Synthesis method of 3-bromo-6-methoxy-2-methyl benzoic acid
By using 2-hydroxy-6-methylbenzoic acid as raw material and using a multi-step reaction process to synthesize 3-bromo-6-methoxy-2-methylbenzoic acid, the safety hazards of diazon intermediates and the high cost of palladium catalysts in the prior art are solved, and high yield and high purity product production is achieved.
Patent Information
- Application Number
- CN202510488073.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-04-18
- Publication Date
- 2025-07-22
AI Technical Summary
The existing synthesis process of 3-bromo-6-methoxy-2-methylbenzoic acid has problems with the safety hazards of diazon intermediates and the high cost of palladium catalysts, making it difficult to achieve industrialization.
Using 2-hydroxy-6-methylbenzoic acid as raw material, hydroxy etherification is performed first, then bromine reaction is performed, and finally hydrolyzed to obtain 3-bromo-6-methoxy-2-methylbenzoic acid. Basic reagents such as sodium hydroxide, potassium hydroxide, sodium carbonate and other solvents are used to control the temperature and conduct multiple reactions.
It improves the reaction yield, solves the by-product problem, improves the separation efficiency of intermediates, realizes high-purity product production, and reduces energy consumption.
Smart Images
Figure CN120349233A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the field of organic synthesis, and particularly to a method for synthesizing 3-bromo-6-methoxy-2-methylbenzoic acid.
Background Art
[0002] 3-Benzoylacetone is a benzophenone fungicide developed by BASF AG in Germany. It was first developed by American Cyanamid Company (now part of BASF) in 1998 and is mainly used to control diseases such as powdery mildew and eyespot of crops such as cereals, cucumbers, and grapes. It has attracted much attention due to its unique mechanism of action. It was registered in European countries in 2004. The global sales of benzoylacetone reached 75 million US dollars in 2013, and the registration of benzoylacetone technical and formulated products was obtained in China at the end of 2015. And 3-bromo-6-methoxy-2-methylbenzoic acid is an important synthetic intermediate for synthesizing benzoylacetone. Due to the wide application of benzoylacetone, it brings great market potential to 3-bromo-6-methoxy-2-methylbenzoic acid.
[0003] There are mainly two existing process routes. The first one is that 2,3-dimethylaniline undergoes diazotization, hydrolysis, and selective oxidation. This method has problems such as the safety hazard of diazo intermediates and poor selectivity in the oxidation step. The second one is that 2-methylbenzoic acid (or o-hydroxybenzoic acid) undergoes hydroxylation (or methylation) catalyzed by transition metal palladium, and then undergoes etherification and bromination to synthesize 3-bromo-6-methoxy-2-methylbenzoic acid, which has the problem that the cost of palladium catalyst is expensive and it is difficult to realize industrialization. Therefore, the optimization and improvement of the process route in the present invention reduce the problems of the original process route.
Summary of the Invention
[0004] In order to overcome the above-mentioned disadvantages existing in the prior art, the technical problem to be solved by the present invention is to provide a method for synthesizing 3-bromo-6-methoxy-2-methylbenzoic acid, using 2-hydroxy-6-methylbenzoic acid as a raw material, first etherifying the hydroxyl group, then performing a bromination reaction, and finally hydrolyzing to obtain 3-bromo-6-methoxy-2-methylbenzoic acid. This method overcomes the defects existing in the prior art.
[0005] To solve the above technical problem, the technical solution adopted by the present invention is: a method for synthesizing 3-bromo-6-methoxy-2-methylbenzoic acid, characterized in that the synthesis route is as follows:
[0006]
[0007] Specific steps:
[0008] Step Ⅰ: Add 2-hydroxy-6-methylbenzoic acid (raw material A), an alkali, a solvent, and a methylation reagent. After the reaction is completed, acidify, distill under reduced pressure, and then wash with water to obtain methyl 2-methoxy-6-methylbenzoate (intermediate B).
[0009] Step Ⅱ: Dissolve intermediate B in a solvent, dropwise add liquid bromine, and quench the reaction with a sodium bisulfite solution after the reaction is completed to obtain methyl 3-bromo-2-methoxy-6-methylbenzoate (intermediate C).
