Synthesis method of ipratropium bromide

A kind of technology of ipratropium bromide, synthetic method

Active Publication Date: 2017-06-13
WUHAN LEADPHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, in the above-mentioned synthetic route, there is no solvent for the acylation reaction of acetyl tropine acid chloride and isopropyl tropine alcohol, the reaction conditions are relatively harsh, more impurities are produced, the hydrolysis reaction of 5% hydrochloric acid is incomplete, and the total yield is less than 20%. Suitable for industrial production

Method used

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

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Experimental program
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Effect test

Embodiment 1

[0041] The present embodiment provides a kind of synthetic method of ipratropium bromide, specifically comprises the steps:

[0042] (1) Preparation of compound 1

[0043] Add 50 grams (0.3mol) of tropic acid and 59 grams (0.75mol) of acetyl chloride in the reaction bottle, insulate at 20~30 ℃ for 2 hours, and the reaction solution is concentrated to dryness under reduced pressure to obtain 63 grams of colorless oily product, namely It is compound 1, which can be directly used in the next reaction. The HPLC purity of Compound 1 was detected to be 95.2%.

[0044] (2) Preparation of Compound 2

[0045] Add 60 grams (0.29mol) of compound 1 and 180 milliliters of thionyl chloride into the reaction flask, stir and react at 50-60°C for 2 hours, concentrate the reaction solution to dryness under reduced pressure, add 100 milliliters of toluene to the concentrate, and then reduce Concentrate to dryness under reduced pressure to remove residual thionyl chloride to obtain 65 g of a c...

Embodiment 2

[0054] The present embodiment provides a kind of synthetic method of ipratropium bromide, specifically comprises the steps:

[0055] (1) Preparation of compound 1

[0056] Add 20 grams (0.12mol) of tropic acid and 9.5 grams (0.12mol) of acetyl chloride in the reaction bottle, insulate at 40~50 ℃ and react for 2 hours, and the reaction solution is concentrated to dryness under reduced pressure to obtain 25.2 grams of colorless oily product, i.e. It is compound 1, which can be directly used in the next reaction. After detection, the HPLC purity of the obtained compound 1 was 92.8%.

[0057] (2) Preparation of Compound 2

[0058] Add 25 grams (0.12mol) of compound 1 and 75 milliliters of oxalyl chloride into the reaction flask, stir and react at 20-40 °C for 2 hours, concentrate the reaction solution to dryness under reduced pressure, add 50 milliliters of toluene to the concentrate, and then concentrate under reduced pressure To dryness, remove the residual oxalyl chloride to...

Embodiment 3

[0067] The present embodiment provides a kind of synthetic method of ipratropium bromide, specifically comprises the steps:

[0068] (1) Preparation of compound 1

[0069] Add 20 grams (0.12mol) of tropic acid and 47.2 grams (0.6mol) of acetyl chloride in the reaction bottle, insulate at 20~30 ℃ and react for 2 hours, and the reaction solution is concentrated to dryness under reduced pressure to obtain 25.1 grams of colorless oily product, i.e. It is compound 1, which can be directly used in the next reaction. After detection, the HPLC purity of the obtained compound 1 was 93.2%.

[0070] (2) Preparation of compound 2

[0071] Add 25 grams (0.12mol) of compound 1 and 75 milliliters of phosphorus trichloride to the reaction flask, stir and react at 60-80°C for 2 hours, concentrate the reaction solution to dryness under reduced pressure, add 50 milliliters of toluene to the concentrate, and then reduce Concentrate to dryness under reduced pressure to remove residual phosphoru...

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Abstract

The invention provides a synthesis method of ipratropium bromide. The method comprises the steps of (1) carrying out acetyl protection reaction on tropic acid as a raw material to obtain a compound 1; (2) carrying out chloroformylation reaction on the compound 1 to obtain a compound 2; (3) dissolving isopropyl tropine and organic acid into dichloromethane, adding obtained solution to the compound 2 and carrying out acylation reaction to obtain a compound 3; (4) carrying out alcoholysis reaction on the compound 3 to obtain a compound 4; and (5) carrying out bromine methylation reaction on the compound 4 to obtain the ipratropium bromide. The synthesis method of the ipratropium bromide is simple and raw materials are easily available, the operation is simple and stable, various steps are mild in reaction conditions, reaction products of various steps are easy to purify, the purity of the obtained ipratropium bromide product reaches over 97% and the synthesis method is suitable for industrial production of ipratropium bromide.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, in particular to a method for synthesizing medicine i.e. ipratropium bromide. Background technique [0002] Ipratropium bromide ([(1R,5S)-8-methyl-8-isopropyl-8-azabicyclo[3.2.1]oct-3-yl]3-hydroxy-2-phenylpropanoic acid Ester bromide) is a potent anticholinergic drug with high selectivity for bronchial smooth muscle M receptors. It was developed by Boehringer Ingelheim and approved for marketing in the United States in 1986. It is used for the prevention and treatment of bronchial asthma and asthmatic chronic bronchitis , especially suitable for patients who cannot tolerate such drugs due to muscle tremors and tachycardia caused by β-receptor agonists, and combined use with β-receptor agonists can enhance the efficacy of each other. [0003] U.S. Patent US3505337 has announced the synthetic route of following a kind of isopropyl ammonium bromide: [0004] [0005] Howe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D451/10
CPCC07D451/10
Inventor 吴波王革谢树伟徐旻明陈蔚江
Owner WUHAN LEADPHARM TECH CO LTD
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