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Synthesis method of ipratropium bromide

A technology of ipratropium bromide and its synthetic method, which is applied in the field of synthesis of ipratropium bromide, can solve the problems of inability to recycle methyl bromide and low yield, and achieve the effects of improving product quality, increasing conversion rate, and reducing pollution

Active Publication Date: 2020-11-24
CHINA RESOURCES DOUBLE CRANE PHARMA COMPANY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The yield of the prepared ipratropium bromide is only 38.5%~69.3%, the yield fluctuates, and methyl bromide cannot be recovered

Method used

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  • Synthesis method of ipratropium bromide
  • Synthesis method of ipratropium bromide
  • Synthesis method of ipratropium bromide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Put the intermediate 1 (2kg) and 24L of chloroform into the reaction tank to dissolve them all, cool to 0°C, and feed a total of 5kg of methyl bromide three times with an interval of 1 hour between each time, keeping the temperature at 0°C. After passing through, stir at 0°C for 16h, then raise the temperature to 25°C and stir for 4h. At the same time, during the stirring reaction, under the protection of nitrogen, it was cooled with a serpentine condenser at -25°C to prevent the loss of methyl bromide. Then raise the temperature to 40°C and stir for 4 hours, close the condenser, open the distillation device, and fully recover excess methyl bromide.

[0037] After recovery of methyl bromide, cool to room temperature, filter, soak the filter cake fully with chloroform, filter dry, and vacuum-dry at 70°C for 6 hours to obtain the crude product of ipratropium bromide, which is recrystallized in a mixed solvent of methanol and acetone, and washed with acetone , Vacuum dryi...

Embodiment 2

[0040] Put the intermediate 1 (2kg) and 24L of chloroform into the reaction tank to dissolve them all, cool to -5°C, and feed a total of 5.68kg of methyl bromide in three times, with an interval of 1.5h between each time, and keep the temperature at -5°C . After passing through, stir at -5°C for 17h, then raise the temperature to 27°C and stir for 5h. During the stirring reaction, under the protection of nitrogen, it was cooled with a serpentine condenser at -25°C to prevent the loss of methyl bromide. Then raise the temperature to 50°C and stir for 3 hours, close the condenser, open the distillation device, and fully recover excess methyl bromide.

[0041] After recovery of methyl bromide is complete, cool to room temperature, filter, soak the filter cake in chloroform, filter dry, and vacuum-dry at 75°C for 7 hours to obtain the crude product of ipratropium bromide, which is recrystallized from a mixed solvent of methanol and acetone, and washed with acetone. Vacuum drying...

Embodiment 3

[0044] Put intermediate 1 (2.3kg) and 25L of chloroform into the reaction tank to dissolve them all, cool to -3°C, and feed a total of 4.81kg of methyl bromide in four times with an interval of 1 hour between each time, and keep the temperature at -3°C. ℃. After passing through, stir at -3°C for 16h, then raise the temperature to 23°C and stir for 4h. During the stirring reaction, under the protection of nitrogen, it was cooled with a serpentine condenser at -25°C to prevent the loss of methyl bromide. Then raise the temperature to 45°C and stir for 5 hours, close the condenser, open the distillation device, and fully recover excess methyl bromide.

[0045] After recovery of methyl bromide is complete, cool to room temperature, filter, soak the filter cake in chloroform, filter dry, and vacuum-dry at 75°C for 7 hours to obtain the crude product of ipratropium bromide, which is recrystallized from a mixed solvent of methanol and acetone, and washed with acetone. After vacuum ...

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Abstract

The invention relates to a synthesis method of a potent anticholinergic drug ipratropium bromide. On the basis of an original technology, the method adopts (1R,3r,5S)-8-(1-methylethyl)-8-azabicyclo[3.2.1]oct-3-yl(2RS)-3-hydroxy-2-phenylpropanoate as a raw material and chloroform as a solvent, excess methyl bromide is added, and the production yield is increased with a method of heating step by step. With adoption of the synthesis method of ipratropium bromide, the highly-volatile raw material methyl bromide can be recovered, so that damage of the ozone layer is reduced, and the purposes of increasing yield, reducing raw material consumption and protecting environment are achieved. The taken measures are easily implemented in industry, and the conditions are mild, so that the method is applicable to large-scale industrial production.

Description

technical field [0001] The invention relates to the technical fields of organic chemistry and medicinal chemistry, in particular to a synthetic method of ipratropium bromide. Background technique [0002] Ipratropium bromide, also known as ipratropium bromide; ipratropium bromide; ipratropium, chemical name [(1R,5S)-8-methyl-8-isopropyl-8-azabicyclo [3.2.1] Oct-3-yl] 3-hydroxy-2-phenylpropionate bromide is an anticholinergic drug. Ipratropium bromide has higher selectivity to bronchial smooth muscle M receptors, and has a stronger effect on relaxing bronchial smooth muscle, but weaker effects on respiratory glands and cardiovascular system. The main indications of ipratropium bromide are: ① used to relieve bronchospasm and wheezing symptoms caused by chronic obstructive pulmonary disease (COPD); Patients who are unable to tolerate such drugs. It has the advantages of being safe and effective, reaching the effective site quickly, and having few side effects. It has more an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D451/10
CPCC07D451/10
Inventor 刘开湘许丽丽
Owner CHINA RESOURCES DOUBLE CRANE PHARMA COMPANY
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