[0010] Step Ⅲ: Add intermediate C to an alkali solution, neutralize after the reaction is completed, cool down, filter by suction, and wash with water to obtain 3-bromo-6-methoxy-2-methylbenzoic acid (product D).
[0011] In Step Ⅰ, the alkali is one or a mixture of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate; the solvent is acetone; the methylation reagent is one or a mixture of dimethyl sulfate, dimethyl carbonate, iodomethane, and bromomethane; the reaction temperature is -10 to 120 °C.
[0012] In Step Ⅱ, the dropping temperature of liquid bromine is 0 to 20 °C, the reaction temperature is 0 to 35 °C, and the solvent is one or a mixture of dichloromethane, 1,2-dichloroethane, and chloroform.
[0013] In Step Ⅲ, the alkali is one or a mixture of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate.
[0014] Compared with the prior art, the present invention has the following advantages:
[0015] (1) The present invention solves the problem of by-products generated in the reaction and improves the reaction yield.
[0016] (2) The present invention solves the problem of intermediate separation and improves the degree of production automation.
[0017] (3) The HPLC purity of the product of the present invention can reach 99%.
[0018] (4) The present invention does not require the use of high temperature and has low energy consumption.
Description of the Drawings
[0019] Figure 1 It is the NMR spectrum of 3-bromo-6-methoxy-2-methylbenzoic acid.
[0020] Figure 2 It is the liquid chromatogram of the standard product of raw material A.
[0021] Figure 3 It is the liquid chromatogram of the standard product of intermediate B.
[0022] Figure 4It is the liquid chromatogram of Intermediate C reference substance.
[0023] Figure 5 It is the liquid chromatogram of Product D reference substance.
Specific Embodiments
[0024] The present invention will be further described below in conjunction with specific embodiments, but the present invention is not limited to the following embodiments.
[0025] Example 1:
[0026] Step I: In a 1000 mL two-necked flask, 152.15 g (1 mol) of 2-hydroxy-6-methylbenzoic acid (A) and 456.45 g of acetone were successively added to the two-necked flask. After dissolution, 138.21 g (1 mol) of potassium carbonate was slowly added. Dimethyl sulfate was slowly added dropwise under an ice bath at 10 °C, and the reaction was controlled at low temperature. After the addition was completed, the reaction was carried out at 57 °C. After the reaction was detected by TLC and completed, hydrochloric acid was added. After removing acetone by vacuum distillation, the mixture was extracted with dichloromethane and stirred for 0.5 h to obtain Solution I containing Intermediate B after treatment.
[0027] Step II: To the obtained Solution I, 191.77 g (1.2 mol) of liquid bromine was added dropwise below 10 °C. After the addition was completed, the mixture was stirred and reacted at 35 °C for 3 hours. The tail gas was absorbed with 32 wt% alkali solution. After the reaction was completed, the reaction was quenched with sodium bisulfite solution to obtain Solution II of Intermediate C.
[0028] Step III: After distilling off dichloromethane from Solution II under reduced pressure, 133.33 g of 16% NaOH aqueous solution was added, and the reaction was carried out at 100 °C for 6 h. The reaction solution was neutralized with HCl aqueous solution, filtered by suction after cooling to room temperature, and the filter cake was washed with water to obtain Product D.
[0029] The total yield of the three-step reaction was 83.73%, and the HPLC purity was 96.67%.
[0030] Example 2:
[0031] Step I: In a 1000 mL two-necked flask, 152.15 g (1 mol) of 2-hydroxy-6-methylbenzoic acid (A) and 456.45 g of acetone were successively added to the two-necked flask. After dissolution, 105.99 g (1 mol) of sodium carbonate was slowly added. Dimethyl sulfate was slowly added dropwise under an ice bath at 5 °C, and the reaction was controlled at low temperature. After the addition was completed, the reaction was carried out at 57 °C. After the reaction was detected by TLC and completed, hydrochloric acid was added. After removing acetone by vacuum distillation, the mixture was extracted with dichloromethane and stirred for 0.5 h to obtain Solution I containing Intermediate B after treatment.
