A method for synthesizing 2-bromo-6-hydroxybenzaldehyde
By using 2,6-dibromobenzaldehyde as the raw material and combining aldehyde protection with the bromine exchange reaction of an isopropyl Grignard reagent, the problems of low yield and harsh reaction conditions in the existing technology are solved, and efficient synthesis of 2-bromo-6-hydroxybenzaldehyde is achieved, which is suitable for industrial production.
Patent Information
- Application Number
- CN202211714962.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2022-12-27
- Publication Date
- 2025-09-05
- Estimated Expiration
- 2042-12-27
AI Technical Summary
Existing methods for synthesizing 2-bromo-6-hydroxybenzaldehyde have problems such as low yield, poor reaction selectivity, and harsh reaction conditions, especially the use of dangerous organolithium reagents and ultra-low temperature conditions.
Using 2,6-dibromobenzaldehyde as the raw material, through aldehyde protection, boration and hydrogen peroxide oxidation, using 1,3-propylene glycol as the aldehyde protecting group and isopropyl Grignard reagent as the bromine exchange reagent, ultra-low temperature reaction is avoided and the selectivity of the bromination reaction is enhanced.
The method achieves high-yield synthesis of 2-bromo-6-hydroxybenzaldehyde, avoids energy consumption and use of hazardous reagents in low-temperature reactions, and is suitable for industrial production.
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Abstract
Description
Technical Field
[0001] The invention relates to a method for synthesizing 2-bromo-6-hydroxybenzaldehyde, belonging to the technical field of organic synthesis. Background Art
[0002] 2-Bromo-6-hydroxybenzaldehyde is an important organic compound, mainly used as an intermediate for physiologically active compounds such as medicines or pesticides. It is a widely used organic building block compound. Its structure contains bromine, aldehyde group, and phenolic hydroxyl group, all of which can be added or replaced by other functional groups.
[0003] At present, there are four main methods for synthesizing 2-bromo-6-hydroxybenzaldehyde: (1) using m-bromophenol as a raw material, reacting it with chloroform under strong alkaline conditions to produce 2-bromo-6-hydroxybenzaldehyde with a yield of 35%; (2) using m-bromophenol as a raw material, reacting it with N,N-diethylchloroformamide under the action of sodium hydride for protection reaction, then reacting it with lithium diisopropylamide at -78°C, and then reacting it with N,N-dimethylformamide to form an aldehyde group, and finally hydrolyzing it with acid to obtain 2-bromo-6- Hydroxybenzaldehyde; (3) Using m-fluorobromobenzene as the raw material, it reacts with lithium diisopropylamide at -78°C, and then reacts with N,N-dimethylformamide to form an aldehyde group, and then reacts with sodium methoxide to replace the fluorine with methoxy, and finally demethylates with boron tribromide to generate 2-bromo-6-hydroxybenzaldehyde; (4) Using 2-methoxybenzaldehyde as the raw material, it first protects the aldehyde group, and then uses tert-butyl lithium to extract the hydrogen to form bromine, and finally demethylates with boron tribromide to obtain 2-bromo-6-hydroxybenzaldehyde, with a total yield of <50%.
[0004] Among the above-mentioned synthesis methods, the first method, although short, has low yields and poor reaction selectivity. The second, third, and fourth methods all have longer routes, require the use of dangerous organolithium reagents and harsh ultra-low temperature, anhydrous, and oxygen-free conditions, and also have low overall reaction yields. Summary of the Invention
[0005] In order to overcome the above-mentioned defects, the present invention provides an improved method for synthesizing 2-bromo-6-hydroxybenzaldehyde. 2,6-dibromobenzaldehyde is used as the raw material, and after aldehyde group protection, boronization and hydrogen peroxide oxidation, 2-bromo-6-hydroxybenzaldehyde is generated. The method has short steps, high yield and mild reaction conditions. 1,3-propylene glycol is used as the aldehyde group protecting group, and an isopropyl Grignard reagent is used as the bromine exchange reagent. Both technical measures increase the steric hindrance of the bromination reaction. Even if the Grignard reagent equivalent is increased, it still has good selectivity. Only one bromine atom is exchanged, and the occurrence of two bromine atom exchange side reactions does not exceed 5%. At the same time, this method avoids the problems of low yield and harsh reaction conditions of the literature method, has potential technical advantages, and is suitable for industrial scale-up production.
