CN114573534B - A preparation method of 5-bromobenzofuranone - Google Patents
A preparation method of 5-bromobenzofuranone Download PDFInfo
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- CN114573534B CN114573534B CN202210326663.7A CN202210326663A CN114573534B CN 114573534 B CN114573534 B CN 114573534B CN 202210326663 A CN202210326663 A CN 202210326663A CN 114573534 B CN114573534 B CN 114573534B
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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Abstract
本发明涉及医药中间体合成技术领域，提供了一种5‑溴苯并呋喃酮的制备方法。本发明提供的制备方法，包括以下步骤：将2‑羟基‑5‑溴苯乙酮、溴代试剂、催化剂和第一有机溶剂混合，进行溴代反应，得到2‑溴‑1‑(5‑溴‑2‑羟基苯基)‑乙酮；将所述2‑溴‑1‑(5‑溴‑2‑羟基苯基)‑乙酮、有机碱和第二有机溶剂混合，进行环化反应，得到5‑溴苯并呋喃酮。本发明以2‑羟基‑5‑溴苯乙酮为原料，依次进行溴代反应和环化反应制备得到5‑溴苯并呋喃，操作简单，产率收率和纯度较高。进一步的，本发明采用的方法所需的原料更容易得到，反应时间短，更有利于降低制备方法的复杂性。
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 higher. 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
The invention relates to the technical field of synthesis of medical intermediates, in particular to a preparation method of 5-bromobenzofuranone.
Background
Depressive disorder refers to a type of mood disorder with marked and persistent mood drop as a main clinical feature caused by various reasons, and is a chronic mental disease with high morbidity, high recurrence rate and high disability rate, accompanied by different degrees of cognitive and behavioral changes, and part of patients have self-injury and suicide behaviors. Most of the diseases are acute or subacute diseases, the average onset age is 20-30 years, and almost every age group has the possibility of suffering from depressive disorder, and women are more than men. The average course of a single depressive episode is about 16 weeks, with an average 20 weeks following the episode. Without treatment, the course of the disease generally lasts for 6 months or more.
Currently, drug therapy is the primary treatment for depressive disorders. Among the therapeutic drugs, citalopram is used as a 5-hydroxytryptamine reuptake inhibitor (SSRIs), has the advantages of good curative effect, good tolerance and relatively less adverse reaction, is most commonly used in clinic, and is one of the first-line medicaments recommended by various guidelines for depression.
5-Bromobenzofuranone (5-Bromo-3 (2H) -benzofuran-one, C 8H5BrO2) is a Y-endo compound with an aromatic structure, which is one of the very important intermediates for the synthesis of citalopram. There are many documents currently reporting methods for synthesizing 5-bromobenzofuranone. In 2001, SAFDAR HAYAT et al reported that the yield of 5-bromobenzofuranone was not high by oxidizing 4-bromo-2-methylbenzoic acid under NaBrO 3-NaHSO3, 42％(Safdar,H.;Rahman,M.lqbalC.Ernst,B.;An improved method for the synthesis ofΥ-lactones using Sodium Bormate and Sodium Hydrogen Sulfite[J];Tetra.Lett.2001,42:1647-1649);2002, and Jiang national defense et al reported that 5-bromobenzofuranone was prepared from o-xylene by bromination and catalytic oxidation, but the yield of 5-bromobenzofuranone was 69.1%, and was not high as such (Jiang Guofang, wei Guobing, method of synthesis of 5-bromobenzofuranone, J. University of Hunan, J. School of study, 2002,29 (3): 12-15).
In summary, the existing method for preparing 5-bromobenzofuranone has the problem of low yield.
Disclosure of Invention
In view of this, the present invention provides a process for the preparation of 5-bromobenzofuranone. The method provided by the invention is simple to operate and high in yield.
In order to achieve the above object, the present invention provides the following technical solutions:
A process for the preparation of 5-bromobenzofuranone comprising the steps of:
mixing 2-hydroxy-5-bromoacetophenone, a brominating reagent, a catalyst and a first organic solvent, and performing bromination reaction to obtain 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 cyclization reaction to obtain 5-bromobenzofuranone.
