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Preparation method of glycopyrronium bromide

A technology of glycopyrronium bromide and intermediate, applied in the preparation field of glycopyrronium bromide, can solve problems such as unfavorable industrialized production, high production operation requirements, low intermediate yield, etc., and achieves low production cost, simplified aftertreatment, The effect of increasing productivity

Active Publication Date: 2018-04-06
ANHUI DEXINJIA BIOPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this method has short steps, the yield of intermediates is low, and the cost of using CDI and other reaction reagents is high, and the post-treatment is easy to introduce impurities, which is not conducive to industrial production.
[0013] Then Wang blunt etc. published a kind of preparation method of glycopyrronium bromide on Chem MedChem. in Journal of Shenyang Medical University etc. and Hongbin Sun, Xiaoan Wen etc., all exist intermediate productive rate lower, production cost height, production operation requirement Advanced Disadvantages

Method used

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  • Preparation method of glycopyrronium bromide
  • Preparation method of glycopyrronium bromide
  • Preparation method of glycopyrronium bromide

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preparation example Construction

[0033] The preparation method of glycopyrrolate of the present invention includes the following steps:

[0034] 1. Add α-cyclopentylmandelic acid to NaOH DMF solvent, react at 30-80℃ for 0.5-2h, then add a little excess benzyl chloride to the reaction solution, and then heat up to 90-130℃ React for 1-72h. Water is continuously separated during the reaction. After the reaction is completed, purified water is added to the reaction solution, and the small polar organic solvent is extracted and separated. The pH of the aqueous phase is adjusted to 5-6 to precipitate solids, and intermediate I is obtained by filtration. -Benzyl-protected mandelic acid;

[0035] 2. Add the intermediate I obtained in step 1 to a slight excess of 1-methyl-3-pyrrolidinol in THF solution, slowly add a catalytic amount of concentrated sulfuric acid dropwise at 40-75°C, and cool down after the reaction is complete To room temperature, add lye dropwise to adjust pH=12-13, and extract with organic solvent to ob...

Embodiment 1

[0042] The preparation method of glycopyrrolate in this embodiment is as follows:

[0043] 1. Add 220g of α-cyclopentylmandelic acid to 600g of DMF solvent containing 88g of NaOH, stir and react at 60℃ for 1h, then add 139g of benzyl chloride dropwise to the reaction solution, after dripping, heat to 110℃ and stir for 3h. Water was continuously separated during the process. After the reaction was completed, 1kg of purified water was added to the reaction solution, and then 100g of ether was added for liquid separation. The aqueous phase was adjusted to pH 5-6 with dilute hydrochloric acid (4M) to precipitate solids, and intermediate I was obtained by filtration. -Benzyl-protected mandelic acid, 285g;

[0044] 2. Add 285g of Intermediate I obtained in step 1 to 400g of THF solution containing 111g of 1-methyl-3-pyrrolidol, and slowly add 19.6g of concentrated sulfuric acid (98wt%) at 70°C. After the reaction is complete , Cooled to room temperature, 30wt% NaOH solution was added dr...

Embodiment 2

[0049] The preparation method of glycopyrrolate in this embodiment is as follows:

[0050] 1. Add 440g of α-cyclopentylmandelic acid to 1200g of DMF solvent containing 176g of NaOH, stir and react at 60°C for 1.5h, then add 278g of benzyl chloride dropwise to the reaction solution, and then heat up to 110°C and stir for 4h. Water was continuously separated during the reaction. After the reaction was completed, 2kg of purified water was added to the reaction solution, and then 200g of ether was added for liquid separation. The aqueous phase was adjusted to pH 5-6 with dilute hydrochloric acid (4M) to precipitate solids, and intermediate I was obtained by filtration. ——Mandelic acid protected by benzyl group, 562g;

[0051] 2. Add 562g of Intermediate I obtained in step 1 to 700g of THF solution containing 222g of 1-methyl-3-pyrrolidinol, and slowly drop 35g of concentrated sulfuric acid (98wt%) at 70°C. After the reaction is complete, Cool to room temperature, add 30wt% NaOH soluti...

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Abstract

The invention discloses a preparation method of glycopyrronium bromide. The preparation method comprises the following steps: firstly, protecting hydroxyl of alpha-cyclopentyl mandelic acid with benzyl; then carrying out esterification with 1-methyl-3-pyrrolidinol by means of a conventional method to obtain a key intermediate ester of pyrrolidinol; carrying out debenzylation on the key intermediate ester under a condition of Pd / C; and finally, carrying out quaterniziation and salification on methyl bromide to separate out a solid, filtering the solid to obtain a coarse product of glycopyrronium bromide, and refining the coarse product to obtain a qualified product of glycopyrronium bromide. In order to prevent side reactions, hydroxyl is introduced with a very low cost to protect benzyl, so that the yield is improved greatly, the post-treatment is reduced, and the wastewater amount is reduced. The method disclosed by the invention has the characteristics of being simple in production operation, low in production cost, easily available in raw material, high in yield, small in pollution and the like. The obtained product meets the drug standard.

Description

Technical field [0001] The invention relates to a preparation method of glycopyrrolate and belongs to the technical field of medicine synthesis. Background technique [0002] Glycopyrronium Bromide (Glycopyrronium Bromide) is a quaternary ammonium anti-toxic stingycin cholinergic drug. It was researched and developed by SHIONOGI INC in the United States, and was launched in the United States in 1982. The drug is used to reduce salivary secretion related to the administration of specific anesthetics. It can effectively treat asthma symptoms and can be used as a duodenal ulcer, chronic gastritis, and hypersecretion of gastritis. Clinical treatment. In recent years, with the continuous development of the domestic pharmaceutical industry, clinicians have paid more and more attention to the clinical advantages of glycopyrrolate, and the domestic clinical demand for glycopyrrolate has become increasingly prominent. [0003] The existing preparation methods of glycopyrrolate are as foll...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/12
CPCC07D207/12
Inventor 谭亚军许坤
Owner ANHUI DEXINJIA BIOPHARM
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