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Preparation method of 5-bromo-2-chlorobenzoic acid

A chlorobenzoic acid, chlorination reaction technology, applied in the preparation of carboxylate, the preparation of carboxylic acid amide, the preparation of organic compounds and other directions, can solve the problems of unsuitable industrial production, affecting production and application, increasing production cost, etc., and achieving high industrialization Prospects, improved safety, effect of mild reaction conditions

Inactive Publication Date: 2020-11-13
ZHEJIANG MENOVO PHARMA +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The publication number is CN107954852A, which uses sodium periodate solution as the bromination reagent to complete the process, but a large amount of iodine-containing wastewater is produced in the later stage, which is difficult to deal with. At the same time, the use of sodium periodate increases the production cost and is not suitable for industrial production.
[0006] 4. In the Chinese invention patent application "A preparation method of 5-bromo-2-chlorobenzaldehyde" (application number: CN201310724204.5) with the application publication number CN104744227A, it is reported that in NBS (N-bromosuccinyl Carry out monobromination reaction in imine) / sulfuric acid system and obtain the method for 5-bromo-2-chlorobenzoic acid, the method reaction process is simple, and raw material is easy to get, and has improved the selectivity of the bromination process of 2-chlorobenzoic acid , but the selectivity of 5-bromo-2-chlorobenzoic acid generally only has 60~70%, and still has the generation of 4-bromo-2-chlorobenzoic acid impurity about 10%, and this impurity is similar to product polarity, is difficult to Removal by conventional methods often requires repeated recrystallization to obtain products with ideal purity, resulting in low product yields, which affect production and application

Method used

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  • Preparation method of 5-bromo-2-chlorobenzoic acid

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Effect test

Embodiment 1

[0033] The preparation method of 5-bromo-2-chlorobenzoic acid in the present embodiment may further comprise the steps:

[0034] (1) Preparation of Compound III

[0035] Add 300mL of toluene, 40.0g of o-chlorobenzoic acid, 22mL of thionyl chloride, and 0.5mL of DMF into a 500mL single-port reaction flask, stir at room temperature, slowly raise the temperature to 70°C, stop heating after four hours of heat preservation, and cool down to room temperature; the reaction system is concentrated To dryness, add 100mL of dichloromethane; take another 500mL four-neck reaction flask, add 25g of 2-amino-2methyl-propanol, 100mL of dichloromethane, 20g of triethylamine, cool to -10°C, add dropwise The solution in the above-mentioned single-necked bottle was kept at a temperature lower than 0°C during the dropwise addition, and reacted at room temperature for 2 hours after the dropwise addition was completed;

[0036] Use 0.01moL of hydrochloric acid to adjust the pH to 5.5~6.5, separate l...

Embodiment 2

[0042] The preparation method of 5-bromo-2-chlorobenzoic acid in the present embodiment may further comprise the steps:

[0043] (1) Preparation of Compound III

[0044]Add 300mL of toluene, 40.0g of o-chlorobenzoic acid, 12mL of thionyl chloride, 0.5mL of DMF into a 500mL single-port reaction flask, stir at room temperature, slowly raise the temperature to 75°C, stop heating after four hours of heat preservation reaction, and cool down to room temperature; the reaction system is concentrated To dryness, add 100mL of dichloromethane; take another 500mL four-neck reaction flask, add 15g of 2-amino-2methyl-propanol, 100mL of dichloromethane, 25g of triethylamine, cool to -10°C, add dropwise The solution in the above-mentioned single-necked bottle was kept at a temperature lower than 0°C during the dropwise addition, and reacted at room temperature for 2 hours after the dropwise addition was completed;

[0045] Use 0.01moL of hydrochloric acid to adjust the pH to 5.5~6.5, separa...

Embodiment 3

[0050] The preparation method of 5-bromo-2-chlorobenzoic acid in the present embodiment may further comprise the steps:

[0051] (1) Preparation of Compound III

[0052] Add 300mL of toluene, 40.0g of o-chlorobenzoic acid, 50mL of thionyl chloride, and 0.5mL of DMF into a 500mL single-port reaction flask, stir at room temperature, slowly raise the temperature to 70°C, stop heating after keeping the reaction for eight hours, and cool down to room temperature; the reaction system is concentrated To dryness, add 100mL of dichloromethane; take another 500mL four-neck reaction flask, add 35g of 2-amino-2methyl-propanol, 100mL of dichloromethane, 50g of triethylamine, cool to -10°C, add dropwise The solution in the one-necked bottle mentioned above was kept at a temperature lower than 0°C during the dropping process, and reacted at room temperature for 3 hours after the dropping was completed;

[0053] Use 0.01moL of hydrochloric acid to adjust the pH to 5.5~6.5, separate layers, c...

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Abstract

The invention relates to a preparation method of 5-bromo-2-chlorobenzoic acid. The preparation method comprises the following steps: taking 2-chlorobenzoic acid as an initial reactant, sequentially carrying out chlorination, acylation and cyclization reactions to obtain a protective group o-chlorobenzoic acid (a compound represented by formula III), and sequentially carrying out bromination and hydrolysis to obtain 5-bromo-2-chlorobenzoic acid. The reaction conditions are mild, and the safety of the preparation process is improved. The yield of the prepared product can reach 75% or above, thepurity can reach 99% or above, and the purity and yield are much higher than those of an existing preparation method. Meanwhile, the preparation method is simple in process step, the product is easy to purify, 5-bromo-2-chlorobenzoic acid can be synthesized on a large scale, and the preparation method has a good industrial development prospect.

Description

Technical field [0001] The invention relates to the technical field of organic synthesis, and specifically relates to a preparation method of 5-bromo-2-chlorobenzoic acid. Background technique [0002] 5-Bromo-2-chlorobenzoic acid is an important intermediate in the synthesis of anti-diabetic drugs dapagliflozin, apagliflozin and other antiviral drugs and renin inhibitors. There are currently four main methods for synthesizing 5-bromo-2-chlorobenzoic acid that have been reported: [0003] 1. The Chinese invention patent "Method for 2,5-dihalobenzoic acid" with the authorization announcement number CN1740135B (application number: CN200410057247.3) discloses a method from 5-bromo-2-chlorotrifluorotoluene Start by heating and hydrolyzing in fuming sulfuric acid, then add the reaction solution to crushed ice to precipitate the crude product, and the crude product is recrystallized from toluene to obtain the product. This route adds a lot of sulfuric acid and cannot be recycled...

Claims

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Application Information

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IPC IPC(8): C07C63/70C07C51/00C07C51/42
CPCC07C51/60C07C231/02C07C51/00C07D263/10C07C51/42C07C63/70C07C233/69Y02P20/55
Inventor 刘雄阮张寅周国斌黄想亮曹倩姚成志
Owner ZHEJIANG MENOVO PHARMA
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