Preferably, the brominating reagent comprises any one or more of hydrobromic acid, hypobromous acid, N-bromosuccinimide, bromooctane, liquid bromine, 1, 3-dibromo-5, 5-dimethylhydantoin and benzyl ammonium tribromide.
Preferably, the molar ratio of the 2-hydroxy-5-bromoacetophenone to the brominating reagent is 1 (0.5-5).
Preferably, the catalyst comprises any one or more of an iron-based catalyst, a copper-based catalyst, a zinc-based catalyst and an aluminum-based catalyst;
The mass of the catalyst is 5-10% of the mass of the 2-hydroxy-5-bromoacetophenone.
Preferably, the bromination reaction is carried out at a temperature of 80-100 ℃ for 10-15 hours.
Preferably, the organic base comprises any one or more of triethylamine, pyridine, sodium methoxide, sodium ethoxide and potassium ethoxide.
Preferably, the molar ratio of the 2-hydroxy-5-bromoacetophenone to the organic base is 1 (0.5-3).
Preferably, the temperature of the cyclization reaction is 20-30 ℃ and the time is 4-8 hours.
Preferably, the first organic solvent includes any one or more of 1, 2-dichloroethane, chloroform, dichloromethane, ethyl acetate and butyl acetate.
Preferably, the second organic solvent includes any one of dichloromethane, toluene, benzene, chloroform and ethyl acetate.
The invention provides a preparation method of 5-bromobenzofuranone, which comprises the following steps of mixing 2-hydroxy-5-bromoacetophenone, a bromination reagent, a catalyst and a first organic solvent, carrying out bromination reaction to obtain 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone, mixing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone, organic base and a second organic solvent, and carrying out cyclization reaction to obtain 5-bromobenzofuranone. The invention takes 2-hydroxy-5-bromoacetophenone as a raw material, and sequentially carries out bromination reaction and cyclization reaction to prepare the 5-bromobenzofuran. Experimental data in the embodiment of the invention show that the highest yield of 5-bromobenzofuran is 83.7%, and the yield is higher.
Furthermore, the raw materials and the catalyst required by the method are more easily obtained, the reaction time is short, and the operation is simpler.
Drawings
FIG. 1 is a 1 H-NMR chart of 5-bromobenzofuranone prepared in example 1.
Detailed Description
The invention provides a preparation method of 5-bromobenzofuranone, which comprises the following steps:
mixing 2-hydroxy-5-bromoacetophenone, a brominating reagent, a catalyst and a first organic solvent, and performing bromination reaction to obtain 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 cyclization reaction to obtain 5-bromobenzofuranone.
The preparation raw materials used in the invention are all commercially available unless otherwise specified.
In the invention, the synthetic route of the 5-bromobenzofuranone is shown as a formula 1:
The invention mixes 2-hydroxy-5-bromoacetophenone, a brominating reagent, a catalyst and a first organic solvent for brominating reaction to obtain 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone. In the present invention, the brominating reagent 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), even more 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, iron tribromide, and ferric chloride, more preferably includes iron powder and/or iron tribromide. The copper-based catalyst preferably comprises cuprous bromide and/or cupric bromide, more preferably 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%, more preferably 6 to 9%, even more preferably 6.5 to 8.5%, and most preferably 7 to 8.5% of the mass of 2-hydroxy-5-bromoacetophenone. In the invention, the catalyst of the type is relatively easy to obtain, has better catalytic activity and is beneficial to reducing the complexity of a reaction system. In the present invention, the first organic solvent preferably includes any one or more of 1, 2-dichloroethane, chloroform, methylene chloride, 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 to ethyl acetate is preferably 1 (1-2), more preferably 1 (1-1.5), further preferably 1:1, and when the mixed solvent is a mixed solvent of chloroform and ethyl acetate, the volume ratio of chloroform to ethyl acetate is preferably 1 (1-2), more preferably 1 (1-1.5), further preferably 1:1. The invention preferably adopts a mixed solvent, so that the yield of the bromination reaction can be further improved.
