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Synthesis method of ipratropium bromide

A technology for the synthesis of ipratropium bromide and its synthesis method, which is applied in the field of drug synthesis, can solve the problems of complex synthesis process, large material consumption, and high synthesis cost, and achieve the effects of high product purity, improved purity and yield, and simplified process steps

Active Publication Date: 2020-06-12
SHIJIAZHUANG NO 4 PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Aiming at the problems of complex synthesis process, low yield, large material consumption and high synthesis cost of existing ipratropium bromide, the invention provides a synthetic method of ipratropium bromide

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] A kind of synthetic method of different third detropammonium bromide, comprises the following processing steps:

[0034] a. Dissolve 5mol of 2-phenyl-3-acetoxypropionic acid in dichloromethane so that the concentration of 2-phenyl-3-acetoxypropionic acid in the solvent is 2mol / L, add 208g of DMF, after mixing evenly, add 7.5mol of oxalyl chloride at a rate of 0.05mL / s, react at 20°C for 0.5h, after the reaction is completed, add 2.5L of 2mol / L isopropyltropine mesylate solution After reacting at 20°C for 1.5h, raise the temperature to 40°C, continue to react for 20h, then move to a rotary evaporator to remove the organic solvent in the reaction solution, and add 0.25mol of hydrochloric acid to the remaining reaction solution, hydrolyze at 20°C 2h, to obtain a hydrolyzate; wherein, the preparation method of isopropyltropine mesylate solution is: add isopropyltropine to dichloromethane, at 0 ℃, with a drop rate of 0.05ml / s Add methanesulfonic acid and react and obtain, a...

Embodiment 2

[0040] A kind of synthetic method of different third detropammonium bromide, comprises the following processing steps:

[0041]a. Dissolve 5mol of 2-phenyl-3-acetoxypropionic acid in dichloromethane so that the concentration of 2-phenyl-3-acetoxypropionic acid in the solution is 2.5mol / L, add 250g After mixing evenly, add 10mol of oxalyl chloride at a rate of 0.1mL / s, react for 40min at 25°C, and add 2.5L of isopropyltropine mesylate solution of 2.5mol / L after the reaction is completed , after 2 hours of reaction at 25°C, the temperature was raised to 42°C, and the reaction was continued for 22 hours, then moved to a rotary evaporator to remove the organic solvent in the reaction solution, and added 0.5mol of hydrochloric acid to the remaining reaction solution, hydrolyzed at 25°C for 2.5 h, to obtain a hydrolyzate; wherein, the preparation method of isopropyltropine mesylate solution is: add isopropyltropine alcohol in dichloromethane, at 5 ℃, with the drop rate of 0.1ml / s A...

Embodiment 3

[0046] A kind of synthetic method of different third detropammonium bromide, comprises the following processing steps:

[0047] a. Dissolve 5mol of 2-phenyl-3-acetoxypropionic acid in dichloromethane so that the concentration of 2-phenyl-3-acetoxypropionic acid in the solution is 3mol / L, add 312g of DMF, after mixing evenly, add 15mol of oxalyl chloride at a rate of 0.1mL / s, react at 30°C for 1h, after the reaction is completed, add 2.5L of 3mol / L isopropyltropine mesylate solution, 30 After reacting at ℃ for 2 hours, raise the temperature to 45℃, continue to react for 24h, then move to a rotary evaporator to remove the organic solvent in the reaction solution, and add 0.5mol of hydrochloric acid to the remaining reaction solution, and hydrolyze it at 30℃ for 3h to obtain Hydrolyzate; Wherein, the preparation method of isopropyl tropinol methanesulfonate solution is: add isopropyltropine alcohol in dichloromethane, at 10 ℃, add methanesulfonic acid with the drop speed of 0.1ml...

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Abstract

The invention relates to the technical field of medicine synthesis, and particularly discloses a synthesis method of ipratropium bromide. The synthesis method of the ipratropium bromide comprises thefollowing steps: carrying out an acylating chlorination reaction on 2-phenyl-3-acetoxypropionic acid and oxalyl chloride in an organic solvent, then adding an isopropylnortropine mesylate solution, performing a reaction, removing the organic solvent, and adding an inorganic acid into the remaining reaction solution for hydrolysis; and extracting and separating out a reaction product in the hydrolysate, and carrying out a bromomethylation reaction on the reaction product and added bromomethane to obtain the ipratropium bromide. The method can be carried out at low temperature, and the product obtained by the reaction has the advantages of high purity, high yield, low enantiomer content and higher quality.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing ipratropium bromide. Background technique [0002] The chemical name of ipratropium bromide is: (1R,3r,5S,8r)-3-[[(2RS)-3-hydroxy-2-phenylpropionyl]oxy]-8-methyl-8-(1 -Methylethyl)-8-azabicyclo[3.2.1]octyl ammonium bromide is an M receptor blocker, belongs to the fourth generation derivative of atropine, and is a potent and highly selective anticholinergic drug. Ipratropium bromide inhibits the vagal reflex by antagonizing the release of acetylcholine from the vagus nerve, prevents smooth muscle spasm caused by the interaction between acetylcholine and the M receptor on bronchial smooth muscle, increases intracellular cGMP concentration, reduces bronchial inflammatory spasm, and quickly relieves bronchoconstriction and Accompanying acute clinical symptoms. Ipratropium bromide carries out the structure of drug action as However, its enantiomers...

Claims

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Application Information

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IPC IPC(8): C07D451/10
CPCC07D451/10
Inventor 孙立杰吕金伟张伟刘玉强褚海龙韩珊石俭白雪
Owner SHIJIAZHUANG NO 4 PHARMA
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