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Prepn process of (1R, 2S)-(-)-ephedrine or its hydrochloride

A technology of ephedrine and methyl benzoyl tartaric acid is applied in the preparation of organic compounds, chemical instruments and methods, preparation of amino hydroxy compounds, etc., can solve problems such as high cost, increase consumption of metal borohydride, etc., and achieve utilization rate high effect

Active Publication Date: 2005-12-14
APELOA PHARM CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The above-mentioned documents reduce α-methylaminopropiophenone or chiral α-methylaminopropiophenone with catalytic hydrogenation method or metal borohydride, and contain more pseudoephedrine in its product, can reach 25.9%, need to be separated; And because α-methylaminopropiophenone is easier to enolize, especially under alkaline conditions, resulting in the racemization of chiral α-methylaminopropiophenone during the reduction process
If Raney Ni is used to catalyze the reduction of chiral α-methylaminopropiophenone hydrochloride, Raney Ni is easy to deactivate, while Pd / C catalyzes the reduction of chiral α-methylaminopropiophenone hydrochloride, the cost is too high; metal When borohydride reduces chiral α-methylaminopropiophenone hydrochloride, while reducing the carbonyl group, the metal borohydride will also react with the hydrogen chloride in the hydrochloride, increasing the consumption of the metal borohydride

Method used

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  • Prepn process of (1R, 2S)-(-)-ephedrine or its hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] 20.0g [(S)-(-)-α-methylaminopropiophenone] 2 ·(2R,3R)-(-)-dibenzoyl tartaric acid was placed in 80ml of water, slowly added 0.8gKBH under stirring 4 , react for 15min. Add concentrated hydrochloric acid until the pH value is about 2, extract the aqueous layer with 20ml×3 ethyl acetate, and concentrate to obtain (2R,3R)-(-)-dibenzoyltartaric acid. Adjust the pH value of the acidic water layer to 14 with 30% sodium hydroxide aqueous solution, and an oily substance precipitates out, extracts with toluene 20ml×3, and concentrates the toluene layer to obtain (1R, 2S)-(-)-ephedrine and a little (+ )-pseudoephedrine.

[0030] Its hydrochloride was prepared as follows:

[0031] Neutralize the toluene layer with 4N hydrochloric acid to a pH value of 6, remove the toluene, and concentrate the water layer to obtain a white solid, which is recrystallized with water to obtain 8.2 g of (1R, 2S)-(-)-ephedrine hydrochloride, mp 217.5 -218.5°C, [α] D -34.2° (c=5.0, H 2 O), yield: ...

Embodiment 2

[0033] 19.7g [(-)-α-methylaminopropiophenone] 2 Put phthalic acid in 40ml water and 40ml ethanol, slowly add 0.7gKBH under stirring 4 , react for 15min. Concentrate to recover ethanol, then add 30% sodium hydroxide aqueous solution to pH to 10, oily matter precipitates out, extract with toluene 20ml×3, concentrate to obtain (1R,2S)-(-)-ephedrine and a little pseudoephedrine.

[0034] Its hydrochloride was prepared as follows:

[0035] Neutralize the toluene layer with 4N hydrochloric acid until the pH reaches 4, remove the toluene, and concentrate the water layer to obtain a white solid, which is recrystallized with water to obtain 12.2 g of (1R, 2S)-(+)-ephedrine hydrochloride, mp 217.2 -218.6°C, [α] D -34.1° (c=5.0, H 2 O), yield: 75.3%.

Embodiment 3～5

[0037]Using the same method as in Example 1, with ethanol as a solvent, respectively with 20.7g [(S)-(-)-α-methylaminopropiophenone] 2 (2R, 3R)-(-)-di-p-toluyl tartaric acid (Example 3), 13.9 g [(S)-(-)-α-methylaminopropiophenone] 2 d-tartaric acid (Example 4) and 13.5 g [(S)-(-)-α-methylaminopropiophenone] 2 Malic acid (Example 5) was used as raw material to obtain 8.3g, 8.4g and 8.2g (1R, 2S)-(+)-ephedrine hydrochloride respectively; mp 217.2-218.6°C, [α] D -34.1° (c=5.0, H2O) yields were 70.1%, 71.3% and 74.8%, respectively.

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Abstract

The present invention prepares (1R, 2S)-(-) ephedrine with [(S)-(-)-alpha-methylamino propiophenone]2.(2R, 3R)-tartaric acid derivative or salt formed with (S)-(-)-alpha-methylamino propiophenone and other organic acid as material, and through reaction with metal borohydride or the mixture of metal borohydride and Lewis acid. The present invention has reaction material no racemizing of reaction material during reduction, reduction product with ephedrine as main component and high utilization of metal borohydride.

Description

Technical field [0001] The present invention relates to a preparation method of (1R, 2S)-(-)-ephedrine or its hydrochloride. Background technique [0002] (1R, 2S)-(-)-ephedrine is an important pharmaceutical product. It is mainly used clinically to prevent and treat certain hypotensive states, especially to prevent blood pressure drop during spinal anesthesia or epidural anesthesia; to treat nasal mucosa Nasal congestion caused by congestion and swelling; preventing or relieving bronchial asthma attacks; relieving skin and mucosal symptoms of urticaria and angioedema. Its chemical structural formula is as follows: [0003] [0004] The traditional production method of ephedrine is the extraction method, that is, extracting ephedrine from natural ephedra. However, ephedra is a sand-fixing plant. Long-term indiscriminate mining and excavation have led to a decrease in the area and amount of grass production, and the desertification of the production area has become increa...

Claims

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Application Information

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IPC IPC(8): C07C213/00C07C215/30
CPCC07C213/00
Inventor 黄成军周后元
Owner APELOA PHARM CO LTD
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