[0006] The process for synthesizing 2-bromo-6-hydroxybenzaldehyde of the present invention comprises the following steps:
[0007]
[0008] Step A: 2,6-dibromobenzaldehyde, toluene, 1,3-propylene glycol and concentrated sulfuric acid were heated to reflux and water was separated. After the reaction was completed, the mixture was cooled to room temperature, sodium methoxide was added for neutralization, and the mixture was distilled under reduced pressure to obtain intermediate A;
[0009] Step B: Cool Intermediate A and tetrahydrofuran to -10°C to 5°C, add isopropyl Grignard reagent, complete Grignard exchange, then add trialkyl borate and incubate for reaction; quench with hydrochloric acid, extract with an organic solvent, separate the liquids, and evaporate to dryness to obtain Intermediate B;
[0010] Step C: adding intermediate B to an alcohol / water mixed solvent and a copper catalyst, and adding hydrogen peroxide to react; quenching with a sodium thiosulfate solution, extracting and separating the liquids, adding an organic solvent to slurry, and filtering to obtain 2-bromo-6-hydroxybenzaldehyde.
[0011] Furthermore, in step A, the sodium methoxide is sodium methoxide solid or 30% sodium methoxide methanol solution.
[0012] Furthermore, in step A, the mass ratio of 2,6-dibromobenzaldehyde to concentrated sulfuric acid is 1:0.01-0.1; and the molar ratio of 2,6-dibromobenzaldehyde to 1,3-propylene glycol is 1:1-2.5.
[0013] Furthermore, in step B, the molar ratio of intermediate A, isopropyl Grignard reagent and trialkyl borate is 1:1-2.5:1-2.5.
[0014] Furthermore, in step B, the organic solvent is ethyl acetate, dichloromethane, diethyl ether, toluene or methyl tert-butyl ether.
[0015] Furthermore, in step B, the alcohol / water mixed solvent is a methanol / water mixed solvent or an ethanol / water mixed solvent.
[0016] Furthermore, in step C, the mass ratio of alcohol to water in the alcohol / water mixed solvent is 1:0.75-1.25.
[0017] Furthermore, in step C, the copper catalyst is cuprous chloride, cuprous bromide or cuprous iodide.
[0018] Furthermore, in step C, the molar ratio of intermediate B, copper catalyst and hydrogen peroxide is 1:0.005-0.05:1-1.5.
[0019] Furthermore, in step C, the organic solvent is n-hexane or n-heptane.
[0020] Advantageous Effects of the Invention
[0021] The process of the present invention is simple to operate, does not require an ultra-low temperature reaction condition of -78°C, saves energy, does not use dangerous reagents such as tert-butyl lithium that is prone to spontaneous combustion, and has safety assurance.
[0022] The present invention adopts 1,3-propylene glycol as an aldehyde protecting group and an isopropyl Grignard reagent as a bromine exchange reagent. Both technical measures increase the steric hindrance of the bromination reaction. Even if the equivalent of the Grignard reagent is increased, the method still has good selectivity. Only one bromine atom is exchanged, and the occurrence of two bromine atom exchange side reactions does not exceed 5%.
[0023] The present invention avoids the shortcomings of other literature methods such as low yield, harsh reaction conditions, and high process risk level, has potential technical advantages, and is suitable for industrial scale-up production. BRIEF DESCRIPTION OF THE DRAWINGS
[0024] Figure 1 This is the HNMR spectrum of the 2-bromo-6-hydroxybenzaldehyde product in Example 1. Specific embodiments
[0025] Example 1
[0026] Step A: 26.4 g of 2,6-dibromobenzaldehyde, 11.4 g of 1,3-propylene glycol, 80 g of toluene and 0.8 g of concentrated sulfuric acid were added to a reaction flask, stirred and heated to reflux to separate water. After the separation was completed, sampling was performed for detection. If the reaction of 2,6-dibromobenzaldehyde was complete, the temperature was lowered to room temperature, and 3 g of 30% sodium methoxide methanol solution was slowly added to the reaction flask. Stirring was continued for 0.5 hour, sampling was performed, and pH was detected to be ≥7 after adding water. The product was distilled under reduced pressure. Toluene was first evaporated off using a rotary evaporator, and then distilled under reduced pressure using an oil pump. The fractions at 115°C to 125°C were collected to obtain 29.7 g of intermediate A as a colorless oil with a GC purity of 99.1% and a yield of 96%.
