A preparation method of 5-bromobenzofuranone

Abstract

The present invention relates to the technical field of pharmaceutical intermediate synthesis, and a preparation method of 5-bromobenzofuranone is provided. The preparation method provided by the present invention comprises the following steps: 2-hydroxy-5-bromoacetophenone, a bromination reagent, a catalyst and a first organic solvent are mixed, and a bromination reaction is carried out to obtain 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone; the 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone, an organic base and a second organic solvent are mixed, and a cyclization reaction is carried out to obtain 5-bromobenzofuranone. The present invention uses 2-hydroxy-5-bromoacetophenone as a raw material, and bromination reaction and cyclization reaction are carried out successively to prepare 5-bromobenzofuran, which is simple to operate, and the yield yield and purity are relatively high. Further, the raw materials required for the method used in the present invention are more easily obtained, and the reaction time is short, which is more conducive to reducing the complexity of the preparation method.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical intermediate synthesis, and in particular to a method for preparing 5-bromobenzofuranone. Background Art

[0002] Depressive disorder refers to a type of mood disorder caused by various reasons with significant and persistent low mood as the main clinical feature. It is a chronic mental illness with high incidence, high recurrence rate and high disability rate, accompanied by varying degrees of cognitive and behavioral changes. Some patients have self-harm and suicidal behaviors. Most of the diseases have acute or subacute onset, with an average age of onset of 20 to 30 years old. Almost every age group is likely to suffer from depressive disorder, and women are more likely to suffer from it than men. The average course of a single depressive episode is about 16 weeks, and it takes an average of about 20 weeks to recover after the episode. If not treated, the course of the disease will generally last for 6 months or longer.

[0003] At present, drug therapy is the main method for treating depressive disorders. Among the therapeutic drugs, citalopram, as a serotonin reuptake inhibitor (SSRIs), has the advantages of good efficacy, good tolerability, and relatively few adverse reactions. It is the most commonly used in clinical practice and is also one of the first-line drugs for depression recommended by major guidelines.

[0004] 5-Bromo-3(2H)-benzofuran-one (C8H5BrO2) is a γ-lactone compound with an aromatic structure, and is one of the very important intermediates for the synthesis of Citalopram. Currently, many literatures have reported the synthesis methods of 5-bromobenzofuran-one. In 2001, Safdar Hayat et al. reported a method for oxidizing 4-bromo-2-methylbenzoic acid under the conditions of NaBrO3-NaHSO3 to generate 5-bromobenzofuranone. The yield of this method was not high, only 42% (Safdar, H.; Rahman, M.lqbalC.Ernst, B.; An improved method for the synthesis of Υ-lactones using Sodium Bormate and Sodium Hydrogen Sulfite[J]; Tetra.Lett.2001,42:1647-1649); in 2002, Jiang Guofang et al. reported a method for preparing 5-bromobenzofuranone by bromination reaction and catalytic oxidation reaction using o-xylene as a raw material, but the yield of 5-bromobenzofuranone was 69.1%, which was also not high (Jiang Guofang, Wei Guobing. Study on the Synthesis Method of 5-Bromobenzofuranone[J]. Journal of Hunan University, 2002, 29(3):12-15).

[0005] In summary, the existing method for preparing 5-bromobenzofuranone has the problem of low yield. Summary of the invention

[0006] In view of this, the present invention provides a method for preparing 5-bromobenzofuranone. The method provided by the present invention is simple to operate and has a high yield.

[0007] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0008] A method for preparing 5-bromobenzofuranone comprises the following steps:

[0009] Mixing 2-hydroxy-5-bromoacetophenone, a bromination reagent, a catalyst and a first organic solvent, and performing a bromination reaction to obtain 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone;

[0010] The 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone, an organic base and a second organic solvent are mixed and subjected to a cyclization reaction to obtain 5-bromobenzofuranone.

[0011] Preferably, the bromination agent includes any one or more of hydrobromic acid, hypobromous acid, N-bromosuccinimide, octane bromide, liquid bromine, 1,3-dibromo-5,5-dimethylhydantoin and benzylammonium tribromide.

[0012] Preferably, the molar ratio of the 2-hydroxy-5-bromoacetophenone to the bromination reagent is 1:(0.5-5).

