grinding frequency is 10 to 30 Hz, and the diameter of the grinding balls is 6 to 12 mm (add 2 to 4) (preferably the volume of the grinding jar is 25 ml, the grinding frequency is 20 to 30 Hz, and the diameter of the stainless steel balls is 10 mm (3 or 4), grinding until the reaction is complete, the entire reaction mixture is transferred from the grinding jar, and the grinding balls are taken out, the contents are dissolved with an organic solvent, and after being fully soaked, suction filtered, washed, and separated by silica gel column chromatography to obtain a pure product.

[0021] By adopting the above technology, compared with the prior art, the beneficial effects of the present invention are as follows:

[0022] The invention uses mechanical grinding technology to efficiently synthesize a series of brominated acetophenone compounds without solvent. Compared with the existing chemical method, the invention is simple to operate, mild in reaction conditions, less polluting, and can effectively realize the synthesis of α-bromoacetophenone compounds. The invention adopts a specific catalyst to achieve a substantially complete reaction within a relatively short reaction time, thereby greatly improving the reaction efficiency. DETAILED DESCRIPTION

[0023] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

[0024] Example 1

[0025] Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then the grinding aid silica gel (200 mg), substrate 3', 4'-difluoroacetophenone (0.5 mmol), bromination reagent N-bromosuccinimide (0.5 mmol) and acidic catalyst trifluoromethanesulfonic acid (45 μL) were added in sequence, and the grinding was stopped at a grinding frequency of 30 Hz for 30 min. After the grinding was completed, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, saturated sodium bicarbonate aqueous solution was added to neutralize after filtering, the upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phases were combined, the organic phases were dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (the eluent used was dichloromethane: petroleum ether = 1:8, v / v), and yellow oily 2-bromo-3', 4'-difluoroacetophenone was obtained with a yield of 83.43%.

[0026] The NMR characterization data of the compound:

[0027] 1H NMR (400MHz, Chloroform-d) δ7.87-7.76(m,2H,ArH),7.33-7.25(m,1H,ArH),4.39(s,2H,CH2).

[0028] Example 2

[0029] Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then the grinding aid silica gel (200 mg), substrate 3', 4'-difluoroacetophenone (0.5 mmol), bromination reagent N-bromosuccinimide (0.5 mmol) and acidic catalyst p-toluenesulfonic acid (0.5 mmol) were added in sequence, and grinding was stopped at a grinding frequency of 30 Hz for 30 min. After grinding, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, filtrated and neutralized with saturated sodium bicarbonate aqueous solution, the upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phases were combined, the organic phases were dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (the eluent used was dichloromethane: petroleum ether = 1:8, v / v), and yellow oily 2-bromo-3', 4'-difluoroacetophenone was obtained with a yield of 20.7%.

[0030] Example 3

[0031] Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then grinding aid silica gel (200 mg), substrate 3', 4'-difluoroacetophenone (0.5 mmol), bromination reagent N-bromosuccinimide (0.5 mmol) and trifluoromethanesulfonic acid (20 μL) were added in sequence, and grinding was stopped at a grinding frequency of 30 Hz for 30 min. After grinding, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, filtrated and neutralized with saturated sodium bicarbonate aqueous solution, the upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phases were combined, the organic phases were dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (the eluent used was dichloromethane: petroleum ether = 1:8, v / v), and yellow oily 2-bromo-3', 4'-difluoroacetophenone was obtained with a yield of 27.05%.

[0032] Example 4

[0033] Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then the grinding aid silica gel (200 mg), substrate 3', 4'-difluoroacetophenone (0.5 mmol), bromination reagent N-bromosuccinimide (0.5 mmol) and acidic catalyst trifluoromethanesulfonic acid (60 μL) were added in sequence, and the grinding was stopped at a grinding frequency of 30 Hz for 30 min. After the grinding was completed, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, saturated sodium bicarbonate aqueous solution was added to neutralize after filtering, the upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phase was combined, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (the eluent used was dichloromethane: petroleum ether = 1:8, v / v), and yellow oily 2-bromo-3', 4'-difluoroacetophenone was obtained with a yield of 73.51%.