[0027] Step B: Add 31.0 g of intermediate A and 124 g of tetrahydrofuran to the reaction flask, under nitrogen protection, stir and cool to -5 ° C, control the temperature from -5 ° C to 0 ° C, add 1 mol / L isopropyl magnesium chloride tetrahydrofuran solution 115 ml, complete the addition, keep warm and stir for 1 hour, take samples for detection, Grignard exchange is complete, control the temperature from -10 ° C to -5 ° C, add 13.5 g of trimethyl borate, complete the addition, keep warm and stir for 1 hour, take samples for detection, the reaction is complete, control the temperature from 5 ° C to 25 ° C, add 10% dilute hydrochloric acid to quench the reaction, measure the pH of the aqueous layer = 4-5, quenching is complete, continue stirring at room temperature for 1 hour, add 80 g of ethyl acetate and extract twice (80 g * 2 times), separate the liquid, and return the organic layer to the reaction The solvent was evaporated, 90 g of ethanol, 90 g of water, and 0.9 g of cuprous iodide were added to the bottle, stirred, and the temperature was controlled at 20°C to 25°C. 16.3 g of 25% hydrogen peroxide was slowly added dropwise. After the addition was complete, the reaction was kept warm for 30 minutes, and sampling was performed. After the reaction was complete, 5% aqueous sodium thiosulfate solution was added dropwise to quench the reaction. The aqueous layer was sampled and tested with starch potassium iodide paper to ensure that the product did not turn blue. After quenching, 80 g of ethyl acetate was added and extracted twice (80 g * 2 times), the liquid was separated, and the solvent of the organic layer was evaporated. 80 g of n-heptane was added to the bottle, stirred for 1 hour, and filtered to obtain 17.1 g of 2-bromo-6-hydroxybenzaldehyde as a white solid product with a GC purity of 99.8% and a yield of 85%.
[0028] Example 2
[0029] Step A: 26.4 g of 2,6-dibromobenzaldehyde, 19.0 g of 1,3-propylene glycol, 130 g of toluene, and 1.32 g of concentrated sulfuric acid were added to a reaction flask, stirred and heated to reflux to separate water. After the separation was completed, sampling was performed for detection. If the reaction of 2,6-dibromobenzaldehyde was complete, the temperature was lowered to room temperature, and 5 g of 30% sodium methoxide methanol solution was slowly added to the reaction flask. Stirring was continued for 0.5 hour, sampling was performed, and pH was detected to be ≥7 after adding water. The product was distilled under reduced pressure. Toluene was first evaporated off using a rotary evaporator, and then distilled under reduced pressure using an oil pump. The fractions at 115°C to 125°C were collected to obtain 30.4 g of intermediate A as a colorless oil with a GC purity of 99.3% and a yield of 98%.