[0013] Preferably, the catalyst includes any one or more of an iron-based catalyst, a copper-based catalyst, a zinc-based catalyst and an aluminum-based catalyst;

[0014] The mass of the catalyst is 5-10% of the mass of 2-hydroxy-5-bromoacetophenone.

[0015] Preferably, the temperature of the bromination reaction is 80-100° C. and the time is 10-15 hours.

[0016] Preferably, the organic base includes any one or more of triethylamine, pyridine, sodium methoxide, sodium ethoxide and potassium ethoxide.

[0017] Preferably, the molar ratio of the 2-hydroxy-5-bromoacetophenone to the organic base is 1:(0.5-3).

[0018] Preferably, the cyclization reaction is carried out at a temperature of 20 to 30° C. and for a time of 4 to 8 hours.

[0019] Preferably, the first organic solvent includes any one or more of 1,2-dichloroethane, chloroform, dichloromethane, ethyl acetate and butyl acetate.

[0020] Preferably, the second organic solvent includes any one of dichloromethane, toluene, benzene, chloroform and ethyl acetate.

[0021] The present invention provides a method for preparing 5-bromobenzofuranone, comprising the following steps: mixing 2-hydroxy-5-bromoacetophenone, a bromination reagent, a catalyst and a first organic solvent, performing a bromination reaction, and obtaining 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone; mixing the 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone, an organic base and a second organic solvent, and performing a cyclization reaction to obtain 5-bromobenzofuranone. The present invention uses 2-hydroxy-5-bromoacetophenone as a raw material, and sequentially performs a bromination reaction and a cyclization reaction to prepare 5-bromobenzofuran. The experimental data of the embodiment of the present invention show that the yield of 5-bromobenzofuran is up to 83.7%, which has a high yield.

[0022] Furthermore, the raw materials and catalysts required for the method adopted by the present invention are easier to obtain, the reaction time is short, and the operation is simpler. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 The 5-bromobenzofuranone prepared in Example 1 1 H-NMR spectrum. DETAILED DESCRIPTION

[0024] The present invention provides a method for preparing 5-bromobenzofuranone, comprising the following steps:

[0025] Mixing 2-hydroxy-5-bromoacetophenone, a bromination reagent, a catalyst and a first organic solvent, and performing a bromination reaction to obtain 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone;

[0026] The 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone, an organic base and a second organic solvent are mixed and subjected to a cyclization reaction to obtain 5-bromobenzofuranone.

[0027] Unless otherwise specified, the raw materials used in the present invention are all commercially available.

[0028] In the present invention, the synthesis route of the 5-bromobenzofuranone is shown in Formula 1:

[0029]

[0030] The present invention mixes 2-hydroxy-5-bromoacetophenone, a brominating agent, a catalyst and a first organic solvent, performs a brominating reaction, and obtains 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone. In the present invention, the brominating agent preferably includes any one or more of hydrobromic acid, hypobromous acid, N-bromosuccinimide, bromooctane, liquid bromine, 1,3-dibromo-5,5-dimethylhydantoin and benzyl ammonium tribromide, more preferably liquid bromine, hydrobromic acid, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin or bromooctane. The molar ratio of the 2-hydroxy-5-bromoacetophenone to the brominating agent is preferably 1:(0.5-5), more preferably 1:(0.5-3), further preferably 1:(0.8-3), and most preferably 1:(1-2). In the present invention, the catalyst preferably includes any one or more of an iron-based catalyst, a copper-based catalyst, a zinc-based catalyst and an aluminum-based catalyst. In the present invention, the iron-based catalyst preferably includes one or more of iron powder, ferric bromide and ferric chloride, and more preferably includes iron powder and / or ferric bromide. The copper-based catalyst preferably includes cuprous bromide and / or cupric bromide, and more preferably includes cupric bromide. In the present invention, the zinc-based catalyst preferably includes zinc chloride, and the aluminum-based catalyst preferably includes aluminum chloride. In the present invention, the mass of the catalyst is preferably 5 to 10% of the mass of 2-hydroxy-5-bromoacetophenone, more preferably 6 to 9%, further preferably 6.5 to 8.5%, and most preferably 7 to 8.5%. In the present invention, the above-mentioned types of catalysts are relatively easy to obtain and have good catalytic activity, which is conducive to reducing the complexity of the reaction system. In the present invention, the first organic solvent preferably includes any one or more of 1,2-dichloroethane, chloroform, dichloromethane, ethyl acetate and butyl acetate. When the first organic solvent is preferably a mixed solvent of two solvents, the mixed solvent is preferably a mixed solvent of 1,2-dichloroethane and ethyl acetate, a mixed solvent of dichloromethane and butyl acetate, a mixed solvent of 1,2-dichloroethane and butyl acetate, or a mixed solvent of chloroform and ethyl acetate, more preferably a mixed solvent of 1,2-dichloroethane and ethyl acetate or a mixed solvent of chloroform and ethyl acetate. When the mixed solvent is a mixed solvent of 1,2-dichloroethane and ethyl acetate, the volume ratio of 1,2-dichloroethane and ethyl acetate is preferably 1: (1-2), more preferably 1: (1-1.5), and further preferably 1: 1; when the mixed solvent is a mixed solvent of chloroform and ethyl acetate, the volume ratio of chloroform and ethyl acetate is preferably 1: (1-2), more preferably 1: (1-1.5), and further preferably 1: 1. The preferred use of a mixed solvent in the present invention can further improve the yield of the bromination reaction.

