Erdosteine purifying method

A purification method and technology of crude erdosteine, applied in the direction of organic chemistry, can solve the problems of long operation time, cumbersome operation, difficult industrial production, etc., and achieve the effect of simple operation and high yield

Inactive Publication Date: 2018-10-12
JIANGSU HAICI BIOLOGICAL PHARMA CO LTD OF YANGTZE RIVER PHARMA GRP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The column chromatography method needs to consider the column efficiency to achieve different adsorption, desorption, re-adsorption, and re-desorption capabilities of different substances, and the separation process requires a large amount of elution solvent, which is easy to introduce new impurities; and each purification batch is small and the operation time is long. Very long and cumbersome to operate
[0007] Operators have high requirements and are difficult to apply to industrial production

Method used

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  • Erdosteine purifying method

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Effect test

Embodiment 1

[0031] In the present embodiment, the purification method of erdosteine ​​comprises the following steps:

[0032] 1) Add 10Kg of crude erdosteine ​​to a 200L reaction kettle, then add 100L of purified water, adjust the pH to 8.5 with 1% NaOH aqueous solution, stir and dissolve at 25±5°C, then add 20L of ethyl acetate, and stir for 10min , static layering for 20 min, liquid separation, repeat the above extraction and washing twice, liquid separation to obtain crude erdosteine ​​aqueous solution.

[0033] 2) Adjust the pH of the crude erdosteine ​​aqueous solution obtained above to 2.5 with hydrochloric acid, stir and crystallize at 25±5°C for 5 hours, filter, and dry to obtain 9.2Kg of fine erdosteine ​​with a yield of 92% and a purity of HPLC 99.7%, the highest simple and impurity is 0.07%.

Embodiment 2

[0035] In the present embodiment, the purification method of erdosteine ​​comprises the following steps:

[0036] 1) Add 10Kg of crude erdosteine ​​to a 200L reaction kettle, then add 100L of purified water, adjust the pH to 5.0 with aqueous sodium bicarbonate solution, stir and dissolve at 25±5°C, then add 5L of isopropyl ether, and stir for 10min. Static layering for 20 min, liquid separation, repeated extraction and washing twice, liquid separation to obtain crude erdosteine ​​aqueous solution.

[0037] 2) Adjust the pH of the crude erdosteine ​​aqueous solution obtained above to 1.0 with phosphoric acid, stir and crystallize at 25±5°C for 5 hours, filter, and dry to obtain 8.9Kg of fine erdosteine ​​with a yield of 89% and a purity of HPLC 99.5%, the highest single impurity is 0.05%.

Embodiment 3

[0039] In the present embodiment, the purification method of erdosteine ​​comprises the following steps:

[0040] 1) Add 10Kg of crude erdosteine ​​to a 200L reaction kettle, then add 100L of purified water, adjust the pH to 14 with 1% potassium hydroxide aqueous solution, stir and dissolve at 25±5°C, and then add 2000L of dichloromethane, Stirring for 10 minutes, static layering for 20 minutes, liquid separation, repeating the above extraction and washing twice, liquid separation to obtain crude erdosteine ​​aqueous solution.

[0041] 2) Adjust the pH of the crude erdosteine ​​aqueous solution obtained above to 6.0 with sulfuric acid, stir and crystallize at 25±5°C for 5 hours, filter, and dry to obtain 9.0Kg of fine erdosteine, with a yield of 90%, HPLC purity 99.4%, the highest single impurity is 0.08%.

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Abstract

The invention provides an erdosteine purifying method. The method comprises the following steps: 1) preparing an aqueous solution of crude erdosteine: dissolving crude erdosteine in an aqueous solution which is near-neutral to alkaline, adding an organic solvent capable of being layered with water for extraction to obtain the aqueous solution of crude erdosteine, wherein the volume ratio of the organic solvent to the alkaline aqueous solution is 0.05-20:1; 2) preparing fine erdosteine: regulating the aqueous solution of the crude erdosteine obtained in step 1) to be acidic by acid, separatingout solids, and performing filtering and drying to obtain the fine erdosteine. On the basis of the specificity that the erdosteine structure contains carboxyl groups, column chromatography which is high in operation difficulty and not suitable for industrial production is not needed for purification, only an alkali-solution and acid-isolation method is adopted for purification, operation is convenient in the purifying process, impurities in the crude erdosteine can be removed effectively, finally, purity of the fine erdosteine can reach 99.4% or higher, any individual impurity is lower than 0.1%, yield is high, and the method is applicable to industrial production.

Description

technical field [0001] The invention relates to a purification method of erdosteine, which belongs to the technical field of medicine and chemical industry. Background technique [0002] Erdosteine ​​(Erdosteine), chemical name: (±)-N-[2-(carboxymethylthiol)-acetyl]-homocysteine ​​thiolactone, molecular formula: C 8 h 11 NO 4 S 2 , molecular weight: 249.3, CAS number: 84611-23-4, the structural formula is as follows: [0003] [0004] Erdosteine ​​is a mucolytic drug developed by Edmond Pharma in Italy and Refarmed in Switzerland. It is mainly used for the treatment of acute and chronic bronchitis, obstructive pulmonary disease and other diseases when the sputum is sticky and difficult to cough up. [0005] There is no special report on the purification method of erdosteine ​​in the existing literature, but the commonly used purification method is recrystallization, and the recrystallization solvent is generally ethanol, acetone, etc. The prior art can easily obtain ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/36
CPCC07D333/36
Inventor 史登健马振千金荣章李生勤鹿贵花
Owner JIANGSU HAICI BIOLOGICAL PHARMA CO LTD OF YANGTZE RIVER PHARMA GRP
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