[0030] Step B: Add 30.4 g of intermediate A and 150 g of tetrahydrofuran to the reaction flask, under nitrogen protection, stir and cool to -5 ° C, control the temperature from -5 ° C to 0 ° C, add 216 ml of 1 mol / L isopropyl magnesium chloride tetrahydrofuran solution dropwise, complete the addition, keep warm and stir for 1 hour, take samples for detection, Grignard exchange is completed, control the temperature from -10 ° C to -5 ° C, add 25.5 g of trimethyl borate dropwise, complete the addition, keep warm and stir for 1 hour, take samples for detection, the reaction is complete, control the temperature from 5 ° C to 25 ° C, add 10% dilute hydrochloric acid to quench the reaction, measure the pH of the aqueous layer = 4-5, quenching is complete, continue stirring at room temperature for 1 hour, add 80 g of ethyl acetate and extract twice (80 g * 2 times), separate the liquid, and return the organic layer to the reaction The solvent was evaporated, 90 g of ethanol, 90 g of water, and 0.9 g of cuprous iodide were added to the bottle, stirred, and the temperature was controlled at 20°C to 25°C. 16.3 g of 25% hydrogen peroxide was slowly added dropwise. After the addition was complete, the reaction was kept warm for 30 minutes, and sampling was performed. After the reaction was complete, 5% aqueous sodium thiosulfate solution was added dropwise to quench the reaction. The aqueous layer was sampled and tested with starch potassium iodide paper to ensure that the product did not turn blue. After quenching, 80 g of ethyl acetate was added and extracted twice (80 g * 2 times), the liquid was separated, and the solvent of the organic layer was evaporated. 80 g of n-heptane was added to the bottle, stirred for 1 hour, and filtered to obtain 16.4 g of 2-bromo-6-hydroxybenzaldehyde as a white solid product with a GC purity of 99.6% and a yield of 83%.
[0031] Example 3
[0032] Step A: 26.4 g of 2,6-dibromobenzaldehyde, 15.2 g of 1,3-propylene glycol, 150 g of toluene, and 1.32 g of concentrated sulfuric acid were added to a reaction flask, stirred and heated to reflux to separate water. After the separation was completed, sampling was performed for detection. If the reaction of 2,6-dibromobenzaldehyde was complete, the temperature was lowered to room temperature, and 5 g of 30% sodium methoxide methanol solution was slowly added to the reaction flask. Stirring was continued for 0.5 hour, sampling was performed, and the pH was detected to be ≥7 after adding water. The product was distilled under reduced pressure. Toluene was first evaporated off using a rotary evaporator, and then distilled under reduced pressure using an oil pump. The fractions at 115°C to 125°C were collected to obtain 30.1 g of intermediate A as a colorless oil with a GC purity of 99.1% and a yield of 97%.
[0033] Step B: Add 30.1g of intermediate A and 120g of tetrahydrofuran to the reaction flask, under nitrogen protection, stir and cool to -5°C, control the temperature from -5°C to 0°C, add 146ml of 1mol / L isopropylmagnesium bromide tetrahydrofuran solution dropwise, complete the addition, keep warm and stir for 1 hour, take samples for detection, Grignard exchange is completed, control the temperature from -10°C to -5°C, add 15.1g of trimethyl borate dropwise, complete the addition, keep warm and stir for 1 hour, take samples for detection, the reaction is complete, control the temperature from 5°C to 25°C, add 10% dilute hydrochloric acid dropwise to quench the reaction, measure the pH of the aqueous layer = 4-5, quenching is complete, continue stirring at room temperature for 1 hour, add 80g of ethyl acetate and extract twice (80g*2 times), separate the liquid, and return the organic layer to the reaction The solvent was evaporated, 80 g of ethanol, 80 g of water, and 0.5 g of cuprous chloride were added to the bottle, stirred, and the temperature was controlled at 20°C to 25°C. 17.2 g of 25% hydrogen peroxide was slowly added dropwise. After the addition was complete, the reaction was kept warm for 30 minutes, and sampling was performed. After the reaction was complete, 5% aqueous sodium thiosulfate solution was added dropwise to quench the reaction. The aqueous layer was sampled and tested with starch potassium iodide paper to ensure that the product did not turn blue. After quenching, 80 g of ethyl acetate was added and extracted twice (80 g * 2 times), and the liquid was separated. The solvent in the organic layer was evaporated, 40 g of n-heptane was added to the bottle, stirred for 1 hour, and filtered to obtain 14.6 g of 2-bromo-6-hydroxybenzaldehyde as a white solid product with a GC purity of 99.2% and a yield of 75%.
