Preparation method of 5-bromo-2-chlorobenzoic acid

A technology of chlorobenzoic acid and aminobenzoic acid, which is applied in the preparation of carboxylate, organic compound, and cyanide reaction, etc., can solve the problems of unfavorable industrial production, long reaction time, and high environmental pressure, and achieve effective Benefits of industrial production, short production cycle, high yield and purity

Inactive Publication Date: 2021-12-17
山东诚创蓝海医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this method, when carrying out the chlorination reaction, because phosphorus pentachloride and o-chlorotoluene are solid-liquid two-phase in the early stage of the reaction, ultraviolet light has poor penetration rate to ordinary glass, resulting in longer reaction time, and after the reaction is completed, it is necessary to reduce the Pressure distillation purification, resulting in low yield, only 40%
Therefore the production cycle of this method is longer, the yield is on the low side, and the environmental protection pressure is bigger, is unfavorable for industrialized production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Add 2-nitrobenzoic acid (50g, 0.299mol) into dichloromethane (200mL), stir, add thionyl chloride (42.7g, 0.359mol), heat up to reflux temperature, reflux for 5 hours, the remaining raw materials < 1%, stop the reaction; drop the temperature below 5°C, add methanol (15g, 0.469mol) dropwise, control the temperature below 10°C during the dropwise addition, stir for 30 minutes after the dropwise addition, and concentrate under reduced pressure at 40°C to obtain light Yellow liquid methyl 2-nitrobenzoate (first intermediate) 48.8g, yield 90%, purity 99.2%.

Embodiment 2

[0043] Add 2-nitrobenzoic acid (50g, 0.299mol) into methanol (200mL), stir, cool down to 0-5°C, add thionyl chloride (42.7g, 0.359mol) dropwise, after the dropwise addition, in React at a temperature of 0-5°C for 1 hour. After the reaction is completed, slowly raise the temperature to reflux temperature and react at reflux for 2 hours. If the remaining raw materials are <1%, stop the reaction and concentrate under reduced pressure at 40°C to obtain 2- Methyl nitrobenzoate (first intermediate) 49.3g, yield 91%, purity 99.3%.

Embodiment 3

[0045] Add 2-nitrobenzoic acid (50g, 0.299mol) into toluene (200mL), stir, add anhydrous magnesium sulfate (20g), ethanol (22g, 0.478mol), heat up to reflux temperature, and reflux for 7 hours. <1% of the raw material remained, the reaction was stopped, filtered, and the filtrate was concentrated under reduced pressure to obtain 51.3 g of ethyl 2-nitrobenzoate (the first intermediate) as a light yellow liquid, with a yield of 87.8% and a purity of 99.6%.

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PUM

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Abstract

The invention discloses a preparation method of 5-bromo-2-chlorobenzoic acid, and belongs to the field of medicine synthesis. The preparation method comprises the following steps: (1) carrying out esterification reaction on 2-nitrobenzoic acid and alcohol to obtain a first intermediate; (2) carrying out reduction reaction on the first intermediate and a first reducing agent to obtain a second intermediate; (3) carrying out a halogenation reaction on the second intermediate and a first halogenation reagent, adding a second reducing agent into the reaction system after the halogenation reaction is completed, carrying out a reduction reaction, and then carrying out a hydrolysis reaction with alkali to obtain 5-bromo-2-aminobenzoic acid; and (4) carrying out diazotization reaction on the 5-bromo-2-aminobenzoic acid and a diazotization reagent, and then carrying out halogenation reaction on the 5-bromo-2-aminobenzoic acid and a second halogenation reagent to obtain the 5-bromo-2-chlorobenzoic acid. The preparation method has the advantages of mild reaction conditions, safe and simple operation, short production period, cheap and easily available raw materials and solvents, no explosive or highly toxic products, and facilitation of environmental protection; and the prepared product has high yield and purity, and is beneficial to industrial production.

Description

Technical field [0001] This application belongs to the field of drug synthesis, and specifically relates to a preparation method of 5-bromo-2chlorobenzoic acid. Background technique [0002] 5-Bromo-2-chlorobenzoic acid has an important use in pharmaceutical synthesis. It is the synthetic raw material for hypoglycemic drugs such as empagliflozin, dapagliflozin, sogliflozin, and epagliflozin. This type of drugs is Sodium-glucose cotransporter 2 inhibitors, which reduce renal glucose reabsorption and are used to treat patients with type 2 diabetes. [0003] According to literature reports, there are two main methods for the synthesis of 5-bromo-2-chlorobenzoic acid: [0004] The first method: use toluene as the starting material, react with chlorine to obtain o-chlorotoluene, then oxidize the methyl group with potassium permanganate to obtain o-chlorobenzoic acid, and then perform bromination reaction with liquid bromine or NBS to obtain 5- Bromo-2-chlorobenzoic acid. Howev...

Claims

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Application Information

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IPC IPC(8): C07C51/363C07C63/70C07C227/04C07C227/18C07C229/56C07C201/12C07C205/57
CPCC07C51/363C07C227/04C07C227/18C07C201/12C07C205/57C07C229/56C07C63/70
Inventor 吕志涛谭光明于华智刘彬彬高长彬王士忠陈立伟
Owner 山东诚创蓝海医药科技有限公司
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