Preparation method of 2,6-dichloro-3-fluorobenzaldehyde and preparation method of fluoroquinolones

A technology of fluorobenzaldehyde and fluorobenzoic acid, which is applied in the preparation of organic compounds, carbon-based compounds, magnesium organic compounds, etc., can solve the problems of complicated operation, difficult to obtain raw materials, expensive raw materials, etc., and achieve simple preparation process, Good economic value and high product purity

Active Publication Date: 2020-08-14
ZHEJIANG LANGHUA PHARMA
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Problems solved by technology

[0004] (1) Patent WO2014142086 uses 2,6-dichloro-3-fluorobenzoic acid as the raw material, 2,6-dichloro-3-fluorobenzyl alcohol is obtained after reduction of borane dimethyl sulfide, and then treated with pyridine sulfur trioxide Oxidation in DMSO solvent to prepare 2,6-dichloro-3-fluorobenzaldehyde; however, the raw materials of this route method are not easy to get, the reaction conditions are harsh, and the operation process is complicated;
[0005] (2) The patent CN103087050 uses 2,4-dichlorofluorobenzene as a raw material, reacts with n-butyllithium at -78°C, and then reacts with methyl formate to obtain 2,6-dichloro-3- Fluorobenzaldehyde, this method also has the disadvantages of expensive raw materials, harsh reaction conditions, complicated operation, etc.

Method used

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  • Preparation method of 2,6-dichloro-3-fluorobenzaldehyde and preparation method of fluoroquinolones
  • Preparation method of 2,6-dichloro-3-fluorobenzaldehyde and preparation method of fluoroquinolones
  • Preparation method of 2,6-dichloro-3-fluorobenzaldehyde and preparation method of fluoroquinolones

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preparation example Construction

[0033] The preparation method of the present invention uses 2,4-dichloro-5-fluorobenzoic acid as a raw material, reacts in a concentrated sulfuric acid solvent under the action of a brominating reagent to generate 2,4-dichloro-3-bromo-5- Fluorobenzoic acid; Grignard for the preparation of 2,4-dichloro-3-bromo-5-fluorobenzoic acid by halogen-metal exchange reaction between 2,4-dichloro-3-bromo-5-fluorobenzoic acid and Grignard reagent Reagent, and further formylation reaction, then decarboxylation to obtain the target compound 2,6-dichloro-3-fluorobenzaldehyde, specifically, the steps of the preparation method of the present invention are as follows:

[0034] (1) 2,4-dichloro-5-fluorobenzoic acid and brominated reagent are dissolved in concentrated sulfuric acid and reacted to obtain 2,4-dichloro-3-bromo-5-fluorobenzoic acid;

[0035] In a preferred embodiment, the brominated reagent used is N-bromosuccinimide (NBS).

[0036] In a preferred embodiment, the molar ratio of NBS t...

Embodiment 1

[0060] Prepare 2,6-dichloro-3-fluorobenzaldehyde according to the method described below, and the specific steps are as follows:

[0061] (1) Add 96g of concentrated sulfuric acid with a mass concentration of 98% and 19.2g of 2,4 dichloro-5-fluorobenzoic acid into the reaction flask, and heat to 30-35°C, stir to dissolve;

[0062] Then, add 19.7gNBS in batches, after adding, keep warm for 12 hours, TLC (ethanol / ethyl acetate=1 / 1) analysis, raw material reaction is complete, is cooled to room temperature, reaction solution is poured into 300g ice water, and control The temperature of the system is less than 10°C;

[0063] Next, the obtained mixed system was filtered, washed with water, and dried, and the yield of the product 2,4 dichloro-3-bromo-5-fluorobenzoic acid was 98%;

[0064] (2) In the reaction flask, add 28.8g of 2,4 dichloro-3-bromo-5-fluorobenzoic acid and 116.2g of tetrahydrofuran, stir to dissolve, and cool to -20~30°C;

[0065] Then, add 50ml 2M i-PrMgCl / THF so...

Embodiment 2

[0071] Prepare 2,6-dichloro-3-fluorobenzaldehyde according to the method described below, and the specific steps are as follows:

[0072] (1) Add 192g of concentrated sulfuric acid with a mass concentration of 95% and 19.2g of 2,4 dichloro-5-fluorobenzoic acid into the reaction flask, heat to 50-55°C, stir to dissolve;

[0073] Then, add 19.7g NBS in batches, then keep the temperature for 5 hours, TLC (ethanol / ethyl acetate=1 / 1) analysis, the raw material reaction is complete, cool to room temperature, the reaction solution is poured into 600g ice water, and control system The temperature is less than 10°C;

[0074] Then, the obtained mixed system was filtered, washed with water and dried, and the yield of the product 2,4 dichloro-3-bromo-5-fluorobenzoic acid was 98%.

[0075] (2) In the reaction bottle, add 28.8g 2,4 dichloro-3-bromo-5-fluorobenzoic acid, 144g tetrahydrofuran, stir to dissolve, cool to 0~-5℃, add dropwise 110ml 2M i-PrMgCl / THF solution, keep warm for half ...

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Abstract

The invention relates to methods for preparing 2,6-dichloro-3-fluorobenzaldehyde and a fluoroquinolone compound.2,4-dichloro-5-fluorobenzoic acid is taken as the raw material and is in reaction in a concentrated sulfuric acid solvent under the action of a bromization reagent to generate 2,4-dichloro-3-bromine-5-fluorobenzoic acid; the 2,4-dichloro-3-bromine-5-fluorobenzoic acid and Grignard reagent isopropylmagnesium chloride are in halogen-metal exchange reaction to prepare a 2,4-dichloro-3-bromine-5-fluorobenzoic acid Grignard reagent, and the 2,4-dichloro-3-bromine-5-fluorobenzoic acid Grignard reagent is further in reaction with DMF and heated for decarboxylation to obtain the target compound 2,6-dichloro-3-fluorobenzaldehyde. Compared with the prior art, the methods for preparing the 2,6-dichloro-3-fluorobenzaldehyde and the fluoroquinolone compound have the advantages that the raw materials are easy to get, the operation technology is simple, the cost is low and the like, and the methods are favorable for industrialization scale production and have larger implement values and social and economic benefits.

Description

technical field [0001] The invention relates to the field of preparation of pharmaceutical intermediates, in particular to a preparation method of 2,6-dichloro-3-fluorobenzaldehyde and a preparation method of fluoroquinolone compounds. Background technique [0002] 2,6-Dichloro-3-fluorobenzaldehyde is a key intermediate for the preparation of new fluoroquinolones such as finafloxacin, prafloxacin and aryl kinase inhibitors, and has a good market prospect. [0003] The existing synthetic methods of 2,6-dichloro-3-fluorobenzaldehyde mainly contain the following two kinds: [0004] (1) Patent WO2014142086 uses 2,6-dichloro-3-fluorobenzoic acid as the raw material, 2,6-dichloro-3-fluorobenzyl alcohol is obtained after reduction of borane dimethyl sulfide, and then treated with pyridine sulfur trioxide Oxidation in DMSO solvent to prepare 2,6-dichloro-3-fluorobenzaldehyde; however, the raw materials of this route method are not easy to get, the reaction conditions are harsh, and...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C45/51C07C47/55
CPCC07C45/516C07C51/363C07F3/02C07C47/55C07C63/70
Inventor 林邦平马跃歧陈丹峰安友袁炬超
Owner ZHEJIANG LANGHUA PHARMA
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