CN115160134B - Preparation method of 4-bromo-2-methyl benzoate - Google Patents
Preparation method of 4-bromo-2-methyl benzoate Download PDFInfo
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- CN115160134B CN115160134B CN202210958039.9A CN202210958039A CN115160134B CN 115160134 B CN115160134 B CN 115160134B CN 202210958039 A CN202210958039 A CN 202210958039A CN 115160134 B CN115160134 B CN 115160134B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/18—Preparation of carboxylic acid esters by conversion of a group containing nitrogen into an ester group
- C07C67/22—Preparation of carboxylic acid esters by conversion of a group containing nitrogen into an ester group from nitriles
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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Abstract
The invention discloses a preparation method of 4-bromo-2-methyl benzoate, belonging to the technical field of medical intermediates. 4-bromo-2-fluorobenzonitrile is used as a raw material to carry out substitution decarboxylation reaction with malonic acid diester, then alcoholysis is carried out with methanol, and 4-bromo-2-methylbenzoic acid methyl ester is obtained by distillation. The method has the advantages of short reaction steps, less three wastes, relatively mild and continuous reaction conditions, high product purity up to 99.5 percent, and minimum by-product of the methyl iminoate by screening different acid and methanol ratios, thereby improving the yield.
Description
Technical Field
The invention relates to a preparation method of 4-bromo-2-methyl benzoate, belonging to the technical field of medical intermediates.
Background
4-bromo-2-methylbenzoic acid methyl ester, CAS:99548-55-7, english name: the Methyl 2-Methyl-4-bromoxyzoate is mainly applied to intermediates of physiologically active compounds such as medicines or pesticides, for example, important raw materials of benzofuran medicines or benzoazepine derivative medicines. In addition, methyl 4-bromo-2-methylbenzoate is also a wide range of organic block compounds, the structure of which contains bromine and ester groups, and can add or replace other functional groups.
Methyl 4-bromo-2-methylbenzoate is an important intermediate for the synthesis of isoxazolines as pesticides (Fluralaner), an in vitro parasiticide, which is effective against lice and fleas. Wherein the Fluralaner formula is as follows:
the synthesis of methyl 4-bromo-2-methylbenzoate is not very much carried out, and the main routes [ Journalof Organic Chemistry,1962, vol.27, p.1426-1430] report that 2-methyl-4-nitronitrile is firstly reduced by para-nitro, then the bromoform is obtained by the sandmeyer reaction, then cyano is hydrolyzed under the acidic condition, and finally thionyl chloride is esterified. The reaction equation is as follows:
the route has long steps, and the steps of the route comprise reduction (the reagent is relatively expensive) and diazotization (hidden danger exists in the safety production), so that the cost is relatively high, and the mass production is not facilitated.
Aiming at the defects of the method, the preparation method provided by the invention has the advantages of simple and convenient flow, short steps, continuous reaction, less three wastes and high total yield, and is suitable for factory production so as to meet the increasing market demands.
Disclosure of Invention
In order to overcome the technical defects, the invention provides a preparation method of 4-bromo-2-methyl benzoate. 4-bromo-2-fluorobenzonitrile is used as a raw material to carry out substitution decarboxylation reaction with malonic acid diester, then alcoholysis is carried out with methanol, and 4-bromo-2-methylbenzoic acid methyl ester is obtained by distillation. The method has the advantages of short reaction steps, less three wastes, relatively mild and continuous reaction conditions, high product purity up to 99.5 percent, and minimum by-product of the methyl iminoate by screening different acid and methanol ratios, thereby improving the yield.
The invention relates to a preparation method of 4-bromo-2-methyl benzoate, which comprises the following reaction equation:
the method comprises the following steps:
the first step: mixing 4-bromo-2-fluorobenzonitrile, a phase transfer catalyst 18-crown-6-ether, calcium chloride and malonic acid diester in sulfolane, and heating to react to obtain 4-bromo-2-methylbenzonitrile;
and a second step of: heating 4-bromo-2-methylbenzonitrile in a mixed solvent of methanol and water in the presence of acid to react to obtain a crude product of 4-bromo-2-methylbenzoic acid methyl ester, and then distilling under reduced pressure to obtain 4-bromo-2-methylbenzoic acid methyl ester;
further, in the above technical scheme, in the first step, the malonic acid diester is selected from dimethyl malonate or diethyl malonate.
Further, in the above technical scheme, in the first step, the molar ratio of the 4-bromo-2-fluorobenzonitrile, the 18-crown-6-ether, the calcium chloride and the malonic acid diester is 1:0.05-0.10:2.50-3.50:0.95-1.00.
Further, in the above technical scheme, in the second step, the acid is selected from 98% concentrated sulfuric acid or 10mol/L hydrogen chloride/methanol solution.