[0032] Step II: The obtained Solution I was added dropwise with 191.77 g (1.2 mol) of liquid bromine at a temperature below 5°C. After the addition was completed, the mixture was stirred and reacted at 35°C for 3 hours. The tail gas was absorbed with 32 wt% alkali solution. After the reaction ended, the reaction was quenched with sodium bisulfite solution to obtain Solution II of intermediate C.
[0033] Step III: After Solution II was distilled under reduced pressure to dryness of dichloromethane, 133.33 g of 16% NaOH aqueous solution was added, and the mixture was reacted at 100°C for 6 h. The reaction solution was neutralized with HCl aqueous solution. After cooling to room temperature, it was filtered by suction, and the filter cake was washed with water to obtain Product D.
[0034] The total yield of the three-step reaction was 81.97%, and the HPLC purity was 98.75%.
[0035] Example 3:
[0036] Step I: 152.15 g (1 mol) of 2-hydroxy-6-methylbenzoic acid (A) and 456.45 g of acetone were successively added to a 1000 mL two-necked flask. After dissolution, 138.21 g (1 mol) of potassium carbonate was slowly added. Dimethyl carbonate was slowly added dropwise under an ice bath condition at 5°C, and the reaction was controlled at a low temperature. After the addition was completed, the reaction was carried out at 57°C. After the reaction was detected by TLC and ended, hydrochloric acid was added. After removing acetone by distillation under reduced pressure, the mixture was extracted with dichloromethane and stirred for 0.5 h to obtain Solution I containing intermediate B after treatment.
[0037] Step II: The obtained Solution I was added dropwise with 239.72 g (1.5 mol) of liquid bromine at a temperature below 10°C. After the addition was completed, the mixture was stirred and reacted at 35°C for 2 hours. The tail gas was absorbed with 32 wt% alkali solution. After the reaction ended, the reaction was quenched with sodium bisulfite solution to obtain Solution II of intermediate C.
[0038] Step III: After Solution II was distilled under reduced pressure to dryness of dichloromethane, 133.33 g of 16% NaOH aqueous solution was added, and the mixture was reacted at 100°C for 6 h. The reaction solution was neutralized with HCl aqueous solution. After cooling to room temperature, it was filtered by suction, and the filter cake was washed with water to obtain Product D.
[0039] The total yield of the three-step reaction was 80.56%, and the HPLC purity was 95.62%.
[0040] Example 4:
[0041] Step Ⅰ: Add 152.15 g (1 mol) of 2-hydroxy-6-methylbenzoic acid (A) and 456.45 g of acetone into a 1000 mL two-necked flask in sequence. After dissolution, slowly add 138.21 g (1 mol) of potassium carbonate. Slowly dropwise add methyl iodide under the condition of a 5 °C ice bath, control the low-temperature reaction. After the dropping is completed, react at 57 °C. After detecting the end of the reaction by TLC, add hydrochloric acid. Remove acetone by vacuum distillation, and then extract with dichloromethane and stir for 0.5 h to obtain Solution Ⅰ containing intermediate B after treatment.
[0042] Step Ⅱ: Dropwise add 239.72 g (1.5 mol) of liquid bromine into the obtained Solution Ⅰ drop by drop below 5 °C. After the dropping is completed, stir and react at 35 °C for 3 hours. Absorb the tail gas with 32 wt% lye. Quench the reaction with sodium bisulfite solution after the reaction is completed to obtain Solution Ⅱ of intermediate C.
[0043] Step Ⅲ: After distilling off dichloromethane from Solution Ⅱ by vacuum distillation, add 100 g of ethanol and 133.33 g of 16% NaOH aqueous solution, react at 100 °C for 6 h, neutralize the reaction solution with HCl aqueous solution, filter by suction after cooling to room temperature, and wash the filter cake with water to obtain Product D.
[0044] The total yield of the three-step reaction is 78.58%, and the HPLC purity is 99.28%.