[0034] Example 4
[0035] Step A: 26.4 g of 2,6-dibromobenzaldehyde, 19.0 g of 1,3-propylene glycol, 105 g of toluene, and 2.6 g of concentrated sulfuric acid were added to a reaction flask, stirred and heated to reflux to separate water. After the separation was completed, sampling was performed for detection. If the reaction of 2,6-dibromobenzaldehyde was complete, the temperature was lowered to room temperature, and 10 g of 30% sodium methoxide methanol solution was slowly added to the reaction flask. Stirring was continued for 0.5 hour, sampling was performed, and pH was detected to be ≥7 after adding water. The product was distilled under reduced pressure. Toluene was first evaporated off using a rotary evaporator, and then distilled under reduced pressure using an oil pump. The fractions at 115°C to 125°C were collected to obtain 29.4 g of intermediate A as a colorless oil with a GC purity of 99.2% and a yield of 95%.
[0036] Step B: Add 30.1g of intermediate A and 150g of tetrahydrofuran to the reaction flask, under nitrogen protection, stir and cool to -5°C, control the temperature from -5°C to 0°C, add 75ml of 2mol / L isopropylmagnesium chloride tetrahydrofuran solution dropwise, complete the addition, keep warm and stir for 1 hour, take samples for detection, Grignard exchange is completed, control the temperature from -10°C to -5°C, add 15.6g of trimethyl borate dropwise, complete the addition, keep warm and stir for 1 hour, take samples for detection, the reaction is complete, control the temperature from 5°C to 25°C, add 10% dilute hydrochloric acid to quench the reaction, measure the pH of the aqueous layer = 4-5, quenching is complete, continue stirring at room temperature for 1 hour, add 80g of ethyl acetate and extract twice (80g*2 times), separate the liquid, and return the organic layer to the reaction flask , evaporate the solvent, add 80g of ethanol, 100g of water, 0.6g of cuprous iodide to the bottle, stir, control the temperature at 20℃ to 25℃, slowly add 25% hydrogen peroxide 20.4g, after the addition is complete, keep warm for 30 minutes, take samples for detection, after the reaction is complete, add 5% sodium thiosulfate aqueous solution to quench the reaction, sample the water layer, detect with starch potassium iodide paper that it does not turn blue, quenching is complete, add 80g of ethyl acetate, extract twice (80g*2 times), separate the liquids, evaporate the solvent of the organic layer, add 50g of n-heptane to the bottle, stir for 1 hour, filter, and obtain 15.9g of 2-bromo-6-hydroxybenzaldehyde as a white solid product with GC purity of 99.5% and a yield of 79%.
[0037] The basic principles, main features and advantages of the present invention are shown and described above. It should be understood by those skilled in the art that the present invention is not limited to the above embodiments. The above embodiments and descriptions are merely illustrative of the principles of the present invention. Various changes and modifications may be made to the present invention without departing from the spirit and scope of the present invention, and such changes and modifications fall within the scope of the invention as claimed.
Claims
1. A process for synthesizing 2-bromo-6-hydroxybenzaldehyde, characterized in that: The following steps are involved: Step A: 26.4 g of 2,6-dibromobenzaldehyde, 11.4 g of 1,3-propylene glycol, 80 g of toluene, and 0.8 g of concentrated sulfuric acid were added to a reaction flask, stirred, heated to reflux, and water was separated. After the separation was completed, sampling was performed for detection. If the reaction of 2,6-dibromobenzaldehyde was complete, the temperature was lowered to room temperature, and 3 g of 30% sodium methoxide methanol solution was slowly added to the reaction flask. Stirring was continued for 0.5 hour, sampling was performed, and pH was tested to be ≥7 after adding water. The mixture was distilled under reduced pressure. Toluene was first evaporated using a rotary evaporator, and then distilled under reduced pressure using an oil pump. The fractions at 115°C to 125°C were collected to obtain a colorless oily substance, 2-(2,6-dibromophenyl)-1,3-dioxane. Step B: 31.0 g of 2-(2,6-dibromophenyl)-1,3-dioxane and 124 g of tetrahydrofuran were added to the reaction flask, and under nitrogen protection, the temperature was stirred and cooled to -5 ° C. The temperature was controlled from -5 ° C to 0 ° C. 115 mL of 1 mol / L isopropyl magnesium chloride