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Salbutamol impurity compound as well as preparation method, detection method and application thereof

A technology of salbutamol and its detection method, which is applied in the field of medicine, can solve the problems of salbutamol's toxic and side effects, the production of process impurities and degradation impurities, and the impact on drug quality, etc.

Inactive Publication Date: 2021-06-08
仁合诚益医药技术(天津)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, salbutamol also has potential toxic side effects, thereby causing adverse reactions. The generation of adverse reactions is not only related to the pharmacological activity of salbutamol, but also has a great relationship with the impurities in salbutamol.
During the production and storage of albuterol, process impurities and degradation impurities will inevitably be produced, which will affect the quality of the drug

Method used

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  • Salbutamol impurity compound as well as preparation method, detection method and application thereof
  • Salbutamol impurity compound as well as preparation method, detection method and application thereof
  • Salbutamol impurity compound as well as preparation method, detection method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Add 1g 2-[benzyl (tert-butyl)amino]-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanol, 15ml methanol, 0.9g potassium carbonate, 0.72g bromine to a 50ml three-necked flask Ethane, stirred and heated to 35°C~40°C, reacted for 24h. Filtrate while hot, concentrate the filtrate to dryness under reduced pressure at 40°C~50°C, add 5ml of ethanol to the concentrated residue, heat up to reflux, stir to dissolve, cool down to -5°C~0°C, stir and crystallize for 3h, filter, 50°C~60°C Dry in vacuo for 8 hours to obtain 0.65g salbutamol impurity with a purity of 99.377%. The spectrogram is shown in the attached Figure 4 , yield 59.9%.

[0050] Confirmation of chemical structure

[0051] Mass spectrometry was performed on an Agilent technologies 6120 mass spectrometer with methanol as solvent. Its spectrogram is attached figure 1 shown.

[0052] Molecular weight calculated: 357.0; MS m / e (M+H): 358.0.

[0053] H NMR spectrum ( 1 H-NMR) was performed on a Bruker AVANCE-400 nuclear m...

Embodiment 2

[0058] Add 10g 2-[benzyl (tert-butyl)amino]-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanol, 200ml ethyl acetate, 6.0g potassium carbonate, 8.2 g iodoethane, stirred and heated to 35°C~40°C, and reacted for 24h. Cool down to 20°C~25°C, add 100ml of water to wash and separate the liquid, add 100ml of saturated sodium chloride to the organic phase to wash and separate the liquid, concentrate the organic phase at 40°C~50°C to dryness under reduced pressure, add 30ml of methanol to the concentrated residue and heat up to reflux, Stir to dissolve, lower the temperature to -5°C~0°C, stir and crystallize for 3h, filter, and vacuum dry at 50°C~60°C for 8h to obtain 5.8g of albuterol impurities with a purity of 99.121% and a yield of 53.5%.

Embodiment 3

[0060] Add 10g 2-[benzyl (tert-butyl)amino]-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanol, 200ml dichloromethane, 6.3g pyridine, 7.0g Bromoethane, stirred and heated to reflux, reacted for 24h. Cool down to 20°C~25°C, add 100ml of water to wash and separate the liquid, add 100ml of saturated sodium chloride to the organic phase to wash and separate the liquid, concentrate the organic phase to dryness under reduced pressure at 35°C~40°C, add 30ml of methanol to the concentrated residue and heat up to reflux. Stir to dissolve, lower the temperature to -5°C~0°C, stir and crystallize for 3 hours, filter, and vacuum dry at 50°C~60°C for 8 hours to obtain 6.0 g of albuterol impurities with a purity of 99.340% and a yield of 55.3%.

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Abstract

The invention discloses a salbutamol impurity compound as well as a preparation method, a detection method and application thereof, and belongs to the technical field of medicines. The salbutamol impurity compound is generated by carrying out alkyl substitution reaction on phenolic hydroxyl groups in a salbutamol molecular structure. The invention discloses the salbutamol impurity compound and the preparation method thereof for the first time, the vacancy of the existing method for preparing the impurity is made up, the preparation method is simple to operate and convenient in post-treatment, and the prepared salbutamol impurity is high in purity.

Description

technical field [0001] The invention relates to a salbutamol impurity compound, a preparation method, a detection method and application thereof, and belongs to the technical field of medicine. Background technique [0002] The chemical name of albuterol is 1-(4-hydroxyl-3-hydroxymethylphenyl)-2-(tert-butylamino)ethanol, and its structural formula is as shown in formula III: [0003] [0004] Salbutamol, also known as Kechuanning, is a selective β2 adrenoceptor agonist used to treat asthmatic bronchitis and other diseases. The drug has high selectivity, definite clinical effect and long duration of action. However, salbutamol also has potential toxic side effects, thereby causing adverse reactions. The generation of adverse reactions is not only related to the pharmacological activity of salbutamol, but also has a great relationship with the impurities in salbutamol. During the production and storage of albuterol, process impurities and degradation impurities will inevi...

Claims

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Application Information

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IPC IPC(8): C07C217/70C07C213/06G01N30/02G01N30/34
CPCC07C217/70G01N30/02G01N30/34
Inventor 王进冲陈兴贺刘孟春高飞刘凯
Owner 仁合诚益医药技术(天津)有限公司