[0031] In the present invention, the mass volume ratio of the 2-hydroxy-5-bromoacetophenone to the first organic solvent is preferably 1g:(8-12)mL, more preferably 1g:(9-11)mL, and further preferably 1g:(10-11)mL. In the present invention, the bromination reaction is preferably carried out in a reactor, the temperature of the bromination reaction is preferably 80-100°C, more preferably 80-95°C, and further preferably 85-90°C, and the time of the bromination reaction is preferably 10-15h, more preferably 12-15h, and further preferably 13-14h. The present invention preferably carries out the bromination reaction under stirring. The present invention preferably uses gas phase monitoring to determine the progress of the bromination reaction, and the gas phase monitoring method is a means well known to those skilled in the art, and the gas phase monitoring is based on the fact that no 2-hydroxy-5-bromoacetophenone in the reaction system can be detected, indicating that the raw material has reacted completely. The present invention preferably adjusts the ratio of the raw materials used, the type and amount of the catalyst and the type of the first organic solvent so that the bromine atom is more likely to react with the hydrogen atom on the ketone group on the benzene ring, thereby improving the yield of 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone.

[0032] After obtaining 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone, the present invention mixes the 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone, an organic base and a second organic solvent, and performs a cyclization reaction to obtain 5-bromobenzofuranone. The present invention preferably cools the mixture obtained after the bromination reaction to room temperature, and then sequentially performs solid-liquid separation and rotary evaporation to obtain a crude product of 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone, and redissolves the crude product of 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone in water to obtain a crude product solution, and then the crude product is easily extracted with a second organic solvent, washed with water, dried and desiccant removed in sequence to obtain a second organic solvent solution containing 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone, and then the second organic solvent solution containing 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone and an organic base are mixed for cyclization reaction. The present invention preferably uses the second organic solvent as the extraction phase of 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone, and completes the mixing of the raw materials required for the cyclization reaction while purifying 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone, thereby simplifying the operation steps. In the present invention, the solid-liquid separation is preferably filtration. After the solid-liquid separation, the present invention takes the filtrate part for rotary evaporation, and the temperature of the rotary evaporation is preferably 30 to 42°C, more preferably 35 to 40°C, and further preferably 35 to 38°C. The present invention has no special requirements for the time of the rotary evaporation, and the solvent in the filtrate part is evaporated to dryness. In the present invention, the second organic solvent preferably includes any one of dichloromethane, toluene, benzene, chloroform and ethyl acetate, and more preferably includes any one of dichloromethane, toluene and trichlorotoluene. In the present invention, the water washing is preferably carried out with brine, and the brine is preferably a chloride salt solution, and the chloride salt solution is preferably a sodium chloride solution. The present invention has no specific requirements for the concentration of the sodium chloride solution, and the effect of washing and obvious stratification can be achieved. In the present invention, the drying desiccant is preferably anhydrous sodium sulfate, and the method for removing the desiccant is preferably filtering. The present invention preferably reduces the temperature of the second organic solvent solution containing 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone to 0-5°C, more preferably to 0°C, and then mixes with the organic base. The present invention preferably reduces the temperature of the second organic solvent solution containing 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone to within the above temperature range, which is beneficial to reduce the severity of the reaction when adding a base, improve the safety of the reaction, and at the same time, facilitate the control of the reaction temperature within a suitable range to improve the yield of the product.