[0034] Example 5

[0035] Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then anhydrous sodium sulfate (200 mg), a substrate 3', 4'-difluoroacetophenone (0.5 mmol), a bromination reagent N-bromosuccinimide (0.5 mmol) and an acidic catalyst trifluoromethanesulfonic acid (45 μL) were added in sequence, and the mixture was ground at a grinding frequency of 30 Hz for 30 min and then stopped. After grinding, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, saturated sodium bicarbonate aqueous solution was added to neutralize after filtering, the upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phases were combined, the organic phases were dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (the eluent used was dichloromethane: petroleum ether = 1:8, v / v), and yellow oily 2-bromo-3', 4'-difluoroacetophenone was obtained with a yield of 43.29%.

[0036] Example 6

[0037] Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then the grinding aid sodium chloride (200 mg), substrate 3', 4'-difluoroacetophenone (0.5 mmol), bromination reagent N-bromosuccinimide (0.5 mmol) and acidic catalyst trifluoromethanesulfonic acid (45 μL) were added in sequence, and the grinding was stopped at a grinding frequency of 30 Hz for 30 min. After the grinding was completed, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, saturated sodium bicarbonate aqueous solution was added to neutralize after filtration, the upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phases were combined, the organic phases were dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (the eluent used was dichloromethane: petroleum ether = 1:8, v / v), and yellow oily 2-bromo-3', 4'-difluoroacetophenone was obtained with a yield of 47.93%.

[0038] Example 7

[0039] Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then potassium chloride (200 mg), substrate 3', 4'-difluoroacetophenone (0.5 mmol), bromination reagent N-bromosuccinimide (0.5 mmol) and acidic catalyst trifluoromethanesulfonic acid (45 μL) were added in sequence, and grinding was stopped at a grinding frequency of 30 Hz for 30 min. After grinding, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, saturated sodium bicarbonate aqueous solution was added to neutralize after filtering, the upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phases were combined, the organic phases were dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (the eluent used was dichloromethane: petroleum ether = 1:8, v / v), and yellow oily 2-bromo-3', 4'-difluoroacetophenone was obtained with a yield of 42.69%.

[0040] Example 8

[0041] Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then grinding aid silica gel (50 mg), substrate 3', 4'-difluoroacetophenone (0.5 mmol), bromination reagent N-bromosuccinimide (0.5 mmol) and acidic catalyst trifluoromethanesulfonic acid (45 μL) were added in sequence, and grinding was stopped at a grinding frequency of 30 Hz for 30 min. After grinding, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, saturated sodium bicarbonate aqueous solution was added to neutralize after filtering, the upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phases were combined, the organic phases were dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (the eluent used was dichloromethane: petroleum ether = 1:8, v / v), and yellow oily 2-bromo-3', 4'-difluoroacetophenone was obtained with a yield of 59.06%.

[0042] Example 9

[0043] Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then the grinding aid silica gel (400 mg), substrate 3', 4'-difluoroacetophenone (0.5 mmol), bromination reagent N-bromosuccinimide (0.5 mmol) and acidic catalyst trifluoromethanesulfonic acid (45 μL) were added in sequence, and the grinding was stopped at a grinding frequency of 30 Hz for 30 min. After the grinding was completed, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, saturated sodium bicarbonate aqueous solution was added to neutralize after filtering, the upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phases were combined, the organic phases were dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (the eluent used was dichloromethane: petroleum ether = 1:8, v / v), and yellow oily 2-bromo-3', 4'-difluoroacetophenone was obtained with a yield of 52.72%.

[0044] Example 10

[0045] Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then the grinding aid silica gel (150 mg), substrate 3', 4'-difluoroacetophenone (0.5 mmol), bromination reagent N-bromosuccinimide (0.5 mmol) and acidic catalyst trifluoromethanesulfonic acid (45 μL) were added in sequence, and the grinding was stopped after grinding at a grinding frequency of 20 Hz for 10 min. After grinding, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, saturated sodium bicarbonate aqueous solution was added to neutralize after filtering, the upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phases were combined, the organic phases were dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (the eluent used was dichloromethane: petroleum ether = 1:8, v / v), and yellow oily 2-bromo-3', 4'-difluoroacetophenone was obtained with a yield of 91%.

