CN115160134A

CN115160134A - Preparation method of 4-bromo-2-methyl benzoate

Info

Publication number: CN115160134A
Application number: CN202210958039.9A
Authority: CN
Inventors: 顾徐君; 魏旭
Original assignee: Wuxi Kehua Biotechnology Co ltd
Current assignee: Wuxi Kehua Biotechnology Co ltd
Priority date: 2022-08-10
Filing date: 2022-08-10
Publication date: 2022-10-11
Anticipated expiration: 2042-08-10
Also published as: CN115160134B

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 perform substitution decarboxylation reaction with malonic acid diester, and then alcoholysis reaction is performed with methanol, and methyl 4-bromo-2-methylbenzoate 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 of 99.5 percent, and capability of ensuring the minimum quantity of the methyl imidate byproducts by screening different acid-methanol ratios, thereby improving the yield.

Description

Preparation method of 4-bromo-2-methyl benzoate

Technical Field

The invention relates to a preparation method of 4-bromo-2-methyl benzoate, belonging to the technical field of medical intermediates.

Background

Methyl 4-bromo-2-methylbenzoate, CAS:99548-55-7, english name: methyl 2-Methyl-4-bromobenzoate is mainly applied to intermediates of physiologically active compounds such as medicines or pesticides, and can be used as important raw materials of benzofuran medicines or benzazepine derivative medicines. In addition, methyl 4-bromo-2-methylbenzoate is also a wide range of organic building block compounds, the structure of which contains bromine and ester groups, either in addition to or instead of other functional groups.

Methyl 4-bromo-2-methylbenzoate is an important intermediate for synthesizing isoxazoline insecticides (Fluralaner), which is an ectoparasitic insecticide and can effectively kill lice and fleas. Wherein Fluralaner has the formula:

the synthesis method of methyl 4-bromo-2-methylbenzoate is not many, and the main route [ journal of Organic Chemistry,1962, vol.27, p.1426-1430] reports that 2-methyl-4-nitrobenzonitrile is adopted to firstly reduce nitro, then a sandmeyer reaction is carried out to obtain a bromide, then cyano is hydrolyzed under an acidic condition, and finally thionyl chloride is esterified to obtain the methyl 4-bromo-2-methylbenzoate. The reaction equation is as follows:

the route has long steps, the steps of reduction (reagents are relatively expensive) and diazotization (potential safety hazards exist in production), the cost is relatively high, and the large-scale production is not facilitated.

Aiming at the defects of the method, the invention adopts a preparation method which has simple and convenient flow, short steps, continuous reaction, less three wastes and high total yield, is suitable for factory production and meets the increasing market demand.

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 perform substitution decarboxylation reaction with malonic diester, then alcoholysis reaction is performed with methanol, and methyl 4-bromo-2-methylbenzoate 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 of 99.5 percent, and capability of ensuring the minimum quantity of the methyl imidate byproducts by screening different acid-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 is as follows: mixing 4-bromo-2-fluorobenzonitrile, 18-crown-6-ether serving as a phase transfer catalyst, calcium chloride and malonic diester in sulfolane, and heating to react to obtain 4-bromo-2-methylbenzonitrile;

the second step is that: heating 4-bromo-2-methylbenzonitrile in a mixed solvent of methanol and water for reaction in the presence of acid to obtain a crude product of 4-bromo-2-methyl benzoate, and then carrying out reduced pressure distillation to obtain 4-bromo-2-methyl benzoate;

further, in the above technical solution, 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, 18-crown-6-ether, calcium chloride and malonic acid diester is 1:0.05-0.10:2.50-3.50:0.95-1.00.

Further, in the above technical solution, 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 solution, 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 technical scheme, in the second step, the temperature of the main fraction received by the product purification and reduced pressure distillation 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, which is more beneficial to forward reaction, but the complex is easy to separate out, and a small amount of phase transfer catalyst is added to accelerate the reaction and deacidification reaction.

2. In the second step, the defects of complicated operation and large amount of waste water in the step-by-step (hydrolysis/esterification) reaction are avoided, the alcoholysis is completed in one step by selecting a nitrile group, the steps are simple, the waste water is less, the methyl imidate by-product is effectively controlled by controlling the equivalent ratio 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 are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.

Example 1

Preparation of 4-bromo-2-methylbenzonitrile

Mixing 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 in 1000mL of sulfolane, heating to 120-130 ℃ for reaction for 32 hours, cooling reaction liquid, filtering, adding ethyl acetate into filtrate, adding sodium bicarbonate aqueous solution to wash an organic phase, concentrating the organic phase, replacing n-heptane with n-heptane, stirring at-10 to-5 ℃, separating out solids, filtering and drying to obtain 150.2g of 4-bromo-2-methylbenzonitrile; GC98.8% and yield 76.6%. ¹ HNMR(400MHz,CDCl3):7.70-7.51(m,3H),2.45(s,3H).

Example 2

Mixing 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 in 1000mL of sulfolane, heating to 120-130 ℃ for reacting for 40 hours, cooling the reaction liquid, filtering, adding ethyl acetate into the filtrate, adding an aqueous solution of sodium bicarbonate to wash an organic phase, concentrating the organic phase, replacing n-heptane with n-heptane, stirring at-10 to-5 ℃, separating out solids, filtering and drying to obtain 139.8g of 4-bromo-2-methylbenzonitrile; GC99.1% and yield 71.3%.