[0033] In the present invention, the organic base preferably includes any one or more of triethylamine, pyridine, sodium methoxide, sodium ethoxide and potassium ethoxide, and more preferably includes any one or more of triethylamine, pyridine and sodium methoxide. In the present invention, the molar ratio of the 2-hydroxy-5-bromoacetophenone and the organic base is preferably 1: (0.5-3), more preferably 1: (0.5-2), further preferably 1: (0.5-1.5), and most preferably 1: (0.7-1.0). In the present invention, after the second organic solvent solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone is mixed with the organic base, it is preferably heated to the temperature of the cyclization reaction under stirring conditions for reaction. In the present invention, the temperature of the cyclization reaction is preferably 20-30°C, more preferably 25-28°C, and the time is preferably 4-8h, more preferably 5-7.5h, and more preferably 6-7h. The present invention preferably uses gas phase monitoring to determine the progress of the cyclization reaction. The gas phase monitoring method is a means well known to those skilled in the art. The gas phase monitoring is based on the fact that no 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone can be detected in the reaction system, indicating that the raw materials have been completely reacted.

[0034] After the cyclization reaction is completed, the present invention preferably performs post-treatment on the system after the cyclization reaction to obtain the 5-bromobenzofuran. In the present invention, the post-treatment preferably includes the following steps: sequentially performing quenching, first washing, first separation and first rotary evaporation on the system after the cyclization reaction to obtain a crude product of 5-bromobenzofuran, and sequentially performing redissolution, second washing, second separation, second rotary evaporation, recrystallization, solid-liquid separation and draining on the crude product of 5-bromobenzofuran to obtain the 5-bromobenzofuran. In the present invention, it is preferred to quench the system after the reaction with water, and the volume ratio of the water used for the quenching reaction to the reaction system is preferably (1-3):1, more preferably (1.5-2.5):1, in the present invention, the first washing is preferably washed with brine, the brine is preferably a sodium chloride solution, the concentration of the sodium chloride solution is preferably 1-2 mol / L, and the volume ratio of the brine to the water used for the quenching reaction is preferably 1:(0.5-1.8), more preferably 1:(0.75-1.5), and further preferably 1:(0.75-1.0). The present invention obtains an organic phase containing the crude product of the 5-bromobenzofuran by the first separation, and then performs a first rotary evaporation on the organic phase to obtain the crude product of the 5-bromobenzofuran. The temperature of the first rotary evaporation is preferably 30-45°C, more preferably 35-40°C. The present invention has no specific requirements for the temperature of the first rotary evaporation, and is based on the complete evaporation of the organic phase. In the present invention, the re-dissolution solvent is preferably ethyl acetate, and the volume ratio of the ethyl acetate to the solution is preferably 2: 1. The second washing is preferably washed with brine, and the brine is preferably a sodium chloride solution, and the concentration of the sodium chloride solution is preferably 1-2 mol / L. The volume ratio of the brine to the re-dissolution solvent is preferably (0.5-1): 1, and more preferably (0.5-0.8): 1. The present invention obtains an organic phase containing the 5-bromobenzofuran by the second separation, and then the organic phase is subjected to rotary evaporation. In the present invention, the temperature of the second rotary evaporation is preferably 30-45°C, more preferably 35-40°C, and the volume of the organic phase after the second rotary evaporation is 20-30% of the volume before the second rotary evaporation, and more preferably 25-30%.

[0035] In the present invention, the method of recrystallization is preferably to add a recrystallization solvent to the system after the second rotary evaporation, and the recrystallization solvent is preferably petroleum ether, and the volume ratio of the petroleum ether to the system after the second rotary evaporation is preferably 0.5:1. In the present invention, after adding the recrystallization solvent to the system after the second rotary evaporation, the temperature is lowered to 4°C for recrystallization. In the present invention, the method of solid-liquid separation is filtration, and the present invention preferably obtains recrystallized 5-bromobenzofuran by filtration. The present invention preferably uses an oil pump to drain the recrystallized 5-bromobenzofuran to obtain the 5-bromobenzofuran.

