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Preparation method of L-(-)-ephedrine chloride and d-(+)-pseudoephedrine hydrochloride

A technology of pseudoephedrine hydrochloride and ephedrine hydrochloride, which is applied in the field of medicine and chemical industry, can solve the problems of high price of D-arabonic acid, the restriction of the company's production of pseudoephedrine hydrochloride, and the inability to adapt to large-scale industrial production, so as to achieve weak vasoconstriction of the whole body, eliminate mucosal congestion, The effect of raising blood pressure

Inactive Publication Date: 2010-10-27
QINGHAI LAKE PHARMA COMPANY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are three defects in the production of pseudoephedrine hydrochloride by extracting ephedra grass: First, the lack of wild ephedra grass resources and the national policy of banning wild ephedra grass have severely restricted the company's pseudoephedrine hydrochloride production by insufficient supply of raw materials
[0010] 1) L-(+)-mandelic acid and D-(-)-mandelic acid are resolving agents (a), U.S. Patent: 1867274; b), J.A m.Chem.Soc., 1929, 51: 1906 .): The advantage of this method is high separation efficiency (above 75%); the optical purity of the product is high (above 99%). The disadvantage is: L-(+)-mandelic acid and D-(-) mandelic acid are not easy Obtained, the price is high, and cannot meet the requirements of large-scale industrial production
But D-arabonic acid is expensive and not easy to get

Method used

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  • Preparation method of L-(-)-ephedrine chloride and d-(+)-pseudoephedrine hydrochloride
  • Preparation method of L-(-)-ephedrine chloride and d-(+)-pseudoephedrine hydrochloride
  • Preparation method of L-(-)-ephedrine chloride and d-(+)-pseudoephedrine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0098] 1. In a 2000ml rotary glass evaporation reactor, add 1100ml of toluene solution and 160ml of methylamine aqueous solution, keep the temperature of the water bath at 45°C, start stirring, control the stirring speed at 65 rpm, add α-bromopropiophenone dropwise 210 g, and then added dropwise 15% aqueous sodium hydroxide solution prepared by 50 g of sodium hydroxide, after addition, reacted for two hours, stopped heating, and cooled to room temperature. Separate the organic phase with an extractor, extract the aqueous phase twice with toluene (300ml*2 times), and combine the organic phases. 1500 ml of 15% hydrochloric acid aqueous solution was added dropwise to the organic phase, stirred for 1 hour, the aqueous phase was separated, evaporated under reduced pressure to syrupy state. Add 550ml of acetone to shake, let it stand overnight, and filter out the white solid, which is the hydrochloride of α-methylaminopropiophenone (yield: 74%).

[0099] 2. In a 1000ml glass reactor,...

Embodiment 2

[0102] 1. In a 2000ml rotary glass evaporation reactor, add 1000ml of toluene solution and 150ml of methylamine aqueous solution, keep the temperature of the water bath at 40°C, start stirring, control the stirring speed at 60 rpm, and add α-bromopropiophenone dropwise 210.0 g, then added dropwise a 15% aqueous sodium hydroxide solution prepared by 40 g of sodium hydroxide, after the addition was complete, reacted for two hours, stopped heating, and cooled to room temperature. Separate the organic phase with an extractor, extract the aqueous phase twice with toluene (300ml*2 times), and combine the organic phases. 1000ml of 15% hydrochloric acid aqueous solution was added dropwise to the organic phase, stirred for 1 hour, the aqueous phase was separated, evaporated under reduced pressure to syrupy state. Add 500ml of acetone to shake, let stand overnight, filter out the white solid, which is the hydrochloride of α-methylaminopropiophenone (yield: 73%);

[0103] 2. Take 100g o...

Embodiment 3

[0106] 1. In a 2000ml rotary glass evaporation reactor, add 1100ml of toluene solution and 165ml of methylamine aqueous solution, keep the temperature of the water bath at 43°C, start stirring, control the stirring speed at 65 rpm, and add α-bromopropiophenone dropwise 210 g, then added dropwise 15% aqueous sodium hydroxide solution prepared by 45 g of sodium hydroxide, after addition, reacted for two hours, stopped heating, and cooled to room temperature. Separate the organic phase with an extractor, extract the aqueous phase twice with toluene (300ml*2 times), and combine the organic phases. 1200 ml of 15% hydrochloric acid aqueous solution was added dropwise to the organic phase, stirred for 1 hour, the aqueous phase was separated, evaporated under reduced pressure to syrupy state. Add 600ml of acetone to shake, let stand overnight, filter out the white solid, which is the hydrochloride of α-methylaminopropiophenone (yield: 76%);

[0107] 2. In a 1000ml glass reactor, weig...

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Abstract

The invention relates to a method for preparing L-(-)-ephedrine chloride and d-(+)-pseudoephedrine hydrochloride by taking alpha-bromophenyl ethyl ketone as a raw material through steps of methylamination, resolution, reduction, acylation, acidolysis, hydrolysis and the like. The method has the advantages of mild reaction conditions, available raw material, small equipment investment, simple three wastes treatment, high yield and the like. The ephedrine chloride and the pseudoephedrine hydrochloride which are prepared by the invention belong to beta2 adrenoceptor agonists, and the preparations (tablets and capsules, such as new contac capsules produced by Tianjin Smith Kline & French laboratories Ltd.) of the ephedrine chloride and the pseudoephedrine hydrochloride release norepinephrine by mainly stimulating sympathetic nerve ending after being orally taken to take the sympathomimetic nerve effect in an indirect way. The L-(-)-ephedrine chloride and the d-(+)-pseudoephedrine hydrochloride are used for the adjuvant therapy of cold clinically and can soothe nasal mucosa congestion caused by the cold, allergic rhinitis, rhinitis and nasosinusitis.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry and the industry of synthetic ephedrine. Background technique [0002] Pseudoephedrine hydrochloride is one of the active ingredients in the traditional Chinese medicine ephedra. Ephedra means Ephedraceae The herbaceous stem of the plant Ephedra sinica Stapf, Ephedra intermedia Schrenk ex C.A. Mey. or Ephedra equisetina Bge. The main constituents of ephedra are Alkaloids (0.8%-2%). 80%-85% of alkaloids are pseudo ephedrine (D-pseudoephedrine, D-pseudo-ephedrine); followed by ephedrine (L-ephedrine, and trace amounts of L-N-methyl-ephedrine (L-N-methyl-ephedrine), D-N-methyl-pseudoephedrine (D-N-methyl -pseudo-ephedrine), demethylephedrine (L-nor-ephedrine), demethylephedrine (D-nor-pseudo-ephedrine) and ephedrine (ephedine, ephedrine), etc. In 1887, nagai from Ephedra In 1889, Merck isolated ephedrine from European ephedra plants and obtained pseudoephedrine for the first time...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C215/30C07C213/00C07B57/00
Inventor 骆骏才李新德苏旺平
Owner QINGHAI LAKE PHARMA COMPANY
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