Further, in the above technical scheme, in the second step, the amount of water is 1.5 to 2.0 equivalents of the raw material 4-bromo-2-methylbenzonitrile.
Further, in the above technical scheme, in the second step, the molar ratio of the 4-bromo-2-methylbenzonitrile, acid and methanol is 1:2.5-14:5-20.
Further, in the above technical scheme, in the second step, the temperature of the product purified and distilled under reduced pressure to receive the main fraction is 85-93 ℃ and the pressure is 13-16torr.
Advantageous effects of the invention
1. In the first step, calcium chloride is added to complex fluoride ions, so that forward reaction is facilitated, however, the complex is easy to separate out, and a small amount of phase transfer catalyst is added to make the reaction and deacidification reaction faster.
2. In the second step, the defects of complex operation and large wastewater amount during the stepwise (hydrolysis/esterification) reaction are avoided, the nitrile group is selected to finish alcoholysis in one step, the steps are simple, the wastewater is less, the methyl iminoate by-product is effectively controlled by controlling the equivalent proportion of each material, and the yield is up to more than 90%.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further illustrated by the following specific examples. These examples should be construed as merely illustrative of the present invention and not limiting the scope of the present invention. Various changes and modifications to the present invention may be made by one skilled in the art after reading the description herein, and such equivalent changes and modifications are intended to fall within the scope of the present invention as defined in the appended claims.
Example 1
Preparation of 4-bromo-2-methylbenzonitrile
200g (1 mol) of 4-bromo-2-fluorobenzonitrile, 13.2g (0.05 mol) of 18-crown-6-ether, 332.9g (3.0 mol) of calcium chloride and 132g (1 mol) of dimethyl malonate are mixed in 1000mL of sulfolane, the temperature is raised to 120-130 ℃ for reaction for 32 hours, the reaction solution is cooled and filtered, ethyl acetate is added into the filtrate, an organic phase is washed by adding sodium bicarbonate aqueous solution, the organic phase is concentrated, n-heptane is replaced, stirring is carried out at the temperature of-10 to-5 ℃, solid precipitation is carried out, and 150.2g of 4-bromo-2-methylbenzonitrile is obtained by filtering and drying; GC98.8% yield 76.6%. 1 HNMR(400MHz,CDCl3):7.70-7.51(m,3H),2.45(s,3H).
Example 2
200g (1 mol) of 4-bromo-2-fluorobenzonitrile, 26.4 (0.1 mol) of 18-crown-6-ether, 332.9g (3.0 mol) of calcium chloride and 160.2 (0.1 mol) of diethyl malonate are mixed in 1000mL of sulfolane, the temperature is raised to 120-130 ℃ for reaction for 40 hours, the reaction solution is cooled and filtered, ethyl acetate is added into the filtrate, an aqueous solution of sodium bicarbonate is added for washing an organic phase, the organic phase is concentrated, n-heptane is replaced, stirring is carried out at the temperature of-10 to-5 ℃, solid precipitation is carried out, and 139.8g of 4-bromo-2-methylbenzonitrile is obtained after filtration and drying; GC99.1% yield 71.3%.
Example 3
Preparation of methyl 4-bromo-2-methylbenzoate
137.2g (0.7 mol) of 4-bromo-2-methylbenzonitrile, 171.5g (1.75 mol) of 98% concentrated sulfuric acid, 40g of water andmethanol 960mL is stirred uniformly, the temperature is programmed to be increased to reflux reaction for 6 hours, the reaction liquid is cooled to room temperature, poured into ice water, dichloromethane is used for extraction, 5% sodium bicarbonate of an organic phase is washed to be neutral, the organic phase is concentrated under reduced pressure to obtain a crude product, then the crude product is heated to 85-93 ℃ per pressure of 13-16torr and distilled under reduced pressure to obtain 139.7g of 4-bromo-2-methyl benzoate pure product, HPLC is 99.7%, and the yield is 87.1%. 1 HNMR(400MHz,CDCl3):7.71-7.31(m,3H),3.82(s,3H),2.51(s,3H).
Example 4
137.2g (0.7 mol) of 4-bromo-2-methylbenzonitrile, 960mL of 10mol/L hydrogen chloride/methanol solution and 40mL of water are mixed, the system is sealed in an autoclave, the temperature is raised to 70-75 ℃ for reaction for 20 hours, the reaction solution is concentrated under reduced pressure, methylene dichloride is added, the mixture is poured into ice water for layering, the methylene dichloride is extracted, an organic phase is washed with 5% sodium bicarbonate water to be neutral, an organic phase is concentrated under reduced pressure to obtain a crude product, then the crude product is heated to 85-93 ℃ per pressure to 13-16torr and distilled under reduced pressure to obtain 134.4g of 4-bromo-2-methylbenzoic acid methyl ester pure product, HPLC is 99.7%, and the yield is 83.8%.