[0036] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention.

[0037] Example 1

[0038] Add 10g of 2-hydroxy-5-bromoacetophenone to the reactor, dissolve it in a solvent consisting of 50mL of ethyl acetate and 50mL of 1,2-dichloroethane, then add 7.43g of liquid bromine and 0.8g of copper bromide in sequence, heat the reactor to 100°C and stir for 12h, and monitor the reaction progress in the gas phase. After the reaction is completed, wait for the reactor to cool to room temperature, filter and remove solid impurities in the reaction system to obtain a filtrate, and rotary evaporate the filtrate at 40°C until the solvent is evaporated to dryness to obtain a crude product of 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone. Then, 20 mL of water was added to the crude product of 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone to redissolve it, and 60 mL of dichloromethane was added for extraction. The dichloromethane phase was separated and layered. The dichloromethane phase was washed with 60 mL of brine, and then the dichloromethane phase was dried over 6 g of anhydrous sodium sulfate. The desiccant was removed by filtration to obtain a dichloromethane solution containing 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone, which was directly used in the next reaction.

[0039] The dichloromethane solution containing 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone was cooled to 0°C, 4.7g triethylamine was added dropwise, the reaction system was heated to 25°C, stirred for 6h, and the reaction progress was monitored by gas phase. After the reaction was completed, 30mL of water was added to the reaction system to quench, and then 40mL of brine was added for washing. After washing, the dichloromethane phase was separated from the aqueous phase. The dichloromethane phase was rotary evaporated at 40°C until the solvent was completely rotary evaporated to obtain a crude product of 5-bromobenzofuranone. The crude product was redissolved with 80mL of ethyl acetate, washed with 40mL of brine, and the organic phase was separated from the aqueous phase. The organic phase was rotary evaporated and concentrated to 25% of the original volume at 40°C, and then 20mL of petroleum ether was added to the rotary evaporated solution for recrystallization, and then the solid was collected by filtration, and the solid was pumped dry with an oil pump to obtain a pure product of 5-bromobenzofuranone. Through calculation and determination, the yield of 5-bromobenzofuranone is 83.6% and the purity is 99.4%. Figure 1 The 5-bromobenzofuranone prepared in Example 1 1 H-NMR spectrum. Figure 1 It can be seen that the characteristic peak of 5-bromobenzofuranone is obvious, indicating that the 5-bromobenzofuranone prepared by the preparation method of Example 1 has high purity.

[0040] Example 2

[0041] Add 20g of 2-hydroxy-5-bromoacetophenone to the reactor, dissolve it in a solvent consisting of 100mL of ethyl acetate and 100mL of chloroform, then add 14.86g of hydrobromic acid and 1.5g of iron powder in sequence, heat the reactor to 80°C, stir and react for 15h, and monitor the reaction progress in gas phase. After the reaction is completed, wait for the reactor to cool to room temperature, filter and remove solid impurities in the reaction system to obtain a filtrate, and rotary evaporate the filtrate at 35°C until the solvent is evaporated to dryness to obtain a crude product of 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone. Then, 40 mL of water was added to the crude product of 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone to redissolve it, and 120 mL of chloroform was added for extraction. The chloroform phase was separated and washed with 120 mL of brine. The chloroform phase was then dried over 12 g of anhydrous sodium sulfate, and the desiccant was removed by filtration to obtain a chloroform solution containing 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone, which was directly used in the next reaction.

[0042] The chloroform solution containing 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone was cooled to 0°C, 9.4g pyridine was added dropwise, the reaction system was heated to 20°C, stirred for 8h, and the reaction progress was monitored by gas phase. After the reaction was completed, 60mL of water was added to the reaction system to quench, and then 80mL of brine was added for washing. After washing, the chloroform phase was separated from the aqueous phase. The chloroform phase was rotary evaporated at 35°C until the solvent was completely rotary evaporated to obtain a crude product of 5-bromobenzofuranone. The crude product was redissolved with 160mL of ethyl acetate, washed with 80mL of brine, and the organic phase was separated from the aqueous phase. The organic phase was rotary evaporated and concentrated to 20% of the original volume at 35°C, and then 40mL of petroleum ether was added to the rotary evaporated solution for recrystallization, and then the solid was collected by filtration, and the solid was pumped dry with an oil pump to obtain a pure product of 5-bromobenzofuranone. Through calculation and determination, the yield of 5-bromobenzofuranone is 82.7% and the purity is 99.1%.