tetrahydrofuran solution was added dropwise. After the addition was complete, the mixture was stirred for 1 hour, and the sample was taken for detection. After the Grignard exchange was completed, the temperature was controlled from -10 ° C to -5 ° C. 13.5 g of trimethyl borate was added dropwise. After the addition was complete, the mixture was stirred for 1 hour, and the sample was taken for detection. After the reaction was complete, the temperature was controlled from 5 ° C to 25 ° C. 10% dilute hydrochloric acid was added dropwise to quench the reaction. The pH of the aqueous layer was measured to be 4-5. After the quenching was completed, the mixture was stirred at room temperature for 1 minute. Hours, 80g of ethyl acetate was added, extracted twice, separated, the organic layer was returned to the reaction flask, the solvent was evaporated, 90g of ethanol, 90g of water, 0.9g of cuprous iodide were added to the flask, stirred, the temperature was controlled at 20°C to 25°C, 16.3g of 25% hydrogen peroxide was slowly added dropwise, and the addition was complete. The reaction was kept warm for 30 minutes, and sampling was performed. After the reaction was complete, 5% aqueous sodium thiosulfate solution was added dropwise to quench the reaction. The aqueous layer was sampled and tested with starch potassium iodide paper until it did not turn blue. After quenching, 80g of ethyl acetate was added, extracted twice, separated, the organic layer was evaporated to dryness, 80g of n-heptane was added to the flask, stirred for 1 hour, and filtered to obtain 2-bromo-6-hydroxybenzaldehyde.
2. A process for synthesizing 2-bromo-6-hydroxybenzaldehyde, characterized in that: The following steps are involved: Step A: 26.4 g of 2,6-dibromobenzaldehyde, 19.0 g of 1,3-propylene glycol, 130 g of toluene, and 1.32 g of concentrated sulfuric acid were added to a reaction flask, stirred and heated to reflux to separate water. After the separation was completed, sampling and testing were performed. If the reaction of 2,6-dibromobenzaldehyde was complete, the temperature was lowered to room temperature, and 5 g of 30% sodium methoxide methanol solution was slowly added to the reaction flask. Stirring was continued for 0.5 hour, sampling was performed, and pH was tested to be ≥7 after adding water. The reaction was carried out under reduced pressure distillation. Toluene was first evaporated off using a rotary evaporator, and then distilled under reduced pressure using an oil pump. The fractions at 115°C to 125°C were collected to obtain 2-(2,6-dibromophenyl)-1,3-dioxane. Step B: 30.4 g of 2-(2,6-dibromophenyl)-1,3-dioxane and 150 g of tetrahydrofuran were added to the reaction flask, and under nitrogen protection, the temperature was stirred and cooled to -5 ° C. The temperature was controlled from -5 ° C to 0 ° C. 216 mL of 1 mol / L isopropyl magnesium chloride tetrahydrofuran solution was added dropwise. After the addition was complete, the mixture was stirred for 1 hour, and the sample was taken for detection. After the Grignard exchange was completed, the temperature was controlled from -10 ° C to -5 ° C. 25.5 g of trimethyl borate was added dropwise. After the addition was complete, the mixture was stirred for 1 hour, and the sample was taken for detection. After the reaction was completed, the temperature was controlled from 5 ° C to 25 ° C. 10% dilute hydrochloric acid was added dropwise to quench the reaction. The pH of the aqueous layer was measured to be 4-5. After the quenching was completed, the mixture was stirred at room temperature for 1 minute. Hours, 80g of ethyl acetate was added, extracted twice, separated, the organic layer was returned to the reaction flask, the solvent was evaporated, 90g of ethanol, 90g of water, 0.9g of cuprous iodide were added to the flask, stirred, the temperature was controlled at 20°C to 25°C, 16.3g of 25% hydrogen peroxide was slowly added dropwise, and the addition was complete. The reaction was kept warm for 30 minutes, and sampling was performed. After the reaction was complete, 5% aqueous sodium thiosulfate solution was added dropwise to quench the reaction. The aqueous layer was sampled and tested with starch potassium iodide paper until it did not turn blue. After quenching, 80g of ethyl acetate was added, extracted twice, separated, the organic layer was evaporated to dryness, 80g of n-heptane was added to the flask, stirred for 1 hour, and filtered to obtain 2-bromo-6-hydroxybenzaldehyde.