[0046] Embodiment 11

[0047] Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then the grinding aid silica gel (150 mg), substrate 3', 4'-difluoroacetophenone (0.5 mmol), bromination reagent 1, 3-dibromo-5, 5-dimethylhydantoin (0.25 mmol) and acidic catalyst trifluoromethanesulfonic acid (45 μL) were added in sequence, and the mixture was ground at a grinding frequency of 20 Hz for 10 min and then stopped. After the grinding, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, saturated sodium bicarbonate aqueous solution was added to neutralize after filtration, the upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phases were combined, the organic phases were dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (the eluent used was dichloromethane: petroleum ether = 1:8, v / v), and yellow oily 2-bromo-3', 4'-difluoroacetophenone was obtained with a yield of 71.85%.

[0048] Example 12

[0049] Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then the grinding aid silica gel (150 mg), substrate 3', 4'-difluoroacetophenone (0.5 mmol), bromination reagent 1, 3-dibromo-5, 5-dimethylhydantoin (0.4 mmol) and acidic catalyst trifluoromethanesulfonic acid (45 μL) were added in sequence, and the grinding was stopped after grinding at a grinding frequency of 20 Hz for 10 min. After the grinding was completed, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, saturated sodium bicarbonate aqueous solution was added to neutralize after filtering, the upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phase was combined, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (the eluent used was dichloromethane: petroleum ether = 1:8, v / v), and yellow oily 2-bromo-3', 4'-difluoroacetophenone was obtained with a yield of 72.09%.

[0050] Example 13

[0051] Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then the grinding aid silica gel (150 mg), substrate 3', 4'-difluoroacetophenone (0.5 mmol), bromination reagent copper bromide (0.25 mmol) and acidic catalyst trifluoromethanesulfonic acid (45 μL) were added in sequence, and the mixture was ground at a grinding frequency of 20 Hz for 10 min and then stopped. After the grinding, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, saturated sodium bicarbonate aqueous solution was added to neutralize after filtration, the upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phases were combined, the organic phases were dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (the eluent used was dichloromethane: petroleum ether = 1:8, v / v), and yellow oily 2-bromo-3', 4'-difluoroacetophenone was obtained with a yield of 21.27%.

[0052] Embodiment 14

[0053] Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then the grinding aid silica gel (150 mg), substrate 3', 4'-difluoroacetophenone (0.5 mmol), bromination reagent N-bromosuccinimide (0.55 mmol) and acidic catalyst trifluoromethanesulfonic acid (45 μL) were added in sequence, and the grinding was stopped at a grinding frequency of 20 Hz for 10 min. After the grinding was completed, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, saturated sodium bicarbonate aqueous solution was added to neutralize after filtering, the upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phases were combined, the organic phases were dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (the eluent used was dichloromethane: petroleum ether = 1:8, v / v), and yellow oily 2-bromo-3', 4'-difluoroacetophenone was obtained with a yield of 82.05%.

[0054] Embodiment 15

[0055] Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then the grinding aid silica gel (150 mg), substrate acetophenone (0.5 mmol), bromination reagent N-bromosuccinimide (0.5 mmol) and acidic catalyst trifluoromethanesulfonic acid (45 μL) were added in sequence, and the reaction was stopped after 10 min at a grinding frequency of 20 Hz. After the grinding was completed, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, saturated sodium bicarbonate aqueous solution was added to neutralize after filtering, the upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phases were combined, the organic phases were dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (the eluent used was dichloromethane: petroleum ether = 1:8, v / v) to obtain white crystals of 2-bromoacetophenone with a yield of 52.8%.

[0056] The NMR characterization data of the compound:

[0057] 1 H NMR (400MHz, Chloroform-d) δ8.05–7.97(m,2H,ArH),7.68–7.59(m,1H,ArH),7.52(t,J=7.7Hz,2H,ArH),4.48(s,2H,CH2).

[0058] Example 16

[0059] Add 3 stainless steel grinding balls with a diameter of 10 mm into a 25 ml stainless steel grinding jar, then add grinding aid silica gel (150 mg), substrate 4'-bromoacetophenone (0.5 mmol), bromination reagent N-bromosuccinimide (0.5 mmol) and acidic catalyst trifluoromethanesulfonic acid (45 μL) in sequence, and react at 20 Hz for 10 min before stopping. After grinding, scrape out the reactant, add ethyl acetate to dissolve the reactant, filter and add saturated sodium bicarbonate aqueous solution to neutralize, take the upper organic phase and wash it with water three times (3×15 mL), extract the aqueous phase with ethyl acetate three times (3×15 mL), combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (the eluent used is dichloromethane: petroleum ether = 1:8, v / v) to obtain white solid 2-bromo-4'-bromoacetophenone with a yield of 89.6%.