[0043] Example 3

[0044] 30g of 2-hydroxy-5-bromoacetophenone was added to the reactor, dissolved in a solvent consisting of 150mL of butyl acetate and 150mL of dichloromethane, and then 22.3g of N-bromosuccinimide and 2.5g of ferric bromide were added in sequence, and the reactor temperature was heated to 85°C and stirred for 13h, and the reaction progress was monitored by gas phase. After the reaction was completed, the reactor was cooled to room temperature, and solid impurities in the reaction system were filtered to obtain a filtrate, and the filtrate was rotary evaporated at 40°C until the solvent was evaporated to dryness to obtain a crude product of 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone. Then, 60 mL of water was added to the crude product of 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone to redissolve it, and 180 mL of toluene was added for extraction. The toluene phase was separated and the toluene phase was washed with 180 mL of brine. The toluene phase was then dried over 18 g of anhydrous sodium sulfate, and the desiccant was removed by filtration to obtain a toluene solution containing 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone, which was directly used in the next reaction.

[0045] The toluene solution containing 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone was cooled to 0°C, 14.2g of sodium methoxide was added dropwise, the reaction system was heated to 26°C, stirred for 7h, and the reaction progress was monitored by gas phase. After the reaction was completed, 180mL of water was added to the reaction system to quench, and then 120mL of brine was added for washing. After washing, the toluene phase was separated from the aqueous phase. The toluene phase was rotary evaporated at 40°C until the solvent was completely rotary evaporated to obtain a crude product of 5-bromobenzofuranone. The crude product was re-dissolved with 240mL of ethyl acetate, then washed with 120mL of brine, the organic phase was separated from the aqueous phase, and the organic phase was rotary evaporated and concentrated to 30% of the original volume at 40°C, and then 60mL of petroleum ether was added to the rotary evaporated solution for recrystallization, and then the solid was filtered and collected, and the solid was pumped dry with an oil pump to obtain a pure 5-bromobenzofuranone. After calculation and determination, the yield of 5-bromobenzofuranone was 83.1% and the purity was 98.6%.

[0046] Example 4

[0047] Add 40g of 2-hydroxy-5-bromoacetophenone to the reactor, dissolve it in a solvent consisting of 200mL of butyl acetate and 200mL of dichloroethane, then add 29.7g of 1,3-dibromo-5,5,-dimethylhydantoin and 3g of zinc chloride in sequence, heat the reactor to 90°C and stir for 13h, and monitor the reaction progress in the gas phase. After the reaction is completed, wait for the reactor to cool to room temperature, filter and remove solid impurities in the reaction system to obtain a filtrate, and evaporate the filtrate at 38°C until the solvent is evaporated to dryness to obtain a crude product of 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone. Then, 80 mL of water was added to the crude product of 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone to redissolve it, and 240 mL of ethyl acetate was added for extraction. The ethyl acetate phase was separated and washed with 240 mL of brine. The toluene phase was then dried over 25 g of anhydrous sodium sulfate, and the desiccant was removed by filtration to obtain an ethyl acetate solution containing 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone, which was directly used in the next reaction.

[0048] The ethyl acetate solution containing 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone was cooled to 0°C, 19g of sodium ethoxide was added dropwise, the reaction system was heated to 28°C, stirred for 5h, and the reaction progress was monitored by gas phase. After the reaction was completed, 120mL of water was added to the reaction system to quench, and then 160mL of brine was added for washing. After washing, the ethyl acetate phase was separated from the aqueous phase. The ethyl acetate phase was rotary evaporated at 38°C until the solvent was completely rotary evaporated to obtain a crude product of 5-bromobenzofuranone. The crude product was re-dissolved with 320mL of ethyl acetate, then washed with 160mL of brine, the organic phase was separated from the aqueous phase, and the organic phase was rotary evaporated and concentrated to 25% of the original volume at 40°C, and then 80mL of petroleum ether was added to the rotary evaporated solution for recrystallization, and then the solid was filtered and collected, and the solid was pumped dry with an oil pump to obtain a pure 5-bromobenzofuranone. After calculation and determination, the yield of 5-bromobenzofuranone was 82.1% and the purity was 98.2%.

