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Method for preparing 9-acridinecarboxylic acid by one-pot process

A technology for acridine and formic acid, applied to the field of one-pot preparation of 9-acridinecarboxylic acid, can solve the problems of complicated operation, low natural background, easy agglomeration of intermediate isatin, etc., and achieves the effect of simple operation and saving investment.

Active Publication Date: 2021-11-09
CHONGQING MEDICAL & PHARMA COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Compared with other luminescent reagents, acridinium ester has the advantages of high quantum yield, high luminous efficiency, simple luminescent system as a chemiluminescent marker, low natural background, less interference, and high signal-to-noise ratio. It has been used as an important luminescent Reagents have been widely used in the detection of new coronavirus nucleic acid, but there is no report on the industrial production method of 9-acridine carboxylic acid, so it is of great practical significance to develop a 9-acridine carboxylic acid method suitable for industrial production
[0003] Patent document CN111777556 uses 9-methylacridine as raw material to obtain 9-acridine formic acid through peroxide oxidation, the raw material is expensive, and involves dangerous reaction of peroxidation, which is not conducive to industrialization; in patent document 9802421, aluminum trichloride is used, A large amount of heavy metal acid water is produced, which is not environmentally friendly; the patent document CN104418887A uses diphenylamine as a raw material to react with oxalyl chloride first, and then closes the ring in toluene to obtain the intermediate isatin, and then hydrolyzes with potassium hydroxide to obtain the target product. The raw material is easy to obtain and environmentally friendly. However, the obtained intermediate isatin should be extracted with ethyl acetate, washed with water
The whole operation is cumbersome, and the intermediate isatin is easy to agglomerate after closing the ring, and the solubility is poor. In actual operation, 20 times the solvent is needed to completely dissolve it. In actual production, equipment and raw material resources are wasted, which is not conducive to industrialization

Method used

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  • Method for preparing 9-acridinecarboxylic acid by one-pot process
  • Method for preparing 9-acridinecarboxylic acid by one-pot process
  • Method for preparing 9-acridinecarboxylic acid by one-pot process

Examples

Experimental program
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Effect test

Embodiment 1

[0019]

[0020] Add 10L of toluene and 19kg (0.149mol) of oxalyl chloride into a 200L glass-lined kettle, control the temperature at 5-10°C, and add dropwise a solution of 15.7kg (0.0927mol) of diphenylamine in toluene (30l) under nitrogen protection.

[0021] After the addition, slowly raise the temperature to 55-60°C and react for 2 hours until the reaction is complete. A large amount of gas is generated during the reaction, which is absorbed by the sodium hydroxide solution.

[0022] After the reaction, unreacted oxalyl chloride and toluene were removed under reduced pressure. Cool to room temperature, add 20 L of anhydrous toluene to the above system under nitrogen protection, and continue to evaporate to dryness under reduced pressure.

[0023] The temperature of the remaining residue was raised to 120-130° C. under the protection of nitrogen, and the temperature was continued for 5-6 hours, and the reaction was completed.

[0024] Add 28.8 kg (0.5 mol) of potassium h...

Embodiment 2

[0026]

[0027] Add 10 L of chloroform and 19 kg (0.149 mol) of oxalyl chloride into a 200 L glass-lined kettle. The temperature was controlled at 5-10° C., and a solution of 15.7 kg (0.0927 mol) of diphenylamine in chloroform (30 l) was added dropwise under nitrogen protection. After the addition, slowly raise the temperature to 55-60°C and react for 2 hours until the reaction is complete. A large amount of gas is generated during the reaction, which is absorbed by the sodium hydroxide solution.

[0028] After the reaction, unreacted oxalyl chloride and trichloromethane were removed under reduced pressure. After cooling to room temperature, 20 L of anhydrous chloroform was added to the above system under the protection of nitrogen, and the mixture was evaporated to dryness under reduced pressure.

[0029] The temperature of the remaining residue was raised to 120-130° C. under the protection of nitrogen, and the temperature was continued for 5-6 hours, and the reaction wa...

Embodiment 3

[0032]

[0033] Add 10 L of toluene and 14 kg (0.11 mol) of oxalyl chloride into a 200 L glass-lined kettle. Control the temperature at 5-10° C., and add a solution of 15.7 kg (0.0927 mol) of diphenylamine in toluene (30 l) dropwise under nitrogen protection.

[0034] After the addition, slowly raise the temperature to 55-60°C and react for 2 hours until the reaction is complete. A large amount of gas is generated during the reaction, which is absorbed by the sodium hydroxide solution.

[0035] After the reaction, unreacted oxalyl chloride and toluene were removed under reduced pressure. Cool to room temperature, add 20 L of anhydrous toluene to the above system under nitrogen protection, and continue to evaporate to dryness under reduced pressure.

[0036] The temperature of the remaining residue was raised to 120-130° C. under the protection of nitrogen, and the temperature was continued for 5-6 hours, and the reaction was completed.

[0037] Add 20kg (0.5mol) of sodium...

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Abstract

The invention discloses a method for preparing 9-acridinecarboxylic acid by a one-pot process. The method comprises the following steps: 1) adding oxalyl chloride and a reaction solvent into a reaction kettle, dropwise adding a diphenylamine solution at the temperature of 5-10 DEG C under the protection of nitrogen, heating to 55-60 DEG C after adding, reacting until the reaction is complete, absorbing the gas generated by the reaction by adopting alkali liquor,after the reaction is completed, carrying out reduced pressure distillation to remove unreacted oxalyl chloride and the reaction solvent, cooling to room temperature, adding the reaction solvent, continuing to carry out reduced pressure distillation until the reaction solvent is dried, heating the residue to 120-130 DEG C under the protection of nitrogen, and continuing to carry out heat preservation for 5-6 hours until the reaction is completed; and 2) adding alkali and water into the reaction product in the step 1) to form a yellow suspension, carrying out heating reflux reaction until the reaction is complete, cooling to room temperature, adjusting the pH value to 2-3 by hydrochloric acid, separating out a large amount of yellow solid, filtering, washing and drying to obtain the product. The total yield is 90% or more, and the product purity is 99% or more. The whole synthesis process is simple to operate and environment-friendly, can save a large amount of raw materials, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a method for preparing 9-acridinecarboxylic acid in one pot. Background technique [0002] As an important pharmaceutical intermediate, 9-acridinecarboxylic acid is also an important intermediate of acridinium ester or acridinium sulfonamide compound, which is an important optical detection reagent. Compared with other luminescent reagents, acridinium ester has the advantages of high quantum yield, high luminous efficiency, simple luminescent system as a chemiluminescent marker, low natural background, less interference, and high signal-to-noise ratio. It has been used as an important luminescent Reagents have been widely used in the detection of novel coronavirus nucleic acids. However, there is no report on the industrial production method of 9-acridinecarboxylic acid. Therefore, it is of great practical significance to develop a method suitable for industrial product...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D219/04
CPCC07D219/04
Inventor 侯媛芳刘殿卿何东贤王引珍
Owner CHONGQING MEDICAL & PHARMA COLLEGE