[0045] Example 5:
[0046] Step Ⅰ: Add 152.15 g (1 mol) of 2-hydroxy-6-methylbenzoic acid (A) and 456.45 g of acetone into a 1000 mL two-necked flask in sequence. After dissolution, slowly add 138.21 g (1 mol) of potassium carbonate. Slowly dropwise add dimethyl sulfate under the condition of a 5 °C ice bath, control the low-temperature reaction. After the dropping is completed, react at 57 °C. After detecting the end of the reaction by TLC, add hydrochloric acid. Remove acetone by vacuum distillation, and then extract with dichloromethane and stir for 0.5 h to obtain Solution Ⅰ containing intermediate B after treatment.
[0047] Step Ⅱ: Dropwise add 319.62 g (2 mol) of liquid bromine into the obtained Solution Ⅰ drop by drop below 5 °C. After the dropping is completed, stir and react at 35 °C for 3 hours. Absorb the tail gas with 32 wt% lye. Quench the reaction with sodium bisulfite solution after the reaction is completed to obtain Solution Ⅱ of intermediate C.
[0048] Step Ⅲ: After distilling off dichloromethane from Solution Ⅱ by vacuum distillation, add 133.33 g of 16% NaOH aqueous solution, react at 100 °C for 3 h, neutralize the reaction solution with HCl aqueous solution, filter by suction after cooling to room temperature, and wash the filter cake with water to obtain Product D.
[0049] The total yield of the three-step reaction is 81.58%, and the HPLC purity is 91.28%.
[0050] Example 6:
[0051] Step Ⅰ: In a 1000 mL two-necked flask, 152.15 g (1 mol) of 2-hydroxy-6-methylbenzoic acid (A) and 456.45 g of acetone were successively added to the two-necked flask. After dissolution, 103.66 g (0.75 mol) of potassium carbonate was slowly added. Dimethyl sulfate was slowly added dropwise under an ice bath at 5 °C, and the low-temperature reaction was controlled. After the addition was completed, the reaction was carried out at 57 °C. After the reaction was completed as detected by TLC, hydrochloric acid was added. After removing acetone by vacuum distillation, the mixture was extracted with dichloromethane and stirred for 0.5 h to obtain Solution Ⅰ containing intermediate B after treatment.
[0052] Step Ⅱ: To the obtained Solution Ⅰ, 319.62 g (2 mol) of liquid bromine was added dropwise at a temperature below 5 °C. After the addition was completed, the mixture was stirred and reacted at 35 °C for 3 hours. The tail gas was absorbed with 32 wt% alkali solution. After the reaction was completed, the reaction was quenched with sodium bisulfite solution to obtain Solution Ⅱ of intermediate C.
[0053] Step Ⅲ: After the dichloromethane in Solution Ⅱ was distilled off under reduced pressure, 133.33 g of 16% aqueous NaOH solution was added, and the reaction was carried out at 100 °C for 6 h. The reaction solution was neutralized with aqueous HCl solution, filtered by suction after cooling to room temperature, and the filter cake was washed with water to obtain Product D.
[0054] The total yield of the three-step reaction was 84.73%, and the HPLC purity was 95.65%.
[0055] Example 7:
[0056] Step Ⅰ: In a 1000 mL two-necked flask, 152.15 g (1 mol) of 2-hydroxy-6-methylbenzoic acid (A) and 456.45 g of acetone were successively added to the two-necked flask. After dissolution, 103.66 g (0.75 mol) of potassium carbonate was slowly added. Dimethyl sulfate was slowly added dropwise under an ice bath at 5 °C, and the low-temperature reaction was controlled. After the addition was completed, the reaction was carried out at 57 °C. After the reaction was completed as detected by TLC, hydrochloric acid was added. After removing acetone by vacuum distillation, the mixture was extracted with dichloromethane and stirred for 0.5 h to obtain Solution Ⅰ containing intermediate B after treatment.
