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A kind of preparation method of 5-bromo-4-chloro-2-aminoacetophenone

A technology of aminoacetophenone and aminobenzoic acid, applied in the field of preparation of pharmaceutical intermediates, can solve the problems of complicated product purification and separation, unfavorable for process amplification, harsh reaction conditions, etc., and achieves low cost, convenient operation and good stability. Effect

Active Publication Date: 2019-02-22
CHEMSHUTTLE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The yield reported in the literature is low, about 20%, and the reaction conditions are harsh, the reagents used are highly corrosive, the reaction temperature is high, the product purification and separation are complicated, and it is not conducive to process scale-up, etc.

Method used

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  • A kind of preparation method of 5-bromo-4-chloro-2-aminoacetophenone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] A preparation method of 5-bromo-4-chloro-2-aminoacetophenone, comprising the steps of:

[0019] (1) Preparation of 5-bromo-4-chloro-2-aminobenzoic acid

[0020] Add methanol (1000mL, 24.71mol) to a 2000mL three-neck flask, and add the raw material 4-chloro-2-aminobenzoic acid (20.0g, 0.11mol, 1eq) under stirring. After stirring for 5 minutes, the solution is clear and cooled with an ice-salt bath to -15°C, and then bromine (20.6g, 0.12mol, 1.1eq) was dissolved in methanol (100mL, 2.47mol), and slowly added dropwise to the above solution, the reaction was exothermic, and the rate of addition kept the internal temperature not exceeding -10°C. After the dropwise addition is completed, keep stirring at -10°C for 2 hours, then slowly pour into saturated aqueous sodium thiosulfate solution, and keep stirring, a large amount of white solid precipitates, filter with suction, wash the filter cake with water three times, drain and vacuum The crude product was obtained by drying,...

Embodiment 2

[0027] A preparation method of 5-bromo-4-chloro-2-aminoacetophenone, comprising the steps of:

[0028] (1) Preparation of 5-bromo-4-chloro-2-aminobenzoic acid

[0029] Add methanol (800mL, 19.77mol) to a 2000mL three-necked flask, and add the raw material 4-chloro-2-aminobenzoic acid (20.0g, 0.11mol, 1eq) under stirring. After stirring for 5 minutes, the solution is clear and cooled with an ice-salt bath to -10°C, and then bromine (20.6g, 0.12mol, 1.1eq) was dissolved in methanol (50mL, 1.23mol), and slowly added dropwise to the above solution, the reaction was exothermic, and the rate of addition kept the internal temperature not exceeding -10°C. After the dropwise addition is completed, keep stirring at -10°C for 2 hours, then slowly pour into saturated aqueous sodium thiosulfate solution, and keep stirring, a large amount of white solid precipitates, filter with suction, wash the filter cake with water three times, drain and vacuum The crude product was obtained by drying,...

Embodiment 3

[0035] A preparation method of 5-bromo-4-chloro-2-aminoacetophenone, comprising the steps of:

[0036] (1) Preparation of 5-bromo-4-chloro-2-aminobenzoic acid

[0037] Add methanol (500mL, 12.35mol) to a 2000mL three-necked flask, and add the raw material 4-chloro-2-aminobenzoic acid (20.0g, 0.11mol, 1eq) under stirring. After stirring for 5 minutes, the solution is clear and cooled with an ice-salt bath to -15°C, then bromine (20.6g, 0.12mol, 1.1eq) was dissolved in methanol (50mL, 1.23mol), and slowly added dropwise to the above solution, the reaction was exothermic, and the rate of addition kept the internal temperature not exceeding -10°C. After the dropwise addition is completed, keep stirring at -10°C for 2 hours, then slowly pour into saturated aqueous sodium thiosulfate solution, and keep stirring, a large amount of white solid precipitates, filter with suction, wash the filter cake with water three times, drain and vacuum The crude product was obtained by drying, and...

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Abstract

The invention discloses a preparation method of 5-bromo-4-chloro-2-aminoacetophenone. The method comprises the following steps: taking 4-chloro-2-aminobenzoic acid as a starting raw material, and preparing 5-bromo-4-chloro-2-aminobenzoic acid through a halogenating reaction; then, using the 5-bromo-4-chloro-2-aminobenzoic acid to carry out a condensation reaction to prepare 2-amino-5-bromo-4-chloro-N-methoxy-N-methylbenzamide; and finally, using the 2-amino-5-bromo-4-chloro-N-methoxy-N-methylbenzamide to carry out a substitution reaction with lithium methide to prepare the 5-bromo-4-chloro-2-aminoacetophenone. The method disclosed by the invention is short in process path, convenient in operation, mild and easily controlled in reaction conditions and relatively low in cost, and is more applicable for process amplification; and the product is easy for purification and relatively high in yield.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a method for preparing 5-bromo-4-chloro-2-aminoacetophenone by using 4-chloro-2-aminobenzoic acid as a raw material through halogenation, condensation and substitution reactions Methods. Background technique [0002] 5-bromo-4-chloro-2-aminoacetophenone is an important pharmaceutical intermediate, and its downstream products have important uses. According to the existing literature Journal of medicinal chemistry, 2007, 50, 2108-2116, it is reported that 5-bromo-4-chloro-2-aminoacetophenone and its analogues are active molecules synthesized as substrates against hepatitis C NS5B polymerase The inhibitory effect is more obvious, has potential development and research value, the method for the synthetic 5-bromo-4-chloro-2-aminoacetophenone and its analogues of report in the literature is: Substrate halogenated aniline is in BCl3 / acetonitrile / Reflux overnigh...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C221/00C07C225/22
CPCC07C221/00C07C227/16C07C259/06C07C225/22C07C229/56
Inventor 邵加春
Owner CHEMSHUTTLE