[0049] Example 5

[0050] Add 50g of 2-hydroxy-5-bromoacetophenone to the reactor, dissolve it in 500mL of 1,2-dichloroethane, then add 37g of bromooctane and 4g of aluminum chloride in sequence, heat the reactor to 95°C and stir for 12h, and monitor the reaction progress in the gas phase. After the reaction is completed, wait for the reactor to cool to room temperature, filter and remove solid impurities in the reaction system to obtain a filtrate, and evaporate the filtrate at 40°C until the solvent is evaporated to dryness to obtain a crude product of 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone. Then, 100 mL of water was added to the crude product of 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone to redissolve it, and 300 mL of chloroform was added for extraction. The chloroform phase was separated and washed with 300 mL of brine. The chloroform phase was then dried over 30 g of anhydrous sodium sulfate, and the desiccant was removed by filtration to obtain a chloroform solution containing 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone, which was directly used in the next reaction.

[0051] The chloroform solution containing 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone was cooled to 0°C, 14g potassium ethoxide was added dropwise, the reaction system was heated to 25°C, stirred for 7h, and the reaction progress was monitored by gas phase. After the reaction was completed, 150mL of water was added to the reaction system to quench, and then 200mL of brine was added for washing. After washing, the chloroform phase was separated from the aqueous phase. The chloroform phase was rotary evaporated at 40°C until the solvent was completely rotary evaporated to obtain a crude product of 5-bromobenzofuranone. The crude product was redissolved with 400mL of ethyl acetate, washed with 200mL of brine, and the organic phase was separated from the aqueous phase. The organic phase was rotary evaporated and concentrated to 20% of the original volume at 40°C, and then 100mL of petroleum ether was added to the rotary evaporated solution for recrystallization, and then the solid was collected by filtration, and the solid was pumped dry with an oil pump to obtain a pure product of 5-bromobenzofuranone. Through calculation and determination, the yield of 5-bromobenzofuranone is 82.7% and the purity is 98.3%.

[0052] Example 6

[0053] Add 100g of 2-hydroxy-5-bromoacetophenone to the reactor, dissolve it in a solvent consisting of 500mL of ethyl acetate and 500mL of 1,2-dichloroethane, then add 74.3g of liquid bromine and 8g of copper bromide in sequence, heat the reactor to 100°C and stir for 10h, and monitor the reaction progress in the gas phase. After the reaction is completed, wait for the reactor to cool to room temperature, filter and remove solid impurities in the reaction system to obtain a filtrate, and evaporate the filtrate at 40°C until the solvent is evaporated to dryness to obtain a crude product of 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone. Then, 200 mL of water was added to the crude product of 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone to redissolve it, and 600 mL of dichloromethane was added for extraction. The dichloromethane phase was separated and layered. The dichloromethane phase was washed with 600 mL of brine, and then the dichloromethane phase was dried over 60 g of anhydrous sodium sulfate. The desiccant was removed by filtration to obtain a dichloromethane solution containing 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone, which was directly used in the next reaction.

[0054] The dichloromethane solution containing 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone was cooled to 0°C, 47.1g triethylamine was added dropwise, the reaction system was heated to 25°C, stirred for 6h, and the reaction progress was monitored by gas phase. After the reaction was completed, 300mL of water was added to the reaction system to quench, and then 400mL of brine was added for washing. After washing, the dichloromethane phase was separated from the aqueous phase. The dichloromethane phase was rotary evaporated at 40°C until the solvent was completely rotary evaporated to obtain a crude product of 5-bromobenzofuranone. The crude product was redissolved with 800mL of ethyl acetate, then washed with 400mL of brine, the organic phase was separated from the aqueous phase, and the organic phase was rotary evaporated and concentrated to 25% of the original volume at 40°C, and then 200mL of petroleum ether was added to the rotary evaporated solution for recrystallization, and then the solid was collected by filtration, and the solid was pumped dry with an oil pump to obtain a pure product of 5-bromobenzofuranone. Through calculation and determination, the yield of 5-bromobenzofuranone is 83.7% and the purity is 99.3%.

