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Preparation method of salbutamol sulfate impurities

A technology for salbutamol sulfate and impurities, which is applied in the field of preparation of salbutamol sulfate impurities, can solve the problems that the preparation method has not been reported in the literature, and achieve the effects of mild and controllable reaction conditions, high yield, and convenient operation

Inactive Publication Date: 2021-01-22
CHANGZHOU YABANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] In the quality standard of salbutamol sulfate, the European Pharmacopoeia 9.0 edition and the Chinese Pharmacopoeia 2015 edition do not list the impurity; in the preparation route of salbutamol sulfate, there are literatures mentioning that the impurity may be produced in the process, but the preparation method does not Literature report

Method used

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  • Preparation method of salbutamol sulfate impurities
  • Preparation method of salbutamol sulfate impurities
  • Preparation method of salbutamol sulfate impurities

Examples

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Effect test

Embodiment 1

[0029] Preparation of methyl ether intermediate

[0030]

[0031] Take 100ml of methanol, add 5.0g of salbutamol sulfate, add 1ml of 37% hydrochloric acid; keep the reaction at 10-20°C for 16 hours, and TLC shows that the reaction is complete.

[0032] Post-processing: Add sodium bicarbonate to the reaction solution until the solution is alkaline, concentrate to dryness, add 30ml of water, extract with 2*30ml of dichloromethane, dry the organic phase with anhydrous sodium sulfate, concentrate to dryness, and use column layer Analysis and purification, the eluent is petroleum ether: ethyl acetate = 2:1-1:1, 1.0 g of methyl ether intermediate was obtained, and the yield was 23%.

Embodiment 2

[0034] Preparation of methyl ether intermediate

[0035]

[0036] Take methanol 60ml, add salbutamol sulfate 3.0g, add 98% sulfuric acid 0.2ml. The reaction was incubated at 10-20° C. for 16 hours, and TLC showed that the reaction was complete.

[0037] Post-processing: Add sodium bicarbonate to the reaction solution until the solution is alkaline, concentrate to dryness, add 20ml of water, extract with 2*15ml of dichloromethane, dry the organic phase with anhydrous sodium sulfate, concentrate to dryness, and use column layer Analysis and purification, the eluent is petroleum ether:ethyl acetate=2:1-1:1, 0.52g of methyl ether intermediate was obtained, and the yield was 20%.

Embodiment 3

[0039] Preparation of methyl ether intermediate

[0040]

[0041] Take 60ml of methanol, add 3.0g of salbutamol sulfate, and add 0.6ml of 37% hydrochloric acid. The reaction was incubated at 10-20° C. for 16 hours, and TLC showed that the reaction was complete.

[0042] Post-processing: Add sodium carbonate to the reaction solution until the solution is alkaline, concentrate to dryness, add 20ml of water, extract with 2*15ml of dichloromethane, dry the organic phase with anhydrous sodium sulfate, concentrate to dryness, and perform column chromatography For purification, the eluent was petroleum ether:ethyl acetate=2:1-1:1, and 0.59 g of methyl ether intermediate was obtained with a yield of 23%.

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Abstract

The invention relates to the technical field of chemical synthesis, in particular to a preparation method of salbutamol sulfate impurities. The method comprises the following steps: (1) dissolving salbutamol sulfate in methanol, carrying out etherification reaction under acidic conditions, performing dissociating with alkali, and carrying out column purification to obtain a methyl ether intermediate; and (2) dissolving the methyl ether intermediate in an organic solvent, adding concentrated sulfuric acid to react with a cyclization reagent, carrying out dissociating by using alkali, and performing purifying by using a column to obtain a product. The technical scheme adopted by the invention has the beneficial effects that the operation is convenient, the reaction conditions are mild and controllable, the reaction stability is high, and the reaction product is high in yield and purity. In addition, the compound shown in the formula I can provide an impurity reference substance meeting requirements for quality control of salbutamol sulfate.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to a method for preparing albuterol sulfate impurities. Background technique [0002] Salbutamol Sulfate (Salbutamol Sulfate), the chemical name is 1-(4-hydroxy-3-hydroxymethylphenyl-2-(tert-butylamino)ethanol sulfate, the molecular formula is (C 13 h 21 NO 3 ) 2 .H 2 SO 4 , the molecular weight is 576.70. Salbutamol sulfate is a powerful and fast-acting selective β-receptor agonist developed by Glaxo (GSK) in the United Kingdom. Its trade name is Ventolin. It was first listed in 1968 and registered in my country in 1988. Its mechanism of action is through the selective activation of β 2 Receptors that relax bronchial smooth muscle. Indications include: Asthmatic bronchitis, respiratory diseases such as bronchospasm in patients with bronchial asthma and emphysema. This drug variety still plays an irreplaceable role, and its sales in the world pharmaceutical marke...

Claims

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Application Information

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IPC IPC(8): C07D319/08
CPCC07D319/08
Inventor 马绍明林送张志敏徐树行王德祥
Owner CHANGZHOU YABANG PHARMA
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