[0057] Step Ⅱ: To the obtained Solution Ⅰ, 239.72 g (1.5 mol) of liquid bromine was added dropwise at a temperature below 5 °C. After the addition was completed, the mixture was stirred and reacted at 35 °C for 3 hours. The tail gas was absorbed with 32 wt% alkali solution. After the reaction was completed, the reaction was quenched with sodium bisulfite solution to obtain Solution Ⅱ of intermediate C.
[0058] Step Ⅲ: After the dichloromethane in Solution Ⅱ was distilled off under reduced pressure, 133.33 g of 16% aqueous NaOH solution was added, and the reaction was carried out at 100 °C for 6 h. The reaction solution was neutralized with aqueous HCl solution, filtered by suction after cooling to room temperature, and the filter cake was washed with water to obtain Product D.
[0059] The overall yield of the three-step reaction is 82.73%, and the HPLC purity is 98.46%.
[0060] Example 8:
[0061] Step I: In a 1000 mL two-necked flask, 152.15 g (1 mol) of 2-hydroxy-6-methylbenzoic acid (A) and 456.45 g of acetone were successively added to the two-necked flask. After dissolution, 103.66 g (0.75 mol) of potassium carbonate was slowly added. Dimethyl sulfate was slowly added dropwise under an ice bath at 5 °C, and the reaction was controlled at low temperature. After the addition was completed, the reaction was carried out at 57 °C. After the reaction was completed as detected by TLC, hydrochloric acid was added, and acetone was removed by vacuum distillation. Then, the mixture was extracted with dichloromethane and stirred for 0.5 h to obtain Solution I containing intermediate B after treatment.
[0062] Step II: The obtained Solution I was slowly added dropwise with 239.72 g (1.5 mol) of liquid bromine at a temperature below 5 °C. After the addition was completed, the mixture was stirred and reacted at 35 °C for 2 hours. The tail gas was absorbed with 32 wt% lye. After the reaction was completed, the reaction was quenched with sodium bisulfite solution to obtain Solution II containing intermediate C.
[0063] Step III: After the dichloromethane in Solution II was distilled off under reduced pressure, 200 g of 10% aqueous NaOH solution and 80 g of methanol were added, and the reaction was carried out at 80 °C for 6 h. The reaction solution was neutralized with aqueous HCl solution, filtered by suction after cooling to room temperature, and the filter cake was washed with water to obtain Product D.
[0064] The overall yield of the three-step reaction is 83.39%, and the HPLC purity is 99.05%.
Claims
1. A method for synthesizing 3-bromo-6-methoxy-2-methylbenzoic acid, characterized in that, The synthesis route is as follows: Specific steps: Step I: Add 2-hydroxy-6-methylbenzoic acid (raw material A), an alkali, a solvent, and a methylation reagent. After the reaction is completed, acidify, perform vacuum distillation, and then wash with water to obtain methyl 2-methoxy-6-methylbenzoate (intermediate B); Step II: Dissolve intermediate E in a solvent, dropwise add liquid bromine, and quench the reaction with a sodium bisulfite solution after the reaction is completed to obtain methyl 3-bromo-2-methoxy-6-methylbenzoate (intermediate C); Step III: Add intermediate F to an alkali solution. After the reaction is completed, neutralize, cool down, and then perform suction filtration and wash with water to obtain 3-bromo-6-methoxy-2-methylbenzoic acid (product D).
2. The synthesis method of 3-bromo-6-methoxy-2-methylbenzoic acid according to claim 1, characterized in that, In Step I, the alkali is one or a mixture of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate; the solvent is acetone; and the methylation reagent is one or a mixture of dimethyl sulfate, dimethyl carbonate, methyl iodide, and methyl bromide.
3. The synthesis method of 3-bromo-6-methoxy-2-methylbenzoic acid according to claim 1, characterized in that, In Step II, the dropping temperature of liquid bromine is 0-20°C, the reaction temperature is 0-35°C, and the solvent is one or a mixture of dichloromethane, 1,2-dichloroethane, and chloroform.
4. The synthesis method of 3-bromo-6-methoxy-2-methylbenzoic acid according to claim 1, characterized in that, In Step III, the alkali is one or a mixture of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate.