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Preparation method of 2-bromo-4-chlorobenzaldehyde

A technology of toluene and formic acid, which is applied in the field of preparation of 2-bromo-4 chlorobenzaldehyde, can solve the problems of excessive three wastes, non-environmental protection, and complicated post-treatment

Pending Publication Date: 2021-08-24
湖南华腾制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The literature Journal of Organic Chemistry, 85(1), 248-276; 2020 discloses the synthesis route of compound I, the last step of which uses silver nitrate, the post-treatment is complicated, the product purity is not high, and the reaction yield is low
[0005] Patent WO2009158426 discloses the synthesis route of intermediate I: 2-bromo-4-chlorotoluene is used as the starting material, and intermediate I is obtained through substitution, hydrolysis, and elimination reactions. The reaction yield is low, and each step in the route involves post-treatment , produces a lot of three wastes, is not environmentally friendly, and is not suitable for industrial amplification

Method used

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  • Preparation method of 2-bromo-4-chlorobenzaldehyde
  • Preparation method of 2-bromo-4-chlorobenzaldehyde
  • Preparation method of 2-bromo-4-chlorobenzaldehyde

Examples

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Effect test

Embodiment 1

[0071] The preparation of embodiment 1 compound B

[0072]

[0073] Add 40L of 50% sulfuric acid to the 100L reaction kettle, stir, and slowly add compound A (5kg) that has been melted in advance. Reaction at ℃ for 4-12 hours, HPLC monitoring of the reaction end point, after the reaction, cool down to room temperature, add 40L of water and stir for 2 hours, filter with suction, wash the filter cake with a small amount of water until the filtrate is neutral, drain it, and dry it under normal pressure at 50-55°C to obtain compound B ( 7.7kg), yield 97.8%, purity 98%.

Embodiment 2

[0074] The preparation of embodiment 2 compound C

[0075]

[0076] Add 75L of ethanol and compound B (7.5kg) to a 100L reaction kettle at room temperature, stir and heat up to 60-80°C, after dissolving, add Raney Ni (0.75kg), control the temperature at 60-80°C, and add 80% hydration solution dropwise Hydrazine (10kg), dropwise reacted for 4-12h, TLC controlled the reaction end point, after the reaction, cooled to normal temperature, filtered to remove Raney Ni (be careful not to drain), the filtrate was concentrated and evaporated to remove the solvent to obtain compound C (6.3kg), Yield 97.5%, purity 97%.

Embodiment 3

[0077] The preparation of embodiment 3 compound D

[0078]

[0079] Add 25L of 15% hydrochloric acid to a 50L reactor, below 20°C, slowly add compound C (5kg), control the temperature below 10°C, add dropwise sodium nitrite aqueous solution (2kg dissolved in 6L of water) to complete the reaction for 1-2h, HPLC Monitor the end point of the reaction, and keep it ready for use after the reaction is completed.

[0080] Add 10L of 15% hydrochloric acid to the 100L reactor, then add CuCl (4kg), drop the reaction liquid in the above 50L reactor into the 100L reactor, control the temperature at 0-10°C, finish the reaction for 2-5 hours, and monitor the reaction by HPLC End point, after the reaction is over, add DCM (15L) to separate layers, extract the aqueous layer with DCM (5L), combine the organic layers, add 10L water to wash twice, evaporate the organic layer to remove DCM, and distill the crude product under reduced pressure to obtain compound D (5kg) , yield 90.5%, purity 9...

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Abstract

The invention relates to a preparation method of 2-bromo-4-chlorobenzaldehyde, and belongs to the field of medicinal chemistry. The preparation method comprises the following steps: by taking p-nitrotoluene as a starting material, carrying out substitution, reduction, substitution, substitution, substitution, hydrolysis and elimination reactions to obtain 2-bromo-4-chlorobenzaldehyde. Compared with the prior art, the method has the advantages that the reaction time is shortened, the reaction temperature is reduced to normal temperature from 120 DEG C or above, the reaction conditions become mild, and the yield of the obtained product is increased to 90% or above from about 70%. As the reaction temperature is reduced, a high-boiling-point solvent is not required to participate in the reaction, the post-treatment is simple, and the method is more suitable for increasingly strict safe and environment-friendly industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of 2-bromo-4 chlorobenzaldehyde. Background technique [0002] 2-Bromo-4-chlorobenzaldehyde, CAS: 84459-33-6, is an important organic synthesis intermediate and pharmaceutical intermediate, widely used in laboratory research and development process and chemical production process. Its chemical structural formula is as shown in formula I below: [0003] [0004] The literature Journal of Organic Chemistry, 85(1), 248-276; 2020 discloses the synthesis route of Compound I. Silver nitrate is used in the last step of the route, the post-treatment is complicated, the product purity is not high, and the reaction yield is low. [0005] Patent WO2009158426 discloses the synthesis route of intermediate I: 2-bromo-4-chlorotoluene is used as the starting material, and intermediate I is obtained through substitution, hydrolysis, and elimination reactions. The reacti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C45/42C07C47/55C07D295/073C07C17/093C07C17/14C07C25/02C07C201/12C07C205/12C07C209/36C07C211/52
CPCC07C45/42C07D295/073C07C17/093C07C17/14C07C201/12C07C209/365C07C47/55C07C25/02C07C205/12C07C211/52
Inventor 何光明金艳娟陈仔玲
Owner 湖南华腾制药有限公司
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