In the 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 even more preferably 1g (10-11) mL. In the invention, the bromination reaction is preferably performed in a reaction kettle, the temperature of the bromination reaction is preferably 80-100 ℃, more preferably 80-95 ℃, further preferably 85-90 ℃, and the time of the bromination reaction is preferably 10-15 h, more preferably 12-15 h, further preferably 13-14 h. The bromination reaction is preferably carried out under stirring conditions. The progress of the bromination reaction is preferably determined by means of gas phase monitoring, which is a means well known to those skilled in the art, which is based on the fact that 2-hydroxy-5-bromoacetophenone is not detected in the reaction system, indicating that the starting material has reacted completely. The invention preferably ensures that bromine atoms react with hydrogen atoms on ketone groups on benzene rings more easily by adjusting the proportion of each raw material, the types and the dosage of the catalyst and the types of the first organic solvents, thereby improving the yield of 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone.
After obtaining 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone, the invention mixes the 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone, organic base and second organic solvent, and carries out cyclization reaction to obtain 5-bromobenzofuranone. The method comprises the steps of cooling a mixture obtained after bromination reaction to room temperature, sequentially carrying out solid-liquid separation and rotary evaporation to obtain a crude product of 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone, adding water to the crude product of 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone for re-dissolution to obtain a crude product solution, sequentially carrying out second organic solvent extraction, water washing, drying and drying agent removal on the crude product to obtain a second organic solvent solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone, and then mixing the second organic solvent solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone with an organic base for cyclization reaction. The invention preferably simplifies the operation steps by taking the second organic solvent as an extraction phase of 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone and simultaneously purifying the 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone and completing the mixing of the raw materials required for the cyclization reaction. In the present invention, the solid-liquid separation is preferably filtration. After the solid-liquid separation, the filtrate part is taken for rotary evaporation, wherein the temperature of the rotary evaporation is preferably 30-42 ℃, more preferably 35-40 ℃, and even more preferably 35-38 ℃. The time of the rotary evaporation is not particularly required in the present invention, so long as the solvent in the filtrate fraction is evaporated to dryness. In the present invention, the second organic solvent preferably includes any one of methylene chloride, toluene, benzene, chloroform and ethyl acetate, more preferably includes any one of methylene chloride, toluene and chloroform. In the present invention, the water washing is preferably performed with brine, preferably a chloride salt solution, preferably a sodium chloride solution. The concentration of the sodium chloride solution is not particularly required, and the invention is based on the effect of realizing washing and obvious layering. In the present invention, the drying desiccant is preferably anhydrous sodium sulfate, and the drying agent is preferably removed by filtration. The temperature of the second organic solvent solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone is preferably reduced to 0-5 ℃, more preferably 0 ℃, and then mixed with an organic base, and the temperature of the second organic solvent solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone is preferably reduced to the above temperature range, so that the reaction intensity can be reduced by adding a base, the reaction safety can be improved, the reaction temperature can be conveniently controlled in a proper range, and the product yield can be improved.
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 to the organic base is preferably 1 (0.5 to 3), more preferably 1 (0.5 to 2), still more preferably 1 (0.5 to 1.5), and most preferably 1 (0.7 to 1.0). In the invention, after the second organic solvent solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone and organic base are mixed, the temperature is raised to the temperature of cyclization reaction under stirring condition to perform reaction. In the present invention, the temperature of the cyclization reaction is preferably 20 to 30 ℃, more preferably 25 to 28 ℃, and the time is preferably 4 to 8 hours, more preferably 5 to 7.5 hours, and further preferably 6 to 7 hours. The progress of the cyclization reaction is preferably determined by means of gas phase monitoring, which is well known to those skilled in the art, based on the fact that 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone is not detected in the reaction system, indicating that the starting material has reacted completely.
