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Ambroxol hydrochloride compound refining method

A technology for ambroxol hydrochloride and crude ambroxol hydrochloride, which is applied in the field of medicine to achieve the effects of reducing the amount of raw and auxiliary materials, eliminating amino side reactions, and fast reaction speed

Active Publication Date: 2013-05-01
SHANDONG YUXIN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] But in the quality standard of imported ambroxol hydrochloride injection, also only the content of external standard method is calculated impurity to related substance, trans-4-[6,8-dibromo-1,4-dihydroquinazoline-3( H)] The total amount of cyclohexanol hydrochloride (impurity B) and (2-amino-3,5-dibromophenyl) formaldehyde (impurity E) shall not be 1% of the marked amount of ambroxol perhydrochloride

Method used

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  • Ambroxol hydrochloride compound refining method

Examples

Experimental program
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Effect test

Embodiment 1

[0056] (1) Synthesis of Ambroxol intermediate

[0057] Add 10g of p-aminocyclohexanol to a clean anhydrous reaction bottle, add 180ml of absolute ethanol, stir quickly to dissolve, after dissolving, add 16.5g of potassium hydroxide, 0.1g of DMAP, 1.2g of 4-dimethylaminocyclohexanol in sequence , Control the temperature at 60°C and slowly add 40g of the compound of formula (I) in batches, continue to control the temperature at 60°C for 3 hours, after the reaction, control the temperature at 45°C to evaporate 110ml of absolute ethanol under reduced pressure, and control the time Slowly cool down to 5°C for 1 hour, grow crystals for 1 hour, filter with suction, and dry to obtain the intermediate of ambroxol, which is directly used in the next reaction without purification. The reaction formula is as follows:

[0058]

[0059] (2) Synthesis of ambroxol hydrochloride crude product

[0060] Add 160ml of ethanol, 65ml of water, 59ml of concentrated hydrochloric acid and 25ml of ...

Embodiment 2

[0065] (1) Synthesis of Ambroxol intermediate

[0066] Add 10g of p-aminocyclohexanol to a clean anhydrous reaction flask, add 190ml of anhydrous methanol, stir and dissolve quickly, after dissolving, add 15g of potassium hydroxide, 0.05g of DMAP, and 1.0g of 4-dimethylaminocyclohexanol in sequence, Control the temperature at 75°C and slowly add 60g of the compound of formula (I) in batches, and continue to control the temperature at 75°C for 1 hour. The temperature was slowly lowered to 10°C within 1 hour, the crystal was grown for 3 hours, filtered with suction, and dried to obtain the intermediate of ambroxol, which was directly used in the next reaction without purification. Reaction formula is with embodiment 1.

[0067] (2) Synthesis of ambroxol hydrochloride crude product

[0068] Add 160ml of ethanol, 65ml of water, 36ml of concentrated hydrochloric acid and 25ml of glacial acetic acid into a clean and water-free reaction bottle, add 36g of ambroxol intermediate at a...

Embodiment 3

[0072] (1) Synthesis of Ambroxol intermediate

[0073] Add 10g of p-aminocyclohexanol to a clean and water-free reaction bottle, add 180ml of absolute ethanol, stir quickly to dissolve, after dissolving, add 16.5g of potassium hydroxide, 0.1g of DMAP, 1.2g of 4-dimethylaminocyclohexanol in sequence , control the temperature at 70°C and slowly add 40g of the compound of formula (I) in batches, and continue to control the temperature at 70°C for 2 hours. Slowly cool down to 8°C for 1.5 hours, grow crystals for 2 hours, filter with suction, and dry to obtain the intermediate of ambroxol, which is directly used in the next reaction without purification. Reaction formula is with embodiment 1.

[0074] (2) Synthesis of ambroxol hydrochloride crude product

[0075]Add 160ml of ethanol, 65ml of water, 59ml of concentrated hydrochloric acid and 25ml of glacial acetic acid into a clean and water-free reaction bottle, add 36g of ambroxol intermediate at a controlled temperature of 48°C...

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Abstract

The invention relates to an ambroxol hydrochloride compound refining method, comprising a step of synthesizing an ambroxol hydrochloride crude product and a step of refining ambroxol hydrochloride, wherein the refining step comprises the following steps: 1) adding water and the ambroxol hydrochloride crude product into a reaction bottle, heating to a temperature of 70-75 DEG C and stirring, and dissolving the crude product, so as to obtain an ambroxol hydrochloride crude product solution; adding active carbon into the ambroxol hydrochloride crude product solution, decolorizing and filtering in a thermal insulating manner, and collecting filtrate; 2) cooling the filtrate to a temperature of 55-60 DEG C, carrying out thermal insulation and stirring; 3) cooling the filtrate to a temperature of 45-48 DEG C, controlling a stirring speed of 15 r / min, adding seed crystal, and crystallizing for 1 hour by controlling a temperature and a stirring speed; 4) cooling to a temperature of 20-25 DEG C and crystallizing for 20 minutes, slowly cooling to a temperature of 10 DEG C for 1.5 hours again after a crystallizing process, and obtaining an ambroxol hydrochloride fine product by leaching and drying. With the adoption of the ambroxol hydrochloride compound refining method provided by the invention, the ambroxol hydrochloride only contains an impurity B in five know impurities; and a content of the impurity B is controlled below 0.005%.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a method for refining ambroxol hydrochloride compound. Background technique [0002] Ambroxol hydrochloride (ambroxol hydrochloride) is also called bromcyclohexyl hydrochloride, and its chemical name is trans-4-[(2-amino 3.5-dibromobenzyl) amino] cyclohexanol hydrochloride, and its structural formula is as follows, is Mucolytic agent developed by Boehringer Ingelheim, Germany. The drug was launched in Germany in the early 1980s, and subsequently in France, Italy, Japan, Spain and many other countries. It is used for the treatment of various acute and chronic respiratory diseases accompanied by abnormal sputum secretion and poor expectoration function Phlegm treatment, with its positive curative effect and small adverse reactions, has always been at the top of the drug rankings in key hospitals in major cities in my country in recent years. [0003] [0004] Ambroxol hydrochl...

Claims

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Application Information

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IPC IPC(8): C07C215/44C07C213/10C07C233/91C07C231/12B01J31/02
Inventor 李明杰陈雨刘新泉宋良伟
Owner SHANDONG YUXIN PHARMA CO LTD
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