Example 3

Preparation of methyl 4-bromo-2-methylbenzoate

Uniformly stirring 137.2g (0.7 mol) of 4-bromo-2-methylbenzonitrile, 171.5g (1.75 mol) of 98% concentrated sulfuric acid, 40g of water and 960mL of methanol, raising the temperature by program to reflux reaction for 6 hours, cooling the reaction solution to room temperature, pouring the reaction solution into ice water, extracting by dichloromethane, washing an organic phase by 5% sodium bicarbonate water to be neutral, concentrating the organic phase under reduced pressure to obtain a crude product, raising the temperature to 85-93 ℃/at a pressure of 13-16torr, and distilling under reduced pressure to obtain 139.7g of 4-bromo-2-methyl benzoate pure product, wherein HPLC (high performance liquid chromatography) 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

Mixing 137.2g (0.7 mol) of 4-bromo-2-methylbenzonitrile, 960mL of 10mol/L hydrogen chloride/methanol solution and 40mL of water, sealing the system in an autoclave, heating to 70-75 ℃ for reaction for 20 hours, concentrating the reaction liquid under reduced pressure, adding dichloromethane, pouring into ice water for layering, extracting the dichloromethane, washing an organic phase with 5% sodium bicarbonate water to be neutral, concentrating the organic phase under reduced pressure to obtain a crude product, heating to 85-93 ℃/at a pressure of 13-16torr, and distilling under reduced pressure to obtain 134.4g of pure 4-bromo-2-methyl benzoate, wherein the HPLC (high performance liquid chromatography) is 99.7%, and the yield is 83.8%.

Example 5

Step-by-step synthesis of 4-bromo-2-methyl benzoic acid methyl ester

Mixing 137.2g (0.7 mol) of 4-bromo-2-methylbenzonitrile with 400mL of toluene, heating to 60-65 ℃, dropwise adding 343g (2.1 mol) of 60% sulfuric acid, reacting at the temperature for 6 hours after the dropwise adding is finished, cooling to 45 ℃, adding 10% NaOH to adjust the pH =11-12, standing to remove an upper organic phase, keeping the aqueous phase at 40-45 ℃, dropwise adding 5% sulfuric acid to adjust the pH =1.0-2.0, cooling to room temperature, leaching a filter cake with water, and drying to obtain 139.5g of 4-bromo-2-methylbenzoic acid, HPLC99.3%, and the yield is 92.7%.

Example 6

Mixing 137.6g (0.64 mol) of 4-bromo-2-methylbenzoic acid with 500mL of methanol, heating to 40-45 ℃, dropwise adding 100g (1.0 mol) of 98% sulfuric acid, heating to reflux reaction for 3 hours after dropwise adding, concentrating under reduced pressure to evaporate the methanol, cooling, adding MTBE, layering, keeping an organic layer, washing 5% sodium bicarbonate in the organic layer to be neutral, concentrating an organic phase, heating to 85-93 ℃/at a pressure of 13-16torr, and distilling under reduced pressure to obtain 130.9g of 4-bromo-2-methylbenzoic acid methyl ester, HPLC99.9% and a yield of 89.3%.

Example 7

Mixing 137.6g (0.64 mol) of 4-bromo-2-methylbenzoic acid, 0.5mL of DMF0 and 500mL of methanol, dropwise adding 90.4g (0.76 mol) of thionyl chloride at room temperature, heating to reflux for 4 hours after dropwise adding, concentrating under reduced pressure to evaporate the methanol, adding n-heptane for replacement, continuing to concentrate, removing a small amount of black viscous oily matter on the lower layer, concentrating the organic phase under reduced pressure, heating to 85-93 ℃/under 13-16torr, and distilling under reduced pressure to obtain 133.6g of methyl 4-bromo-2-methylbenzoate, HPLC99.2% and 91.1% yield.

The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be able to cover the technical solutions and the inventive concepts of the present invention within the technical scope of the present invention.

Claims

1. A preparation method of 4-bromo-2-methyl benzoate is characterized by comprising the following steps:

the second step is that: 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-methyl benzoate, and then carrying out reduced pressure distillation to obtain the 4-bromo-2-methyl benzoate.

2. The method for producing methyl 4-bromo-2-methylbenzoate according to claim 1, characterized in that: in the first step, the malonic diester is selected from dimethyl malonate or diethyl malonate.

3. The method for producing methyl 4-bromo-2-methylbenzoate according to claim 1, characterized in that: 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.

4. The method for producing methyl 4-bromo-2-methylbenzoate according to claim 1, characterized in that: in the second step, the acid is selected from 98% concentrated sulfuric acid or 10mol/L hydrogen chloride/methanol solution.

5. The process for producing methyl 4-bromo-2-methylbenzoate according to claim 1, characterized in that: in the second step, the amount of water is 1.5-2.0 equivalents of the raw material 4-bromo-2-methylbenzonitrile.

6. The process for producing methyl 4-bromo-2-methylbenzoate according to claim 1, characterized in that: 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.

7. The process for producing methyl 4-bromo-2-methylbenzoate according to claim 1, characterized in that: in the second step, the temperature of the main fraction received by the product purification reduced pressure distillation is 85-93 ℃, and the pressure is 13-16torr.