After the cyclization reaction is finished, the invention preferably carries out post-treatment on the system after the cyclization reaction to obtain the 5-bromobenzofuran. In the invention, the post-treatment preferably comprises the following steps of quenching, first washing, first separation and first rotary evaporation of the system after the cyclization reaction to obtain a crude product of 5-bromobenzofuran, and sequentially carrying out re-dissolution, second washing, second separation, second rotary evaporation, recrystallization, solid-liquid separation and pumping to obtain the 5-bromobenzofuran. In the present invention, the system after the reaction is preferably quenched with water, the volume ratio of the water for the quenching reaction to the reaction system is preferably (1 to 3): 1, more preferably (1.5 to 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 to 2mol/L, the volume ratio of the brine to the water for the quenching reaction is preferably 1 (0.5 to 1.8), more preferably 1 (0.75 to 1.5), and even more preferably 1 (0.75 to 1.0). The organic phase containing the crude product of the 5-bromobenzofuran is obtained through the first separation, and then the organic phase is subjected to the first rotary evaporation to obtain the crude product of the 5-bromobenzofuran. The temperature of the first rotary steaming is preferably 30-45 ℃, more preferably 35-40 ℃. The temperature of the first rotary evaporation is not particularly required, so that the organic phase is completely evaporated. In the present invention, the solvent for reconstitution preferably adopts ethyl acetate, the volume ratio of the ethyl acetate to the solution is preferably 2:1, the second washing preferably adopts brine, the brine is preferably sodium chloride solution, the concentration of the sodium chloride solution is preferably 1 to 2mol/L, and the volume ratio of the brine to the solvent for reconstitution is preferably (0.5 to 1): 1, more preferably (0.5 to 0.8): 1. The invention obtains an organic phase containing the 5-bromobenzofuran through 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 to 45 ℃, more preferably 35 to 40 ℃, and the volume of the organic phase after the second rotary evaporation is 20 to 30%, more preferably 25 to 30% of the volume before the second rotary evaporation.
In the present invention, the recrystallization method is preferably adding a recrystallization solvent to the second system after rotary evaporation, the recrystallization solvent is preferably petroleum ether, and the volume ratio of the petroleum ether to the second system after rotary evaporation is preferably 0.5:1. In the present invention, after adding a solvent for recrystallization to the second-distilled system, the temperature was lowered to 4 ℃ for recrystallization. In the present invention, the solid-liquid separation is filtration, and the present invention preferably provides a filtration to obtain recrystallized 5-bromobenzofuran. The oil pump is preferred to pump the recrystallized 5-bromobenzofuran to obtain the 5-bromobenzofuran.
The technical solutions of the present invention will be clearly and completely described in the following in connection with the embodiments of the present invention.
Example 1
10G of 2-hydroxy-5-bromoacetophenone is added into a reaction kettle, dissolved in a solvent consisting of 50mL of ethyl acetate and 50mL of 1, 2-dichloroethane, 7.43g of liquid bromine and 0.8g of copper bromide are sequentially added, the temperature of the reaction kettle is heated to 100 ℃ and stirred for reaction for 12 hours, and the reaction progress is monitored in a gas phase. After the reaction is finished, the reaction kettle is cooled to room temperature, solid impurities in the reaction system are removed through filtration, filtrate is obtained, the filtrate is subjected to rotary evaporation at 40 ℃ until the solvent is evaporated to dryness, and a crude product of 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone is obtained. Then, 20mL of water was added to the crude 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone for reconstitution, 60mL of dichloromethane was added for extraction, the dichloromethane phase was separated to obtain a dichloromethane phase, the dichloromethane phase was washed with 60mL of brine, after which the dichloromethane phase was dried over 6g of anhydrous sodium sulfate, and the drying agent was removed by filtration to obtain a dichloromethane solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone, which was directly used for the next reaction.
The methylene dichloride solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone is cooled to 0 ℃, 4.7g of triethylamine is added dropwise, the reaction system is heated to 25 ℃, the reaction is stirred for 6 hours, and the reaction progress is monitored in a gas phase. After the reaction, 30mL of water was added to the reaction system, followed by washing with 40mL of brine, and after the washing was completed, the methylene chloride phase was separated from the aqueous phase. The dichloromethane phase was distilled off at 40 ℃ until the solvent was distilled off completely, giving a crude 5-bromobenzofuranone product. The crude product is redissolved with 80mL of ethyl acetate, then washed with 40mL of brine, an organic phase is separated from an aqueous phase, the organic phase is concentrated to 25% of the original volume by rotary evaporation at 40 ℃, then 20mL of petroleum ether is added into the solution after rotary evaporation for recrystallization, then the solid is collected by filtration, and the solid is pumped by an oil pump to obtain a pure product of 5-bromobenzofuranone. Calculated and determined, the yield of 5-bromobenzofuranone was 83.6% and the purity was 99.4%. FIG. 1 is a 1 H-NMR chart of 5-bromobenzofuranone prepared in example 1. As can be seen from FIG. 1, the characteristic peaks of 5-bromobenzofuranone are evident, which indicates that the purity of 5-bromobenzofuranone prepared by the preparation method of example 1 is high.