Example 5
Synthesis of methyl 4-bromo-2-methylbenzoate by stepwise method
137.2g (0.7 mol) of 4-bromo-2-methylbenzonitrile and 400mL of toluene are mixed, the temperature is raised to 60-65 ℃, 343g (2.1 mol) of 60% sulfuric acid is added dropwise, the reaction is carried out for 6 hours at the temperature after the completion of the dropwise addition, the temperature is reduced to 45 ℃, 10% NaOH is added to adjust the pH value to 11-12, the mixture is kept stand for separating an upper organic phase, the water phase is kept at 40-45 ℃, 5% sulfuric acid is added dropwise to adjust the pH value to 1.0-2.0, the mixture is cooled to the room temperature, a filter cake is filtered, leached by water and dried, 139.5g of 4-bromo-2-methylbenzoic acid is obtained, HPLC is 99.3%, and the yield is 92.7%.
Example 6
137.6g (0.64 mol) of 4-bromo-2-methylbenzoic acid and 500mL of methanol are mixed, the temperature is raised to 40-45 ℃, 100g (1.0 mol) of 98% sulfuric acid is added dropwise, the temperature is raised to reflux reaction for 3 hours after the dripping is finished, the methanol is concentrated under reduced pressure, MTBE is added after the temperature is reduced, the layers are separated, the organic layer is remained, 5% sodium bicarbonate of the organic layer is washed to be neutral, the organic phase is concentrated, the temperature is raised to 85-93 ℃ per pressure of 13-16torr, and the 4-bromo-2-methylbenzoic acid methyl ester 130.9g, HPLC99.9% and the yield is 89.3% are obtained through reduced pressure distillation.
Example 7
137.6g (0.64 mol) of 4-bromo-2-methylbenzoic acid, 0.5mL of DMF and 500mL of methanol are mixed, 90.4g (0.76 mol) of thionyl chloride is dropwise added at room temperature, the temperature is raised to reflux reaction for 4 hours after the completion of the dropwise addition, the methanol is evaporated by vacuum concentration, n-heptane is added for replacement, the concentration is continued, a small amount of black viscous oil is found to be discarded at the lower layer, the organic phase is concentrated by vacuum, then the temperature is raised to 85-93 ℃ per pressure of 13-16torr, and the 4-bromo-2-methylbenzoic acid methyl ester 133.6g, HPLC99.2% and the yield of 91.1% are obtained by vacuum distillation.
The foregoing is only a preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art, who is within the scope of the present invention, should be covered by the protection scope of the present invention by making equivalents and modifications to the technical solution and the inventive concept thereof.
Claims (6)
1. The preparation method of the 4-bromo-2-methyl benzoate is characterized by comprising the following steps:
the first step: mixing 4-bromo-2-fluorobenzonitrile, a phase transfer catalyst 18-crown-6-ether, calcium chloride and malonic acid diester in sulfolane, and heating to react to obtain 4-bromo-2-methylbenzonitrile; the malonic acid diester is selected from dimethyl malonate or diethyl malonate;
and a second step of: and (3) heating 4-bromo-2-methylbenzonitrile in a mixed solvent of methanol and water in the presence of acid to react to obtain a crude product of 4-bromo-2-methylbenzoic acid methyl ester, and then distilling under reduced pressure to obtain the 4-bromo-2-methylbenzoic acid methyl ester.
2. The method for preparing 4-bromo-2-methylbenzoate according to claim 1, wherein: in the first step, the molar ratio of the 4-bromo-2-fluorobenzonitrile, the 18-crown-6-ether, the calcium chloride and the malonic acid diester is 1:0.05-0.10:2.50-3.50:0.95-1.00.
3. The method for preparing 4-bromo-2-methylbenzoate according to claim 1, wherein: in the second step, the acid is selected from 98% concentrated sulfuric acid or 10mol/L hydrogen chloride/methanol solution.
4. The method for preparing 4-bromo-2-methylbenzoate according to claim 1, wherein: in the second step, the water content is 1.5-2.0 equivalent of the raw material 4-bromo-2-methylbenzonitrile.
5. The method for preparing 4-bromo-2-methylbenzoate according to claim 1, wherein: in the second step, the molar ratio of the 4-bromo-2-methylbenzonitrile to the acid to the methanol is 1:2.5-14:5-20.
6. The process for producing methyl 4-bromo-2-methylbenzoate according to claim 1, wherein
The method comprises the following steps: in the second step, the temperature of the main fraction received by the product purification and reduced pressure distillation is 85-93 ℃,
the pressure was 13-16torr.
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