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Method for preparing amide impurity of ibuprofen arginine injection

A technology for injection of amide and arginine, which is applied in the field of drug synthesis, can solve the problems of poor water solubility of ibuprofen, and achieve the effects of simple and feasible process, easy-to-obtain raw materials, and mild reaction conditions

Inactive Publication Date: 2018-04-20
SHANDONG XINHUA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, ibuprofen has poor water solubility. In order to study ibuprofen solution formulations, we used ibuprofen and arginine to form ibuprofen arginine salt to improve its water solubility.
However, since arginine has an amino active group, it will produce ibuprofen arginine amide impurities when it is compatible with ibuprofen, so it is necessary for us to study the amide impurities produced by the two to determine its effect on injection liquid stability

Method used

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  • Method for preparing amide impurity of ibuprofen arginine injection
  • Method for preparing amide impurity of ibuprofen arginine injection
  • Method for preparing amide impurity of ibuprofen arginine injection

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Add 1.03g (0.005mol) ibuprofen to a 50ml one-necked flask, then add 2.98g (0.025mol) thionyl chloride, stir to dissolve at 15°C, add 1 drop of DMF dropwise, and stir at room temperature for 1h. Concentrate the excess thionyl chloride to obtain the acid chloride intermediate for use.

[0026] Add 20ml of tetrahydrofuran to the above crude product, stir and dissolve at 15°C, then add 0.87g (0.005mol) arginine, stir until all arginine is dissolved, and continue to react at room temperature for 1h. Tetrahydrofuran was concentrated under reduced pressure to obtain 1.82 g of the crude amide impurity product with a content of 80.23% and a yield of 80.57%; then the methanol solution was quickly passed through the column to obtain a methanol solution of the target product, and methanol was concentrated to obtain 1.25 g of the target product with a content of 99.1% and a yield of The rate is 68.35%.

Embodiment 2

[0028] Add 2.06g (0.01mol) ibuprofen into a 50ml one-necked flask, then add 12.7g (0.1mol) oxalyl chloride, stir to dissolve at 20°C, add 2 drops of pyridine dropwise, and stir at room temperature for 2h. Concentrate the excess oxalyl chloride to obtain the acid chloride intermediate for use.

[0029] Add 20ml of DMF to the above crude product, stir to dissolve at 20°C, then add 1.83g (0.0105mol) arginine, and stir until all arginine is dissolved. Continue to react at room temperature for 2h. DMF was concentrated under reduced pressure to obtain 3.60 g of the crude amide impurity product with a content of 93.45% and a yield of 92.81%; then, the methanol solution of the target product was obtained by quickly passing through the column with methanol, and methanol was concentrated to obtain 2.93 g of the target product with a content of 99.8%. Yield is 80.67%, its structure confirms spectrogram to see attached Figure 1~6 .

Embodiment 3

[0031] Add 1.65g (0.008mol) ibuprofen into a 50ml one-necked flask, then add 18.40g (0.12mol) phosphorus oxychloride, stir to dissolve at 25°C, add 2 drops of triethylamine dropwise, and stir at room temperature for 3h. Concentrate the excess phosphorus oxychloride to obtain the acid chloride intermediate for use.

[0032] Add 20ml of acetonitrile to the above crude product, stir and dissolve at 25°C. Then add 1.53g (0.0088mol) arginine and stir until all arginine is dissolved. Continue to react for 3h. Acetonitrile was concentrated under reduced pressure to obtain 2.92g of crude amide impurity product with a content of 78.28% and a yield of 78.83%. Then, methanol was quickly passed through the column to obtain a methanol solution of the target product, and methanol was concentrated to obtain 1.88 g of the target product with a content of 98.9%. The rate is 64.12%.

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Abstract

The invention belongs to the technical field of medicine synthesis and in particular relates to a method for preparing an amide impurity of an ibuprofen arginine injection. The method comprises the following steps: under the action of a catalyst, an acylation reaction of ibuprofen and an acylation reagent firstly is performed to obtain an ibuprofen acylation intermittent; secondly, a salting reaction with arginine is performed to obtain a crude ibuprofen arginine injection amide impurity product, then the crude ibuprofen arginine injection amide impurity product is fed through a methanol column rapidly, and methanol is concentrated to obtain a pure amide impurity. The method for preparing the amide impurity of the ibuprofen arginine injection, which is provided by the invention, has the advantages of being simple and feasible in process, short in course, gentle in reaction condition, easy in raw material obtaining, free of pollution, simple in reaction aftertreatment, and the like.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, in particular to a method for preparing ibuprofen arginine injection amide impurities. Background technique [0002] Ibuprofen is an aryl alkanoic acid non-steroidal anti-inflammatory drug, which is mainly used for rheumatism and rheumatoid arthritis, and can also be used for general antipyretic and analgesic. However, ibuprofen has poor water solubility. In order to study ibuprofen solution formulations, we used ibuprofen and arginine to form ibuprofen arginine salt to improve its water solubility. However, since arginine has an amino active group, it will produce ibuprofen arginine amide impurities when it is compatible with ibuprofen, so it is necessary for us to study the amide impurities produced by the two to determine its effect on injection influence on the stability of the liquid. Contents of the invention [0003] The purpose of the present invention is to overcome the de...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C279/14C07C277/08C07C51/60C07C57/72
CPCC07C51/60C07C277/08C07C57/72C07C279/14
Inventor 张富强常森
Owner SHANDONG XINHUA PHARMA CO LTD
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