Example 2
20G of 2-hydroxy-5-bromoacetophenone is added into a reaction kettle, the mixture is dissolved in a solvent consisting of 100mL of ethyl acetate and 100mL of chloroform, 14.86g of hydrobromic acid and 1.5g of iron powder are sequentially added, the temperature of the reaction kettle is heated to 80 ℃ and stirred for reaction for 15 hours, and the reaction progress is monitored in a gas phase. After the reaction is finished, the reaction kettle is cooled to room temperature, solid impurities in the reaction system are removed through filtration, filtrate is obtained, the filtrate is subjected to rotary evaporation at 35 ℃ until the solvent is evaporated to dryness, and a crude product of 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone is obtained. Then adding 40mL of water into the crude product of 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone to redissolve the crude product, adding 120mL of chloroform for extraction, layering to obtain a chloroform phase, washing the chloroform phase with 120mL of brine, drying the chloroform phase with 12g of anhydrous sodium sulfate, and filtering to remove a drying agent to obtain a chloroform solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone, wherein the solution is directly used for the next reaction.
The chloroform solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone is cooled to 0 ℃, 9.4g of pyridine is added dropwise, the reaction system is heated to 20 ℃, the reaction is stirred for 8 hours, and the reaction progress is monitored in a gas phase. After the reaction is finished, 60mL of water is added into the reaction system for quenching, 80mL of saline water is added for washing, and after the washing is finished, the chloroform phase is separated from the water phase. And (3) carrying out rotary evaporation on the chloroform phase at 35 ℃ until the solvent is completely rotary evaporated, thus obtaining a 5-bromobenzofuranone crude product. The crude product is redissolved by 160mL of ethyl acetate, then 80mL of brine is used for washing, an organic phase and a water phase are separated, the organic phase is concentrated to 20% of the original volume by rotary evaporation at 35 ℃,40 mL of petroleum ether is added into the solution after rotary evaporation for recrystallization, then the solid is collected by filtration, and the solid is pumped by an oil pump to obtain the pure 5-bromobenzofuranone. Calculated and measured, the yield of 5-bromobenzofuranone was 82.7% and the purity was 99.1%.
Example 3
30G of 2-hydroxy-5-bromoacetophenone is added into a reaction kettle, dissolved in a solvent consisting of 150mL of butyl acetate and 150mL of dichloromethane, 22.3g N-bromosuccinimide and 2.5g of ferric tribromide are sequentially added, the temperature of the reaction kettle is heated to 85 ℃ and stirred for reaction for 13 hours, and the reaction progress is monitored in a gas phase. After the reaction is finished, the reaction kettle is cooled to room temperature, solid impurities in the reaction system are removed through filtration, filtrate is obtained, the filtrate is subjected to rotary evaporation at 40 ℃ until the solvent is evaporated to dryness, and a crude product of 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone is obtained. Then, 60mL of water was added to the crude 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone to re-dissolve it, 180mL of toluene was added to extract it, the toluene phase was separated to obtain a toluene phase, the toluene phase was washed with 180mL of brine, after which the toluene phase was dried over 18g of anhydrous sodium sulfate, and the drying agent was removed by filtration to obtain a toluene solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone, which was directly used for the next reaction.
