Synthesis method of ambroxol hydrochloride compound

A technology of ambroxol hydrochloride and a synthetic method, which is applied in the field of drug synthesis, can solve the problems that impurities cannot be effectively avoided, and the type and content of impurities cannot be effectively reduced, so as to improve the completeness of the reaction, improve the quality of the product, and increase the yield. Effect

Active Publication Date: 2013-05-01
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] 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) must not be 1% of the marked amount of ambroxol perhydrochloride
[0017] After the present inventor has carried out a large amount of studies to the synthesis of ambroxol hydrochloride, finds that adopting the synthetic method of prior art not only can not effectively avoid the generation of above-mentioned impurity, and can not effectively reduce the kind and content of impurity

Method used

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  • Synthesis method of ambroxol hydrochloride compound
  • Synthesis method of ambroxol hydrochloride compound
  • Synthesis method of ambroxol hydrochloride compound

Examples

Experimental program
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Effect test

Embodiment 1

[0050] (1) Synthesis of Ambroxol intermediate

[0051] Add 10g of p-aminocyclohexanol to a clean and 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:

[0052]

[0053] (2) Synthesis of ambroxol hydrochloride crude product

[0054] Add 160ml of ethanol, 65ml of water, 59ml of concentrated hydrochloric acid and 25ml...

Embodiment 2

[0057] (1) Synthesis of Ambroxol intermediate

[0058] Add 10g of p-aminocyclohexanol to a clean anhydrous reaction bottle, 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.

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

[0060] 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 ...

Embodiment 3

[0062] (1) Synthesis of Ambroxol intermediate

[0063] 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 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.

[0064] (2) Synthesis of ambroxol hydrochloride crude product

[0065] 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, st...

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Abstract

The invention relates to a synthesis method of an ambroxol hydrochloride compound, comprising the following steps of: 1) taking a compound of a formula (I) as a starting raw material; taking DMAP (Dimethylaminopyridine) and 4-dimethylamino cyclohexanol as catalysts to react with p-amino cyclohexanol under the condition of the presence of absolute methanol and anhydrous potassium carbonate to obtain an intermediate; and 2) under the condition of the presence of a solvent ethanol, water and glacial acetic acid, taking the intermediate and concentrated hydrochloric acid to react to generate ambroxol hydrochloride. According to the synthesis method disclosed by the invention, diacetylamido is used for carrying out complete protection on active nitrogen atoms of the starting raw material to avoid a benzene ring 2-substituents amino secondary reaction; the difficulties of the prior art that more condensation secondary reactions, low yield, high catalyst cost, harsh process conditions and the like are overcome to form a novel process with a short reaction line, moderate conditions and small pollution; the yield is higher than 67%; impurity types and contents are obviously reduced; and only one of five known impurities exists and the product purity is more than 99.9%. The formula (I) is shown as the specification.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a synthetic method of 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, the 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] The synthetic method of a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C215/44C07C213/08C07C231/12C07C233/91B01J31/02
Inventor 李明华刘新泉刘明霞王平
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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