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Bromofluoro polysubstituted benzaldehyde derivative and preparation method

A technology of bromobenzaldehyde and bromoaniline, applied in the field of pharmaceutical intermediates 3, can solve the problems of short reaction time, cannot be promoted, cannot have higher yield reaction time, etc., and achieves the effects of easy operation, high economic value, and saving raw materials

Active Publication Date: 2018-12-07
上海罕道医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Provided in CN99117201.9 is a method for producing 3-phenoxy-4-fluorobenzaldehyde by p-fluorobenzaldehyde; provides the production method of p-fluorobenzaldehyde in CN98111383.4; provides in CN201410024602.0 A kind of benzaldehyde thiosemicarbazone derivative and its application are disclosed, which are all examples of the application and synthesis of benzaldehyde derivatives, but the 3,5-difluoro-4-bromobenzaldehyde mentioned in the application is rarely used as The application of pharmaceutical intermediates appears, or there are documents or information published
[0003] Due to the properties of this molecule, the method cannot be extended to the synthesis of other similar structures
This is determined by the ingenuity of the preparation method, the higher yield and the non-reproducibility of the shorter reaction time obtained from numerous experiments. Other routes basically cannot have higher yield or acceptable reaction time.

Method used

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  • Bromofluoro polysubstituted benzaldehyde derivative and preparation method
  • Bromofluoro polysubstituted benzaldehyde derivative and preparation method
  • Bromofluoro polysubstituted benzaldehyde derivative and preparation method

Examples

Experimental program
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Effect test

Embodiment 1

[0022] Step S1: Prepare 90g of 2,6-difluoro-4-bromoaniline, 900ml of N,N-dimethylformamide and 124g of cuprous cyanide as raw materials, and select a 2L four-necked flask as the reaction vessel , Blow in nitrogen protection, add the aforementioned 2,6-difluoro-4-bromoaniline to all the N,N-dimethylformamide in the four-neck flask, then add all the cuprous cyanide, and reflux for 18h After confirming the completion of the reaction by TLC detection, cool the reaction mixture to room temperature, prepare a large open container to hold 2.5L of 15% ammonia water, pour the cooled reaction mixture, extract 3 times with appropriate ethyl acetate, and combine The organic phase was washed three times with 400ml of saturated brine, dried with 90g of anhydrous sodium sulfate, and concentrated to dryness under vacuum to obtain the crude product of step S1; the crude product of step S1 was dissolved in 0.9L of dichloromethane, and 100- 140g 200 mesh silica gel, after mixing uniformly, remove...

Embodiment 2

[0029] Step S1: Prepare 100g of 2,6-difluoro-4-bromoaniline, 1000ml of N,N-dimethylformamide and 128g of cuprous cyanide as raw materials, and select a 2.5L four-necked flask as the reaction The container is protected by nitrogen, and the aforementioned 2,6-difluoro-4-bromoaniline is added to all the N,N-dimethylformamide in the four-neck flask, and then all of the cuprous cyanide is added, and refluxed 20h, after confirming the completion of the reaction by TLC, cool the reaction mixture to room temperature, prepare a large open container to hold 3L of 15% ammonia water, pour the cooled reaction mixture, extract 4 times with appropriate amount of ethyl acetate, and combine The organic phase was washed three times with 500ml of saturated brine, dried with 100g of anhydrous sodium sulfate, and concentrated to dryness under vacuum to obtain the crude product of step S1; dissolve the crude product of step S1 with 1L of dichloromethane, and add 100-200 150g mesh silica gel, after m...

Embodiment 3

[0036] Step S1: Prepare 110g of 2,6-difluoro-4-bromoaniline, 1100ml of N,N-dimethylformamide and 132g of cuprous cyanide as raw materials, and select a 3L four-necked flask as the reaction vessel , Blow in nitrogen protection, add the aforementioned 2,6-difluoro-4-bromoaniline to all the N,N-dimethylformamide in the four-neck flask, then add all the cuprous cyanide, and reflux for 22h After confirming the completion of the reaction by TLC detection, cool the reaction mixture to room temperature, prepare a large open container to hold 3.5L of 15% ammonia water, pour the cooled reaction mixture, extract 5 times with appropriate ethyl acetate, and combine The organic phase was washed three times with 600ml of saturated brine, dried with 110g of anhydrous sodium sulfate, and concentrated to dryness under vacuum to obtain the crude product of step S1; the crude product of step S1 was dissolved in 1.1L of dichloromethane and added 100- 160g 200 mesh silica gel, after mixing uniformly...

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Abstract

The invention relates to a bromofluoro polysubstituted benzaldehyde derivative and a preparation method. The preparation method comprises the following steps: obtaining 2,6-difluoro-4-cyano phenylamine under nitrogen protection by using 2,6-difluoro-4-bromaniline and N,N-dimethyl formamide and cuprous cyanide as raw materials to react; carrying out a reaction on 2,6-difloro-4-bromaniline and sodium hydroxide, adjusting the pH value and carrying out decompressed evaporation to obtain 3,5-difluoro-4-aminobenzoic acid; carrying out a reaction on 3,5-difluoro-4-aminobenzoic acid and absolute ethylalcohol and concentrated sulfuric acid to obtain 3,5-difloro-4-ethyl aminobenzoate and carrying out a reaction with 40% hydrobromic acid and cuprous bromide to obtain 3,5-difluoro-4-ethyl bromobenzoate; adding sodium borohydride and carrying out a reaction to obtain 3,5-difloro-4-bromobenzyl alcohol; and carrying out a reaction on 3,5-difloro-4-bromobenzyl alcohol with MnO2 in chloroform to obtain a final product bromofluoro polysubstituted benzaldehyde.

Description

Technical field [0001] The invention relates to the field of pharmaceutical intermediates, in particular to a method for synthesizing 3,5-difluoro-4-bromobenzaldehyde as a pharmaceutical intermediate. Background technique [0002] Benzaldehyde and its derivatives are an important class of compounds with strong biological activity. They are widely used in medicine, pesticides and other fields. Therefore, the synthesis of benzaldehyde derivatives has received extensive attention, especially in pharmaceutical intermediates. widely used. CN99117201.9 provides a method for producing 3-phenoxy-4-fluorobenzaldehyde by p-fluorobenzaldehyde; CN98111383.4 provides a method for producing p-fluorobenzaldehyde; CN201410024602.0 A benzaldehyde thiosemicarbazone derivative and its application are presented. These are all examples of the application and synthesis of benzaldehyde derivatives, but the 3,5-difluoro-4-bromobenzaldehyde mentioned in this application is rarely used. The application ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C45/29C07C47/55
CPCC07C29/147C07C45/298C07C47/55C07C67/307C07C227/18C07C253/14C07C33/46C07C69/76C07C229/60C07C255/58
Inventor 刘建勋江勇军刘波
Owner 上海罕道医药科技有限公司
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