[0060] The NMR characterization data of the compound:

[0061] 1 H NMR (400MHz, Chloroform-d) δ7.89–7.81(m,2H,ArH),7.68–7.60(m,2H,ArH),4.40(s,2H,CH2).

[0062] Embodiment 17

[0063] Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then the grinding aid silica gel (150 mg), substrate 3'-bromoacetophenone (0.5 mmol), bromination reagent N-bromosuccinimide (0.5 mmol) and acidic catalyst trifluoromethanesulfonic acid (45 μL) were added in sequence, and the grinding was stopped after grinding at a grinding frequency of 20 Hz for 10 min. After grinding, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, saturated sodium bicarbonate aqueous solution was added to neutralize after filtering, the upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phases were combined, the organic phases were dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (the eluent used was dichloromethane: petroleum ether = 1:8, v / v), and white solid 2-bromo-3'-bromoacetophenone was obtained with a yield of 79.4%.

[0064] The NMR characterization data of the compound:

[0065] 1 H NMR (400MHz, Chloroform-d) δ8.14–8.09(m,1H,ArH),7.94–7.88(m,1H,ArH),7.77–7.72(m,1H,ArH),7.38(t,J=7.9Hz,1H,ArH),4.41(s,2H,CH2).

[0066] Embodiment 18

[0067] Add 3 stainless steel grinding balls with a diameter of 10 mm into a 25 ml stainless steel grinding jar, then add grinding aid silica gel (150 mg), substrate 2'-bromoacetophenone (0.5 mmol), bromination reagent N-bromosuccinimide (0.5 mmol) and acidic catalyst trifluoromethanesulfonic acid (45 μL) in sequence, grind at a grinding frequency of 20 Hz for 10 min and then stop. After grinding, scrape out the reactant, add ethyl acetate to dissolve the reactant, filter and add saturated sodium bicarbonate aqueous solution to neutralize, take the upper organic phase and wash it three times with water (3×15 mL), extract the aqueous phase with ethyl acetate three times (3×15 mL), combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (the eluent used is dichloromethane: petroleum ether = 1:10, v / v) to obtain colorless liquid 2-bromo-2'-bromoacetophenone with a yield of 64.5%.

[0068] The NMR characterization data of the compound:

[0069] 1 H NMR (400MHz, Chloroform-d) δ7.70–7.56(m,1H,ArH),7.50–7.46(m,1H,ArH),7.44–7.38(m,1H,ArH),7.38–7.33(m,1H,ArH),4.49(s,2H,CH2).

[0070] Embodiment 19

[0071] Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then the grinding aid silica gel (150 mg), substrate 4'-chloroacetophenone (0.5 mmol), bromination reagent N-bromosuccinimide (0.5 mmol) and acidic catalyst trifluoromethanesulfonic acid (45 μL) were added in sequence, and the grinding was stopped after grinding at a grinding frequency of 20 Hz for 10 min. After grinding, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, saturated sodium bicarbonate aqueous solution was added to neutralize after filtering, the upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phases were combined, the organic phases were dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (the eluent used was dichloromethane: petroleum ether = 1:8, v / v), and white solid 2-bromo-4'-chloroacetophenone was obtained with a yield of 85.6%.

[0072] The NMR characterization data of the compound:

[0073] 1H NMR (400MHz, Chloroform-d) δ7.93 (d, J=8.2Hz, 2H, ArH), 7.47 (d, J=8.2Hz, 2H, ArH), 4.41 (s, 2H, CH2).

[0074] Embodiment 20

[0075] Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then grinding aid silica gel (150 mg), 3'-chloroacetophenone (0.5 mmol), N-bromosuccinimide (0.5 mmol) and acidic catalyst trifluoromethanesulfonic acid (45 μL) were added in sequence, and grinding was stopped after grinding at a grinding frequency of 20 Hz for 10 min. After grinding, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, saturated sodium bicarbonate aqueous solution was added to neutralize after filtering, the upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phases were combined, the organic phases were dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (the eluent used was dichloromethane: petroleum ether = 1:8, v / v), and white solid 2-bromo-3'-chloroacetophenone was obtained with a yield of 84.4%.