[0055] Example 7

[0056] Add 1000g of 2-hydroxy-5-bromoacetophenone to the reactor, dissolve it in a solvent consisting of 5000mL of ethyl acetate and 5000mL of 1,2-dichloroethane, then add 743g of liquid bromine and 80g of copper bromide in sequence, heat the reactor to 100°C and stir for 10h, and monitor the reaction progress in the gas phase. After the reaction is completed, wait for the reactor to cool to room temperature, filter and remove solid impurities in the reaction system to obtain a filtrate, and rotary evaporate the filtrate at 40°C until the solvent is evaporated to dryness to obtain a crude product of 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone. Then, 2000 mL of water was added to the crude product of 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone to redissolve it, and 6000 mL of dichloromethane was added for extraction. The dichloromethane phase was separated and layered. The dichloromethane phase was washed with 6000 mL of brine, and then the dichloromethane phase was dried over 600 g of anhydrous sodium sulfate. The desiccant was removed by filtration to obtain a dichloromethane solution containing 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone, which was directly used in the next reaction.

[0057] The dichloromethane solution containing 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone was cooled to 0°C, 471g triethylamine was added dropwise, the reaction system was heated to 25°C, stirred for 6h, and the reaction progress was monitored by gas phase. After the reaction was completed, 3000mL of water was added to the reaction system to quench, and then 4000mL of brine was added for washing. After washing, the dichloromethane phase was separated from the aqueous phase. The dichloromethane phase was rotary evaporated at 40°C until the solvent was completely rotary evaporated to obtain a crude product of 5-bromobenzofuranone. The crude product was redissolved with 8000mL of ethyl acetate, then washed with 4000mL of brine, the organic phase was separated from the aqueous phase, and the organic phase was rotary evaporated and concentrated to 25% of the original volume at 40°C, and then 2000mL of petroleum ether was added to the rotary evaporated solution for recrystallization, and then the solid was collected by filtration, and the solid was pumped dry with an oil pump to obtain a pure product of 5-bromobenzofuranone. Through calculation and determination, the yield of 5-bromobenzofuranone is 83.5% and the purity is 99.5%.

[0058] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing 5-bromobenzofuranone, characterized in that: The following steps are involved: Mixing 2-hydroxy-5-bromoacetophenone, a bromination reagent, a catalyst and a first organic solvent, and performing a bromination reaction to obtain 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone; The 2-bromo-1-(5-bromo-2-hydroxyphenyl)-ethanone, an organic base and a second organic solvent are mixed to carry out a cyclization reaction to obtain 5-bromobenzofuranone; After the cyclization reaction is completed, post-treatment is performed on the system after the cyclization reaction; The bromination reagent includes N-bromosuccinimide, liquid bromine or 1,3-dibromo-5,5-dimethylhydantoin; The molar ratio of the 2-hydroxy-5-bromoacetophenone to the bromination reagent is 1:(0.5-1); The catalyst includes copper bromide, zinc chloride or ferric bromide; The mass of the catalyst is 5 to 10% of the mass of 2-hydroxy-5-bromoacetophenone; The temperature of the bromination reaction is 85-100° C. and the time is 12-13 hours; The first organic solvent includes any one or more of 1,2-dichloroethane, chloroform, dichloromethane, ethyl acetate and butyl acetate; The post-treatment comprises the following steps: sequentially quenching the system after the cyclization reaction, performing a first washing, a first separation and a first rotary evaporation to obtain a crude product of 5-bromobenzofuran, and sequentially performing redissolution, a second washing, a second separation, a second rotary evaporation, recrystallization, solid-liquid separation and drying of the crude product of 5-bromobenzofuran.

2. The preparation method according to claim 1, characterized in that: The organic base includes any one or more of triethylamine, pyridine, sodium methoxide, sodium ethoxide and potassium ethoxide.

3. The preparation method according to claim 1 or 2, characterized in that: The molar ratio of the 2-hydroxy-5-bromoacetophenone to the organic base is 1:(0.5-3).

4. The preparation method according to claim 1, characterized in that: The temperature of the cyclization reaction is 20-30° C. and the time is 4-8 hours.

5. The preparation method according to claim 1, characterized in that: The second organic solvent includes any one of dichloromethane, toluene, benzene, chloroform and ethyl acetate.

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