The toluene solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone is cooled to 0 ℃, 14.2g of sodium methoxide is dropwise added, the reaction system is heated to 26 ℃, the reaction is stirred for 7h, and the reaction progress is monitored in a gas phase. After the reaction, 180mL of water is added into the reaction system for quenching, 120mL of saline water is added for washing, and after the washing is finished, the toluene phase is separated from the water phase. The toluene phase was distilled at 40 ℃ until the solvent was distilled completely, giving a crude 5-bromobenzofuranone product. The crude product is redissolved by 240mL of ethyl acetate, then is washed by 120mL of brine, an organic phase and an aqueous phase are separated, the organic phase is concentrated to 30 percent of the original volume by rotary evaporation at 40 ℃, 60mL of petroleum ether is added into the solution after rotary evaporation for recrystallization, then the solid is filtered and collected, and the solid is pumped by an oil pump to obtain the pure 5-bromobenzofuranone. Calculated and measured, the yield of 5-bromobenzofuranone was 83.1% and the purity was 98.6%.
Example 4
40G of 2-hydroxy-5-bromoacetophenone is added into a reaction kettle, dissolved in a solvent consisting of 200mL of butyl acetate and 200mL of dichloroethane, 29.7g of 1, 3-dibromo-5, 5-dimethylhydantoin and 3g of zinc chloride are sequentially added, the temperature of the reaction kettle is heated to 90 ℃ and stirred for reaction for 13h, and the reaction progress is monitored in a gas phase. After the reaction is finished, the reaction kettle is cooled to room temperature, solid impurities in the reaction system are removed through filtration, filtrate is obtained, the filtrate is subjected to rotary evaporation at 38 ℃ until the solvent is evaporated to dryness, and a crude product of 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone is obtained. Then 80mL of water was added to the crude 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone to re-dissolve it, 240mL of ethyl acetate was added to extract it, the ethyl acetate phase was separated to give an ethyl acetate phase, the ethyl acetate phase was washed with 240mL of brine, after which the toluene phase was dried over 25g of anhydrous sodium sulfate and the drying agent was removed by filtration to give an ethyl acetate solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone, which was directly used for the next reaction.
The ethyl acetate solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone is cooled to 0 ℃, 19g of sodium ethoxide is added dropwise, the reaction system is heated to 28 ℃, the reaction is stirred for 5h, and the reaction progress is monitored in a gas phase. After the reaction, 120mL of water was added to the reaction system, followed by washing with 160mL of brine, and after the washing was completed, the ethyl acetate phase was separated from the aqueous phase. The ethyl acetate phase was rotary distilled at 38 ℃ until the solvent was completely rotary distilled to give a crude 5-bromobenzofuranone product. The crude product is redissolved by 320mL of ethyl acetate, then 160mL of brine is used for washing, an organic phase and a water phase are separated, the organic phase is concentrated to 25% of the original volume by rotary evaporation at 40 ℃, 80mL of petroleum ether is added into the solution after rotary evaporation for recrystallization, then the solid is collected by filtration, and the solid is pumped by an oil pump to obtain the pure 5-bromobenzofuranone. Calculated and measured, the yield of 5-bromobenzofuranone was 82.1% and the purity was 98.2%.
Example 5
50G of 2-hydroxy-5-bromoacetophenone is added into a reaction kettle, dissolved in 500ml of 1, 2-dichloroethane, 37g of bromooctane and 4g of aluminum chloride are sequentially added, the temperature of the reaction kettle is heated to 95 ℃ and stirred for reaction for 12 hours, and the reaction progress is monitored in a gas phase. After the reaction is finished, the reaction kettle is cooled to room temperature, solid impurities in the reaction system are removed through filtration, filtrate is obtained, the filtrate is subjected to rotary evaporation at 40 ℃ until the solvent is evaporated to dryness, and a crude product of 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone is obtained. Then adding 100mL of water into the crude product of 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone to re-dissolve the crude product, adding 300mL of chloroform for extraction, layering to obtain a chloroform phase, washing the chloroform phase with 300mL of saline, drying the chloroform phase with 30g of anhydrous sodium sulfate, and filtering to remove a drying agent to obtain a chloroform solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone, wherein the solution is directly used for the next reaction.
