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Preparation methods for ephedrine or pseudoephedrine and for ephedrine or pseudoephedrine intermediate

A technique for pseudoephedrine and ephedrine is applied in the field of preparation of ephedrine or pseudoephedrine and intermediates of ephedrine or pseudoephedrine, and can solve the problems of large environmental pollution, difficulty in industrialization implementation and high cost

Active Publication Date: 2016-10-12
ZHEJIANG APELOA KANGYU PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0042] In summary, most of the production processes of the key intermediates of ephedrine and pseudoephedrine, 2-methylamino-1-phenyl-acetone, have difficulties in industrial implementation, high risk, high cost, and large environmental pollution. technical problem

Method used

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  • Preparation methods for ephedrine or pseudoephedrine and for ephedrine or pseudoephedrine intermediate
  • Preparation methods for ephedrine or pseudoephedrine and for ephedrine or pseudoephedrine intermediate
  • Preparation methods for ephedrine or pseudoephedrine and for ephedrine or pseudoephedrine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0091] Embodiment 1 (excessive benzene is used for Friedel-Crafts reaction and is directly used as the solvent of methylation reaction)

[0092] Add benzene (500 milliliters, 5.6 moles) and anhydrous aluminum chloride (300 grams, 2.25 moles) in a 2-liter reaction flask under nitrogen protection, stir and cool down to 0-5 ° C, and slowly dissolve the 2 - Chloropropionyl chloride (254 g, 2.0 moles) was added to the reaction flask. Keep the reaction temperature below 10°C and continue the reaction for one hour. Then the temperature was raised to 20-30° C. to react for two hours. Gas phase analysis no longer showed the presence of 2-chloropropionyl chloride.

[0093] Add 600 ml of ice water and 150 ml of 35% hydrochloric acid successively to decompose excess aluminum chloride. The reaction solution was left to stand for stratification, and the upper benzene layer was taken, washed with water once, and then left to stand for thorough separation. The benzene liquid shows that th...

Embodiment 2

[0094] Embodiment 2 (Toluene replaces benzene as the solvent of methylation reaction)

[0095] Benzene (350 ml, 3.94 mol) and anhydrous aluminum trichloride (300 g, 2.25 mol) were added to a 2 liter reaction flask under nitrogen protection. 2-Chloropropionyl chloride (254 g, 2.0 mol) was added dropwise when the temperature was cooled to 0-5°C with stirring. After 30 minutes of dropwise addition, the temperature was raised to 20-30°C, and the reaction was continued for three hours. The gas phase showed no more 2-chloropropionyl chloride remained.

[0096] 600 ml of ice water and 150 ml of 35% concentrated hydrochloric acid were added to the reaction solution successively. Continue to stir for 15 minutes after the dripping, and then let stand to separate layers. The upper benzene layer was washed once with water and allowed to stand for separation. The separated benzene layer solution was evaporated to remove benzene. Add 800 milliliters of toluene until about 1 / 3 volume an...

Embodiment 3

[0097] Embodiment 3 (acetonitrile replaces benzene as the solvent of methylamination reaction)

[0098] Add benzene (600 ml, 6.73 moles) and anhydrous aluminum trichloride (300 grams, 2.25 moles) to a 2-liter reaction flask under nitrogen protection, stir and cool down to 0-5°C, and start to add 2-chloro Propionyl chloride (254 g, 2.0 mol). After 30 minutes of addition, the temperature was raised to 20-30°C for three hours. The gas phase showed that 2-chloropropionyl chloride was completely consumed.

[0099] 400 ml of ice water was slowly added dropwise to the reaction solution, and after stirring for ten minutes, 150 ml of 35% concentrated hydrochloric acid was added. Layering was carried out after stirring for another ten minutes after dropping. The upper benzene layer was washed once with water, and the layers were separated again. The separated benzene layer was concentrated under normal pressure, and when the solution was nearly dry, 500 ml of anhydrous acetonitrile ...

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Abstract

The invention discloses a preparation method for an ephedrine or pseudoephedrine intermediate. The preparation method comprises the following steps: with 2-chloropropionyl chloride and benzene as starting materials, carrying out the Friedel-Crafts reaction under the catalysis of Lewis acid so as to produce 2-chloro-1-phenyl-1-acetone; and reacting produced 2-chloro-1-phenyl-1-acetone with methylamine in an aprotic solvent so as to produce 2-methylamino-1-phenyl-1-acetone. The invention also discloses a preparation method for ephedrine or pseudoephedrine. According to the methods, phosphorus trichloride with severe pollution is not used anymore, and dangerous and expensive bromine is not used any longer; the Friedel-Crafts reaction and methylamination are carried out in the same solvent, so cost for public works is saved; and a safe, simple, cheap, green and novel process is provided for synthesis of ephedrine and pseudoephedrine.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of ephedrine or pseudoephedrine and an intermediate of ephedrine or pseudoephedrine. Background technique [0002] Ephedra is a wild plant that has been used in traditional Chinese medicine for millennia to induce sweating and relieve asthma. In 1885, the Japanese scholar Nagai Nagayoshi first isolated the mixture of its active ingredients from the Ephedra herbaceae plant, the main ingredient of which was ephedrine. In 1889, Merck Pharmaceutical Factory isolated pure ephedrine and pseudoephedrine from European ephedra plants. Freudenberg in 1949 and Brewster et al. in 1950 determined the absolute configuration of the two, as shown in the following formula: [0003] [0004] (1R,2S)-(-)-Ephedrine(1)(1S,2S)-(+)-Pseudoephedrine(2) [0005] Although these two compounds can now be produced through synthetic methods, China still harve...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C45/46C07C49/80C07C221/00C07C225/16C07C213/00C07C215/30C07B57/00
CPCC07C45/46C07C49/80C07C221/00C07B57/00C07B2200/07C07C213/00C07C225/16C07C215/30
Inventor 王哲清葛萌芽叶增芳舒理建曾亮荣方梅芬孙云雷张柯华
Owner ZHEJIANG APELOA KANGYU PHARMA
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