[0076] The NMR characterization data of the compound:

[0077] 1 H NMR (400MHz, Chloroform-d) δ7.96(t,J=1.9Hz,1H,ArH),7.90–7.83(m,1H,ArH),7.63–7.55(m,1H,ArH),7.45(t,J=7.9Hz,1H,ArH),4.42(s,2H,CH2).

[0078] Embodiment 21

[0079] Add 3 stainless steel grinding balls with a diameter of 10 mm into a 25 ml stainless steel grinding jar, then add grinding aid silica gel (150 mg), 2'-chloroacetophenone (0.5 mmol), N-bromosuccinimide (0.5 mmol) and acidic catalyst trifluoromethanesulfonic acid (45 μL) in sequence, grind at a grinding frequency of 20 Hz for 10 min and then stop. After grinding, scrape out the reactant, add ethyl acetate to dissolve the reactant, filter and neutralize with saturated sodium bicarbonate aqueous solution, take the upper organic phase and wash it with water three times (3×15 mL), extract the aqueous phase with ethyl acetate three times (3×15 mL), combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (the eluent used is dichloromethane: petroleum ether = 1:10, v / v) to obtain brown oily liquid 2-bromo-2'-chloroacetophenone with a yield of 65%.

[0080] The NMR characterization data of the compound:

[0081] 1 H NMR (400MHz, Chloroform-d) δ7.56 (d, J=7.3Hz, 1H, ArH), 7.49–7.42 (m, 2H, ArH), 7.42–7.31 (m, 1H, ArH), 4.52 (s, 2H, CH2).

[0082] Embodiment 22

[0083] Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then the grinding aid silica gel (150 mg), substrate 4'-fluoroacetophenone (0.5 mmol), bromination reagent N-bromosuccinimide (0.5 mmol) and acidic catalyst trifluoromethanesulfonic acid (45 μL) were added in sequence, and the grinding was stopped after grinding at a grinding frequency of 20 Hz for 10 min. After the grinding was completed, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, saturated sodium bicarbonate aqueous solution was added to neutralize after filtering, the upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phases were combined, the organic phases were dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (the eluent used was dichloromethane: petroleum ether = 1:8, v / v), and white crystals of 2-bromo-4'-fluoroacetophenone were obtained, with a yield of 62.1%.

[0084] The NMR characterization data of the compound:

[0085] 1 H NMR (400MHz, Chloroform-d) δ8.11–7.90(m,1H,ArH),7.24–7.06(m,1H,ArH),4.41(s,1H,CH2).

[0086] Embodiment 23

[0087] Add 3 stainless steel grinding balls with a diameter of 10 mm into a 25 ml stainless steel grinding jar, then add grinding aid silica gel (150 mg), substrate 3'-fluoroacetophenone (0.5 mmol), bromination reagent N-bromosuccinimide (0.5 mmol) and acidic catalyst trifluoromethanesulfonic acid (45 μL) in sequence, grind at a grinding frequency of 20 Hz for 10 min and then stop. After grinding, scrape out the reactant, add ethyl acetate to dissolve the reactant, filter and add saturated sodium bicarbonate aqueous solution to neutralize, take the upper organic phase and wash it three times with water (3×15 mL), extract the aqueous phase with ethyl acetate three times (3×15 mL), combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (the eluent used is dichloromethane: petroleum ether = 1:8, v / v) to obtain white crystal 2-bromo-3'-fluoroacetophenone with a yield of 50%.

[0088] The NMR characterization data of the compound:

[0089] 1 H NMR (400MHz, Chloroform-d) δ7.82–7.73(m,1H,ArH),7.71–7.64(m,1H,ArH),7.53–7.44(m,1H,ArH),7.37–7.28(m,1H,ArH),4.42(s,2H,CH2).

[0090] Embodiment 24

[0091] Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then the grinding aid silica gel (150 mg), substrate 2'-fluoroacetophenone (0.5 mmol), bromination reagent N-bromosuccinimide (0.5 mmol) and acidic catalyst trifluoromethanesulfonic acid (45 μL) were added in sequence, and the grinding was stopped after grinding at a grinding frequency of 20 Hz for 10 min. After grinding, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, saturated sodium bicarbonate aqueous solution was added to neutralize after filtering, the upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phases were combined, the organic phases were dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (the eluent used was dichloromethane: petroleum ether = 1:10, v / v), and white crystals of 2-bromo-2'-fluoroacetophenone were obtained with a yield of 41.7%.