The chloroform solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone is cooled to 0 ℃, 14g of potassium ethoxide is added dropwise, the reaction system is heated to 25 ℃, the reaction is stirred for 7h, and the reaction progress is monitored in a gas phase. After the reaction is finished, 150mL of water is added into the reaction system for quenching, 200mL of saline water is added for washing, and after the washing is finished, the chloroform phase is separated from the water phase. And (3) carrying out rotary evaporation on the chloroform phase at 40 ℃ until the solvent is completely rotary evaporated, thus obtaining a 5-bromobenzofuranone crude product. The crude product is redissolved by 400mL of ethyl acetate, then 200mL of brine is used for washing, an organic phase and a water phase are separated, the organic phase is concentrated to 20% of the original volume by rotary evaporation at 40 ℃, then 100mL of petroleum ether is added into the solution after rotary evaporation for recrystallization, then the solid is collected by filtration, and the solid is pumped by an oil pump to obtain the pure 5-bromobenzofuranone. Calculated and measured, the yield of 5-bromobenzofuranone was 82.7% and the purity was 98.3%.
Example 6
100G of 2-hydroxy-5-bromoacetophenone is added into a reaction kettle, dissolved in 500mL of solvent consisting of ethyl acetate and 500mL of 1, 2-dichloroethane, 74.3g of liquid bromine and 8g of copper bromide are sequentially added, the temperature of the reaction kettle is heated to 100 ℃ and stirred for reaction for 10 hours, and the reaction progress is monitored in a gas phase. After the reaction is finished, the reaction kettle is cooled to room temperature, solid impurities in the reaction system are removed through filtration, filtrate is obtained, the filtrate is subjected to rotary evaporation at 40 ℃ until the solvent is evaporated to dryness, and a crude product of 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone is obtained. Then 200mL of water was added to the crude 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone to re-dissolve it, 600mL of dichloromethane was added to extract it, the dichloromethane phase was separated to obtain a dichloromethane phase, the dichloromethane phase was washed with 600mL of brine, after which the dichloromethane phase was dried over 60g of anhydrous sodium sulfate, and the drying agent was removed by filtration to obtain a dichloromethane solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone, which was directly used for the next reaction.
The methylene dichloride solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone is cooled to 0 ℃, 47.1g of triethylamine is added dropwise, the reaction system is heated to 25 ℃, the reaction is stirred for 6 hours, and the reaction progress is monitored in a gas phase. After the reaction, 300mL of water was added to the reaction system, followed by washing with 400mL of brine, and after the washing was completed, the methylene chloride phase was separated from the aqueous phase. The dichloromethane phase was distilled off at 40 ℃ until the solvent was distilled off completely, giving a crude 5-bromobenzofuranone product. The crude product is redissolved by 800mL of ethyl acetate, then 400mL of brine is used for washing, an organic phase and an aqueous phase are separated, the organic phase is concentrated to 25% of the original volume by rotary evaporation at 40 ℃, 200mL of petroleum ether is added into the solution after rotary evaporation for recrystallization, then the solid is collected by filtration, and the solid is pumped by an oil pump to obtain the pure 5-bromobenzofuranone. Calculated and determined, the yield of 5-bromobenzofuranone was 83.7% and the purity was 99.3%.
Example 7
1000G of 2-hydroxy-5-bromoacetophenone is added into a reaction kettle, dissolved in 5000mL of a solvent consisting of ethyl acetate and 5000mL of 1, 2-dichloroethane, 743g of liquid bromine and 80g of copper bromide are sequentially added, the temperature of the reaction kettle is heated to 100 ℃ and stirred for reaction for 10 hours, and the reaction progress is monitored in a gas phase. After the reaction is finished, the reaction kettle is cooled to room temperature, solid impurities in the reaction system are removed through filtration, filtrate is obtained, the filtrate is subjected to rotary evaporation at 40 ℃ until the solvent is evaporated to dryness, and a crude product of 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone is obtained. 2000mL of water was then added to the crude 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone to re-dissolve it, 6000mL of dichloromethane was added for extraction, the dichloromethane phase was separated to give a dichloromethane phase, the dichloromethane phase was washed with 6000mL of brine, after which the dichloromethane phase was dried over 600g of anhydrous sodium sulfate and the drying agent was removed by filtration to give a dichloromethane solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone which was directly used for the next reaction.
