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Ambroxol derivative and method for preparing same

A compound and amino acid technology, applied in the field of ambroxol derivatives and its preparation, can solve the problems of unsatisfactory water solubility of ambroxol hydrochloride, limitation of preparation application and clinical application, etc.

Inactive Publication Date: 2009-09-30
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Oral absorption of ambroxol hydrochloride is rapid, and the elimination half-life period is 2-3 hours. Its preparations mainly include tablets, sustained-release pellet capsules, solutions, syrups, aqueous injections and other compound preparations, but due to the insoluble water solubility of ambroxol hydrochloride It is too ideal, so its preparation application and clinical application are subject to certain restrictions

Method used

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  • Ambroxol derivative and method for preparing same
  • Ambroxol derivative and method for preparing same
  • Ambroxol derivative and method for preparing same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] L-Alanine [trans-4-[(2-amino-3,5-dibromobenzyl)amino]cyclohexanol] ester dimesylate

[0023] The specific implementation is as follows:

[0024] The first step: trans-4-[(2-amino-3,5-dibromobenzyl)-N-tert-butoxycarbonylamino]cyclohexanol

[0025] Dissolve 0.16g (4mmol) of sodium hydroxide in 10ml of water, add 10ml of THF, add 1.134g (3mmol) of ambroxol, cool to 0-5°C, add 0.87g (4mmol) of di-tert-butyl dicarbonate dropwise, and keep warm after dropping Stir for 6 hours, add 30 ml of ethyl acetate to the reaction solution, separate the organic layer, wash with water, wash with brine, dry over magnesium sulfate, concentrate to remove the solvent, and obtain 1.3 g of oil, ESI-MS (m / z): 501.01 ([M +Na]).

[0026] The second step: N-tert-butoxycarbonyl-L-alanine [trans-4-[(2-amino-3,5-dibromobenzyl)-N-tert-butoxycarbonylamino]cyclohexanol ]ester

[0027] Trans-4-[(2-amino-3,5-dibromobenzyl)-N-tert-butoxycarbonylamino]cyclohexanol 3.0g (6.28mmol), N-tert-butoxycarbonyl-L...

Embodiment 2

[0031] The specific implementation is as follows:

[0032] The first step: N-tert-butoxycarbonyl-L-alanine [trans-4-[(2-amino-3,5-dibromobenzylidene) amino] cyclohexanol] ester

[0033] Trans-4-[(2-amino-3,5-dibromobenzylidene) amino]cyclohexanol 3g (8mmol), N-tert-butoxycarbonyl-L-alanine 1.89g (10mmol) In 20ml of dry dichloromethane, cool to 0-5°C, add 2.06g (10mmol) of N,N-dicyclohexylcarboimide and 0.36g (3mmol) of 4-dimethylaminopyridine, stir for 0.5 hours, and react Liquid filtration, the filtrate was washed with water, washed with brine, dried over magnesium sulfate, concentrated to remove the solvent to obtain a colorless oil, added 40ml of methanol, stirred at 0-5°C, a solid precipitated, filtered to obtain 3.5g of a white solid, mp: 116-118°C.

[0034] The second step: N-tert-butoxycarbonyl-L-alanine [trans-4-[(2-amino-3,5-dibromobenzyl) amino] cyclohexanol] ester

[0035] 4g of the above product was dissolved in a mixture of 20ml of methanol and 10ml of tetrahydr...

Embodiment 3

[0039] L-Valine [trans-4-[(2-amino-3,5-dibromobenzyl)amino]cyclohexanol] ester dimesylate

[0040] The specific implementation is as follows:

[0041] The first step: N-tert-butoxycarbonyl-L-valine [trans-4-[(2-amino-3,5-dibromobenzylidene) amino] cyclohexanol] ester

[0042] Trans-4-[(2-amino-3,5-dibromobenzylidene)amino]cyclohexanol 3g (8mmol), N-tert-butoxycarbonyl-L-valine 2.17g (10mmol) In 20ml of dry dichloromethane, cool to 0-5°C, add 2.06g (10mmol) of N,N-dicyclohexylcarboimide and 0.36g (3mmol) of 4-dimethylaminopyridine, and stir for 0.5 hours , the reaction solution was filtered, the filtrate was washed with water and brine, dried over magnesium sulfate, concentrated to remove the solvent, and 4.0 g of a colorless oil was obtained.

[0043] The second step: N-tert-butoxycarbonyl-L-valine [trans-4-[(2-amino-3,5-dibromobenzyl) amino] cyclohexanol] ester

[0044] The above oil was dissolved in a mixture of 20ml of methanol and 10ml of tetrahydrofuran, 0.8g of potassiu...

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Abstract

The invention relates to an ambroxol derivative and a method for preparing the same, in particular to the ambroxol derivative of a formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof and application thereof in medical treatment. In the formula (I), R is as defined as description.

Description

technical field [0001] The invention relates to an ambroxol derivative, a preparation method thereof, and an application thereof in expectorant drugs. Background technique [0002] Ambroxol (Ambroxol), whose chemical name is trans-4-[(2-amino-3,5-dibromobenzyl) amino] cyclohexanol, is a commonly used expectorant drug at present, with low toxicity and high efficacy. Indeed, the expectorant effect is stronger than that of bromhexine, and its preparation method and pharmacological effects have been published in US Patent No. 3,536,713. The drug was used clinically in the form of hydrochloride in 1984. Its clinical application has been published in Respiration51 Suppl.1, 37 (1987). At present, ambroxol hydrochloride has been widely used in the treatment of respiratory system diseases in many countries such as the United States, Britain, Germany, Japan, etc., with excellent clinical effects and almost no toxic side effects. Clinical trials have proved that this product can regu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C219/24C07C213/00A61K31/137A61P11/10C07C215/44
CPCY02P20/55
Inventor 岑均达钟慧娟吕爱锋
Owner JIANGSU HANSOH PHARMA CO LTD
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