[0092] The NMR characterization data of the compound:

[0093] 1H NMR (400MHz, Chloroform-d) δ7.98–7.88(m,1H,ArH),7.63–7.53(m,1H,ArH),7.31–7.22(m,1H,ArH),7.22–7.12(m,1H,ArH),4.52(d,J=2.4Hz,2H,CH2).

[0094] Embodiment 25

[0095] Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then the grinding aid silica gel (150 mg), substrate 4'-methylacetophenone (0.5 mmol), bromination reagent N-bromosuccinimide (0.5 mmol) and acidic catalyst trifluoromethanesulfonic acid (45 μL) were added in sequence, and the grinding was stopped after grinding at a grinding frequency of 20 Hz for 10 min. After grinding, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, saturated sodium bicarbonate aqueous solution was added to neutralize after filtering, the upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phases were combined, the organic phases were dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (the eluent used was dichloromethane: petroleum ether = 1:8, v / v), and white crystals of 2-bromo-4'-methylacetophenone were obtained with a yield of 70.5%.

[0096] The NMR characterization data of the compound:

[0097] 1 H NMR (400MHz, Chloroform-d) δ7.88 (d, J=8.2Hz, 2H, ArH), 7.28 (d, J=8.0Hz, 2H, ArH), 4.43 (s, 2H, CH2), 2.42 (s, 3H, CH3).

[0098] Embodiment 26

[0099] Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then the grinding aid silica gel (150 mg), substrate 3'-methylacetophenone (0.5 mmol), bromination reagent N-bromosuccinimide (0.5 mmol) and acidic catalyst trifluoromethanesulfonic acid (45 μL) were added in sequence, and the grinding was stopped after grinding at a grinding frequency of 20 Hz for 10 min. After the grinding was completed, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, saturated sodium bicarbonate aqueous solution was added to neutralize after filtering, the upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phases were combined, the organic phases were dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (the eluent used was dichloromethane: petroleum ether = 1:8, v / v), and a colorless transparent liquid 2-bromo-3'-methylacetophenone was obtained with a yield of 60.4%.

[0100] The NMR characterization data of the compound:

[0101] 1 H NMR (400MHz, Chloroform-d) δ7.82–7.74(m,2H,ArH),7.47–7.34(m,2H,ArH),4.45(s,2H,CH2),2.42(s,3H,CH3).

[0102] Embodiment 27

[0103] Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then the grinding aid silica gel (150 mg), substrate 4'-nitroacetophenone (0.5 mmol), bromination reagent N-bromosuccinimide (0.5 mmol) and acidic catalyst trifluoromethanesulfonic acid (45 μL) were added in sequence, and the mixture was ground at a grinding frequency of 20 Hz for 10 min and then stopped. After the grinding, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, saturated sodium bicarbonate aqueous solution was added to neutralize after filtration, the upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phases were combined, the organic phases were dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (the eluent used was dichloromethane: petroleum ether = 1:10, v / v), and yellow solid 2-bromo-4'-nitroacetophenone was obtained with a yield of 83.2%.

[0104] The NMR characterization data of the compound:

[0105] 1 H NMR (400MHz, Chloroform-d) δ8.34 (d, J=8.9Hz, 2H, ArH), 8.16 (d, J=8.9Hz, 2H, ArH), 4.46 (s, 2H, CH2).

[0106] Embodiment 28

[0107] Add 3 stainless steel grinding balls with a diameter of 10 mm to a 25 ml stainless steel grinding jar, then add grinding aid silica gel (150 mg), substrate 3'-nitroacetophenone (0.5 mmol), bromination reagent N-bromosuccinimide (0.5 mmol) and acidic catalyst trifluoromethanesulfonic acid (45 μL) in sequence, grind at a grinding frequency of 20 Hz for 10 min and then stop. After grinding, scrape out the reactant, add ethyl acetate to dissolve the reactant, filter and add saturated sodium bicarbonate aqueous solution to neutralize, take the upper organic phase and wash it three times with water (3×15 mL), extract the aqueous phase with ethyl acetate three times (3×15 mL), combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (the eluent used is dichloromethane: petroleum ether = 1:8, v / v) to obtain light yellow solid 2-bromo-3'-nitroacetophenone with a yield of 80.7%.

