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Process for separating and refining ambroxol alkali

A kind of technology of ambroxol base and process, applied in the field of pharmaceutical synthesis, can solve the problems of low product purity, poor quality of ambroxol base, etc., and achieve the effects of good product color crystal form, guaranteed yield, and improved product quality

Active Publication Date: 2014-04-23
ZHEJIANG ZHEBANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] As mentioned above, the existing ambroxol base preparation process is mainly completed by extraction, whether it is directly extracted by adding water or extracted by adding water after removing the solvent, the quality of the ambroxol base obtained is relatively poor, even if the patent document CN102557967A is preparing ammonia After the broxoline reaction is complete, the treatment method adopted is to add water first, and its purpose is to use water to quench the residual sodium borohydride in the reaction, rather than using water to crystallize, so the purity of the final product obtained is still not high

Method used

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  • Process for separating and refining ambroxol alkali
  • Process for separating and refining ambroxol alkali
  • Process for separating and refining ambroxol alkali

Examples

Experimental program
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Effect test

Embodiment 1

[0032] (1) According to the patent document CN103012167A "one pot method" to prepare the ambroxol base reaction solution: 100g methanol, 2-amino-3,5-dibromobenzaldehyde (10.0g, 35.9mmol), trans-4-amino Add cyclohexanol (5.0g, 43.4mmol) into the reaction flask, heat it to reflux (63-65°C) under stirring, keep it warm for 5 hours, the reaction is complete as detected by HPLC, cool down to 35-40°C, add sodium borohydride (2.1g, 55.5mmol), the addition was completed, and the reaction was incubated for 20 hours. The reaction was complete by HPLC detection, and the ambroxol base reaction solution was obtained. Control the temperature at 30-35°C, slowly drop in 50 grams of water, the system becomes turbid, stir and crystallize at a slow speed for 1 hour, add the remaining calculated amount of water 450 grams, cool down to 5-10°C and grow the crystals for 1 hour, filter, wash with water, Obtain 15.0 g of ambroxol base crude product wet product, HPLC purity 98.35%.

[0033] (2) Put 15.0...

Embodiment 2

[0037] (1) Add 100 grams of ethanol, 2-amino-3,5-dibromobenzaldehyde (10.0g, 35.9mmol), trans-4-aminocyclohexanol (5.0g, 43.4mmol) into the reaction flask , heated to reflux (75-80°C) under stirring, kept for 4 hours, HPLC detected that the reaction was complete, cooled to 35-40°C, added sodium borohydride (2.1g, 55.5mmol), after the addition was complete, kept the reaction for 21 hours, HPLC detects that reaction is complete, obtains ambroxol base reaction solution. Control the temperature at 30-35°C, slowly drop in 50 grams of water, the system becomes turbid, stir and crystallize at a slow speed for 1 hour, add the remaining calculated amount of water 450 grams, cool down to 5-10°C and grow the crystals for 1 hour, filter, wash with water, Obtain 14.8 g of ambroxol base crude product wet product, HPLC purity 98.47%.

[0038] (2) Put 14.8 g of the wet ambroxol base crude product obtained in the previous step into the reaction bottle, add 35 g of absolute ethanol, stir and h...

Embodiment 3

[0040] (1) Add 100 grams of n-propanol, 2-amino-3,5-dibromobenzaldehyde (10.0g, 35.9mmol), trans-4-aminocyclohexanol (5.0g, 43.4mmol) to the reaction In the bottle, heat to 75-80°C with stirring for 4 hours, and the reaction is complete by HPLC. Cool down to 35-40°C, add sodium borohydride (2.1g, 55.5mmol), after the addition is complete, keep the reaction for 24 hours, and detect by HPLC Reaction is complete, obtains ambroxol base reaction solution. Control the temperature at 30-35°C, slowly drop in 40 grams of water, the system becomes turbid, stir and crystallize at a slow speed for 1 hour, add the remaining calculated amount of water 460 grams, cool down to 5-10°C to grow crystals for 1 hour, filter, wash with water, Obtain 14.1 g of ambroxol base crude product wet product, HPLC purity 98.09%.

[0041] (2) Put 14.1 g of the crude ambroxol base wet product obtained in the previous step into the reaction bottle, add 50 g of n-propanol, stir and heat up to 50-55 ° C, the sys...

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Abstract

The invention discloses a process for separating and refining ambroxol alkali. The process comprises the following steps: (1) adding water to reaction liquid of ambroxol alkali, performing primary crystallization, and filtering to obtain a crude product of the ambroxol alkali; (2) adding the crude product of the ambroxol alkali to a hydrophilic solvent to be dissolved completely, decoloring with active carbon, and filtering to obtain crude product filtrate of the ambroxol alkali; (3) adding water to the crude product filtrate of the ambroxol alkali, performing secondary crystallization, and filtering to obtain a refined product of the ambroxol alkali. By adopting the refining process disclosed by the invention, an ambroxol alkali product with purity higher than 99% can be obtained by primary crystallization, the product has good color and crystal form, the yield can reach 90%, the product quality is obviously improved on the basis of ensuring the yield, and the refining process is simple to operate and is low in cost, thereby being especially suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a separation and refining technology of ambroxol hydrochloride intermediate - ambroxol base. Background technique [0002] Ambroxol base, also known as ambroxol, has a chemical name of 2-amino-3,5-dibromo-N-(4-hydroxycyclohexyl) benzylamine, and its structural formula is: [0003] [0004] Ambroxol base is an important intermediate of ambroxol hydrochloride. At present, when the relevant enterprises in the industry prepare ambroxol hydrochloride, they do not refine ambroxol base separately, but after obtaining the crude product of ambroxol hydrochloride through salt formation, Refined again. It seems that one step of refining process is saved, but in fact, the acid-soluble impurities in ambroxol base (including unreacted trans-4-aminocyclohexanol, 2-amino-3,5-dibromobenzaldehyde, etc.) Into the crude product, it increases the difficulty of refining in the later stag...

Claims

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Application Information

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IPC IPC(8): C07C215/44C07C213/10
Inventor 刘正文鲁承勇陈川
Owner ZHEJIANG ZHEBANG PHARMA