The dichloromethane solution containing 2-bromo-1- (5-bromo-2-hydroxyphenyl) -ethanone is cooled to 0 ℃, 471g of triethylamine is added dropwise, the reaction system is heated to 25 ℃, the reaction is stirred for 6 hours, and the reaction progress is monitored in a gas phase. After the reaction, 3000mL of water was added to the reaction system, followed by washing with 4000mL of brine, and after the washing was completed, the methylene chloride phase was separated from the aqueous phase. The dichloromethane phase was distilled off at 40 ℃ until the solvent was distilled off completely, giving a crude 5-bromobenzofuranone product. The crude product is redissolved with 8000mL of ethyl acetate, then 4000mL of brine is used for washing, an organic phase and an aqueous phase are separated, the organic phase is concentrated to 25% of the original volume by rotary evaporation at 40 ℃, then 2000mL of petroleum ether is added into the solution after rotary evaporation for recrystallization, then the solid is collected by filtration, and the solid is pumped by an oil pump to obtain the pure 5-bromobenzofuranone. Calculated and measured, the yield of 5-bromobenzofuranone was 83.5% and the purity was 99.5%.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (5)
1. A process for the preparation of 5-bromobenzofuranone, comprising the steps of:
mixing 2-hydroxy-5-bromoacetophenone, a brominating reagent, a catalyst and a first organic solvent, and performing bromination reaction to obtain 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 cyclization reaction to obtain 5-bromobenzofuranone;
after the cyclization reaction is finished, carrying out post-treatment on the system after the cyclization reaction;
The brominating reagent comprises N-bromosuccinimide, liquid bromine or 1, 3-dibromo-5, 5-dimethyl hydantoin;
the molar ratio of the 2-hydroxy-5-bromoacetophenone to the brominating reagent is 1 (0.5-1);
the catalyst comprises copper bromide, zinc chloride or ferric bromide;
the mass of the catalyst is 5-10% of that of 2-hydroxy-5-bromoacetophenone;
The temperature of the bromination reaction is 85-100 ℃ and the time is 12-13 h;
the first organic solvent comprises any one or more of 1, 2-dichloroethane, chloroform, dichloromethane, ethyl acetate and butyl acetate;
The post-treatment comprises the following steps of quenching, first washing, first separation and first rotary evaporation of the system after the cyclization reaction to obtain a crude product of 5-bromobenzofuran, and sequentially carrying out re-dissolution, second washing, second separation, second rotary evaporation, recrystallization, solid-liquid separation and pumping.
2. The method of claim 1, wherein the organic base comprises any one or more of triethylamine, pyridine, sodium methoxide, sodium ethoxide, and potassium ethoxide.
3. The preparation method according to claim 1 or 2, wherein the molar ratio of the 2-hydroxy-5-bromoacetophenone to the organic base is 1 (0.5-3).
4. The method according to claim 1, wherein the cyclization reaction is carried out at a temperature of 20 to 30 ℃ for a time of 4 to 8 hours.
5. The production method according to claim 1, wherein the second organic solvent comprises any one of methylene chloride, toluene, benzene, chloroform and ethyl acetate.
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| JP2001072638A (en) * | 1999-09-01 | 2001-03-21 | Nippon Kayaku Co Ltd | PRODUCTION OF alpha-BROMOALKYLPHENONES |
| ES2551293T3 (en) * | 2004-03-24 | 2015-11-17 | Abbvie Inc. | Tricyclic pyrazole kinase inhibitors |
| CN101928208B (en) * | 2010-08-05 | 2013-06-05 | 河北大学 | Method of synthesizing alpha-brominated ketone compound by hydrogen peroxide oxidizing and brominating method |
| CN101948374B (en) * | 2010-08-05 | 2013-08-14 | 河北大学 | Method for synthesizing alpha-bromoketone and coproducing bromohydrocarbon |
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| CN103755540A (en) * | 2013-12-19 | 2014-04-30 | 安徽瑞赛生化科技有限公司 | Synthesis method of 2-chloro-3'-bromoacetophenone |
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| US5821388A (en) * | 1996-03-28 | 1998-10-13 | Sumitomo Seika Chemical Co., Ltd. | Process for preparing α-haloacetophenone derivative |
| WO2021185291A1 (en) * | 2020-03-17 | 2021-09-23 | 南京明德新药研发有限公司 | Proteolysis regulator and method for using same |
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