[0108] The NMR characterization data of the compound:

[0109] 1 H NMR (400MHz, Chloroform-d) δ8.81(t,J=2.0Hz,1H,ArH),8.53–8.41(m,1H,ArH),8.38–8.28(m,1H,ArH),7.73(t,J=8.0Hz,1H,ArH),4.48(s,2H,CH2).

[0110] Embodiment 29

[0111] Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then the grinding aid silica gel (150 mg), substrate 4'-fluoro-3'-methoxyacetophenone (0.5 mmol), bromination reagent N-bromosuccinimide (0.5 mmol) and acidic catalyst trifluoromethanesulfonic acid (45 μL) were added in sequence, and the grinding was stopped after grinding at a grinding frequency of 20 Hz for 10 min. After the grinding was completed, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, saturated sodium bicarbonate aqueous solution was added to neutralize after filtering, the upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phases were combined, the organic phases were dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (the eluent used was dichloromethane: petroleum ether = 1:8, v / v), and a white solid 2-bromo-4'-fluoro-3'-methoxyacetophenone was obtained with a yield of 77.2%.

[0112] The NMR characterization data of the compound:

[0113] 1H NMR (400MHz, Chloroform-d) δ7.71–7.51(m,2H,ArH),7.16(dd,J=10.5,8.4Hz,1H,ArH),4.41(s,2H,CH2),3.95(s,3H,OCH3).

[0114] Compared with the existing inventions, the characteristics of the present invention are mainly reflected in: the present invention provides a new method for synthesizing α-bromoacetophenone compounds, which can react quickly in a short time and has a high yield.

[0115] The contents described in this specification are merely an enumeration of implementation forms of the inventive concept, and the protection scope of the present invention should not be regarded as being limited to the specific forms described in the embodiments.

Claims

1. A method for preparing an α-bromoacetophenone compound, wherein the α-bromoacetophenone compound is 2-bromo-3',4'-difluoroacetophenone, characterized in that Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then 200 mg of grinding aid silica gel, 0.5 mmol of substrate 3', 4'-difluoroacetophenone, 0.5 mmol of bromination reagent N-bromosuccinimide and 45 μL of acidic catalyst trifluoromethanesulfonic acid were added in sequence. The mixture was ground at a grinding frequency of 30 Hz for 30 min and then stopped. After the grinding, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, and saturated sodium bicarbonate aqueous solution was added to neutralize the mixture after filtration. The upper organic phase was washed with water three times for 3×15 mL, and the aqueous phase was extracted with ethyl acetate three times for 3×15 mL. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography. The eluent used was dichloromethane: petroleum ether = 1:8, v / v, to obtain yellow oily 2-bromo-3', 4'-difluoroacetophenone with a yield of 83.43%.

2. A method for preparing an α-bromoacetophenone compound, wherein the α-bromoacetophenone compound is 2-bromo-3',4'-difluoroacetophenone, characterized in that Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then 150 mg of grinding aid silica gel, 0.5 mmol of substrate 3', 4'-difluoroacetophenone, 0.5 mmol of bromination reagent N-bromosuccinimide and 45 μL of acidic catalyst trifluoromethanesulfonic acid were added in sequence. The mixture was ground at a grinding frequency of 20 Hz for 10 min and then stopped. After the grinding, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, and saturated sodium bicarbonate aqueous solution was added to neutralize the mixture after filtration. The upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography. The eluent used was dichloromethane: petroleum ether = 1:8, v / v, to obtain yellow oily 2-bromo-3', 4'-difluoroacetophenone with a yield of 91%.

3. A method for preparing an α-bromoacetophenone compound, wherein the α-bromoacetophenone compound is 2-bromo-3',4'-difluoroacetophenone, characterized in that Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then 150 mg of grinding aid silica gel, 0.5 mmol of substrate 3', 4'-difluoroacetophenone, 0.55 mmol of bromination reagent N-bromosuccinimide and 45 μL of acidic catalyst trifluoromethanesulfonic acid were added in sequence. The mixture was ground at a grinding frequency of 20 Hz for 10 min and then stopped. After the grinding, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, and saturated sodium bicarbonate aqueous solution was added to neutralize the mixture after filtration. The upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography. The eluent used was dichloromethane: petroleum ether = 1:8, v / v, to obtain yellow oily 2-bromo-3', 4'-difluoroacetophenone with a yield of 82.05%.

