Preparation method of dextromethorphan hydrobromide N-oxide impurity

A technology of dextromethorphan hydrobromide and sodium hydroxide, applied in the direction of organic chemistry and the like, can solve the problem of not finding the preparation documents of nitrogen oxides, etc., and achieve the effects of high stability, mild and controllable reaction conditions, and high purity

Pending Publication Date: 2019-08-20
上海葆隆生物科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] European Pharmacopoeia version 8.0 announced 4 impurities, but there is no nitrogen oxide compound impurity. Chinese Pharmacopoeia 2015 version dextromethorphan hydrobromide quality standard also announced 4 impurities, including the nitrogen oxide compound impurity, but no such impurity has been found so far. The relevant preparation literature of nitrogen oxide compounds, therefore, the preparation of the nitrogen oxide compounds is particularly important for the research on other impurities of dextromethorphan hydrobromide and the control of impurity content

Method used

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Examples

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Effect test

Embodiment 1

[0032]

[0033] Take 3.7g (1.0eq) of dextromethorphan hydrobromide, dissolve it in 150ml of water, add 5ml of 5N aqueous sodium hydroxide solution, stir for 3-5 minutes, add 100ml of dichloromethane for extraction, and dry the organic phase with anhydrous sodium sulfate , and concentrated the solvent under reduced pressure to obtain dextromethorphan (free state). Add 50ml of absolute ethanol to dextromethorphan, then add dropwise 1.7g (1.5eq) of 30% hydrogen peroxide, and keep stirring at 10-20°C for 16h after the addition is complete. Post-processing: the reaction solution was concentrated under reduced pressure, purified and separated by silica gel column chromatography, the eluent was DCM / MeOH=20 / 1-10 / 1, and concentrated to obtain 2.5 g of the product with a yield of 87%.

[0034] MS(m / z):288.1[M+H] + , 576.2[2M+H] + .

[0035] 1 HNMR (400MHz, CDCl 3 )δ:0.97-0.98(m,1H),1.22-1.26(m,2H),1.42-1.64(m,5H),2.32(d,1H),2.49(d,1H),2.84(d,1H) , 2.98-3.03 (m, 4H), 3.06 (s, 3H...

Embodiment 2

[0037]

[0038] Take 1.85g (1.0eq) of dextromethorphan hydrobromide, dissolve it in 75ml of water, add 3ml of 5N aqueous sodium hydroxide solution, stir for 3-5 minutes, add 50ml of dichloromethane for extraction, and dry the organic phase with anhydrous sodium sulfate , and concentrated the solvent under reduced pressure to obtain dextromethorphan (free state). Add 25ml of methanol to dextromethorphan, then dropwise add 0.85g (1.5eq) of 30% hydrogen peroxide, and keep stirring at 20-30°C for 16h after the addition is complete. Post-processing: the reaction solution was concentrated under reduced pressure, purified and separated by silica gel column chromatography, the eluent was DCM / MeOH=20 / 1-10 / 1, and concentrated to obtain 1.09 g of the product, with a yield of 76%.

Embodiment 3

[0040]

[0041] Take 7.4g (1.0eq) of dextromethorphan hydrobromide, dissolve it in 300ml of water, add 10ml of 5N aqueous sodium hydroxide solution, stir for 3-5 minutes, add 150ml of dichloromethane for extraction, and dry the organic phase with anhydrous sodium sulfate , and concentrated the solvent under reduced pressure to obtain dextromethorphan (free state). Add 100ml of absolute ethanol to dextromethorphan, then add 8.12g (2.0eq) of 85% m-chloroperoxybenzoic acid, and keep stirring at 0-10°C for 16h after the addition is complete. Post-processing: the reaction solution was concentrated under reduced pressure, purified and separated by silica gel column chromatography, the eluent was DCM / MeOH=20 / 1-10 / 1, and concentrated to obtain 4.6 g of the product with a yield of 80%.

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Abstract

The invention discloses a preparation method of a compound of dextromethorphan hydrobromide N-oxide impurity as shown in the formula I. The invention provides a preparation method of a dextromethorphan hydrobromide N-oxide impurity as shown in the formula I, comprising the following steps: dissolving dextromethorphan hydrobromide in water, dissociating by using alkali, extracting by using an organic solvent, and reacting under the action of an oxidizing agent. The preparation method of the invention is convenient to operate, the reaction condition is mild and controllable, reaction stability is high, yield of the reaction product is high, and purity is also high.

Description

technical field [0001] The invention relates to a preparation method of dextromethorphan hydrobromide nitrogen oxide impurities. Background technique [0002] Dextromethorphan Hydrobromide, chemical name 3-methoxy-17-methyl-(9α,13α,14α)-morphinan hydrobromide monohydrate, molecular formula C 18 h 25 NO.HBr.H 2 O, the molecular weight is 370.32. Dextromethorphan hydrobromide is a non-narcotic, non-drug-resistant, efficient and safe centrally acting antitussive drug developed by Roche, Switzerland. Because it is not easily addictive, people are more and more inclined to use it to replace the more addictive codeine to treat cough. This drug variety still plays an irreplaceable role, and it still occupies a large share in the world drug market in recent years. The dosage forms of dextromethorphan hydrobromide mainly include tablets, capsules, syrups, etc. [0003] It is known in the art that national and international regulations are required to establish extremely low lim...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D221/28
CPCC07D221/28
Inventor 朱高军孙斌陈林胡全艮刘勇赵铭
Owner 上海葆隆生物科技有限公司
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