4. A method for preparing an α-bromoacetophenone compound, wherein the α-bromoacetophenone compound is 2-bromo-4'-bromoacetophenone, characterized in that Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then 150 mg of grinding aid silica gel, 0.5 mmol of substrate 4'-bromoacetophenone, 0.5 mmol of bromination reagent N-bromosuccinimide and 45 μL of acidic catalyst trifluoromethanesulfonic acid were added in sequence. The reaction was stopped after 10 min at 20 Hz. After grinding, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, filtered and neutralized with saturated sodium bicarbonate aqueous solution, the upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography. The eluent used was dichloromethane: petroleum ether = 1:8, v / v, to obtain white solid 2-bromo-4'-bromoacetophenone with a yield of 89.6%.

5. A method for preparing an α-bromoacetophenone compound, wherein the α-bromoacetophenone compound is 2-bromo-4'-chloroacetophenone, characterized in that Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then 150 mg of grinding aid silica gel, 0.5 mmol of substrate 4'-chloroacetophenone, 0.5 mmol of bromination reagent N-bromosuccinimide and 45 μL of acidic catalyst trifluoromethanesulfonic acid were added in sequence. The mixture was ground at a grinding frequency of 20 Hz for 10 min and then stopped. After the grinding, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, and saturated sodium bicarbonate aqueous solution was added to neutralize the mixture after filtration. The upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography. The eluent used was dichloromethane: petroleum ether = 1:8, v / v, to obtain white solid 2-bromo-4'-chloroacetophenone with a yield of 85.6%.

6. A method for preparing an α-bromoacetophenone compound, wherein the α-bromoacetophenone compound is 2-bromo-3'-chloroacetophenone, characterized in that Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then 150 mg of grinding aid silica gel, 0.5 mmol of 3'-chloroacetophenone, 0.5 mmol of N-bromosuccinimide and 45 μL of acidic catalyst trifluoromethanesulfonic acid were added in sequence. The mixture was ground at a grinding frequency of 20 Hz for 10 min and then stopped. After the grinding, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, and saturated sodium bicarbonate aqueous solution was added to neutralize the mixture after filtration. The upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography. The eluent used was dichloromethane: petroleum ether = 1:8, v / v, to obtain white solid 2-bromo-3'-chloroacetophenone with a yield of 84.4%.

7. A method for preparing an α-bromoacetophenone compound, wherein the α-bromoacetophenone compound is 2-bromo-4'-nitroacetophenone, characterized in that Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then 150 mg of grinding aid silica gel, 0.5 mmol of substrate 4'-nitroacetophenone, 0.5 mmol of bromination reagent N-bromosuccinimide and 45 μL of acidic catalyst trifluoromethanesulfonic acid were added in sequence. The mixture was ground at a grinding frequency of 20 Hz for 10 min and then stopped. After the grinding, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, and saturated sodium bicarbonate aqueous solution was added to neutralize the mixture after filtration. The upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (the eluent used was dichloromethane: petroleum ether = 1:10, v / v) to obtain a yellow solid 2-bromo-4'-nitroacetophenone with a yield of 83.2%.

8. A method for preparing an α-bromoacetophenone compound, wherein the α-bromoacetophenone compound is 2-bromo-3'-nitroacetophenone, characterized in that Three stainless steel grinding balls with a diameter of 10 mm were added to a 25 ml stainless steel grinding jar, and then 150 mg of grinding aid silica gel, 0.5 mmol of substrate 3'-nitroacetophenone, 0.5 mmol of bromination reagent N-bromosuccinimide and 45 μL of acidic catalyst trifluoromethanesulfonic acid were added in sequence. The mixture was ground at a grinding frequency of 20 Hz for 10 min and then stopped. After the grinding, the reactants were scraped out, ethyl acetate was added to dissolve the reactants, and saturated sodium bicarbonate aqueous solution was added to neutralize the mixture after filtration. The upper organic phase was washed with water three times (3×15 mL), the aqueous phase was extracted with ethyl acetate three times (3×15 mL), the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography. The eluent used was dichloromethane: petroleum ether = 1:8, v / v, to obtain light yellow solid 2-bromo-3'-nitroacetophenone with a yield of 80.7%.

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