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(r)-Asymmetric preparation method of albuterol hydrochloride

A technology of salbutamol and hydrochloride, which is applied in the preparation of organic compounds, chemical instruments and methods, preparation of amino hydroxy compounds, etc., can solve the problems of heavy metal residues, high-pressure hydrogen sources, poor chemical resolution yield, etc. Production cost, avoidance of splitting process, high optical purity effect

Inactive Publication Date: 2017-03-08
CHENGDU XIANJI BIOCHEM SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The purpose of the present invention is to overcome the shortcomings and deficiencies in the prior art of poor chemical resolution yield, asymmetric catalytic heavy metal residue and high-pressure hydrogen source risk, and provide a safe, efficient and selective surgical synthesis process

Method used

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  • (r)-Asymmetric preparation method of albuterol hydrochloride
  • (r)-Asymmetric preparation method of albuterol hydrochloride
  • (r)-Asymmetric preparation method of albuterol hydrochloride

Examples

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Effect test

Embodiment 1

[0041] (1) Add 200g (0.15mol) of anhydrous aluminum trichloride and 150mL of dichloroethane to a 250mL three-necked flask, raise the temperature to 70°C, add dropwise 150mL of dichloroethane solution of 66.1g (0.042mol) bromoacetyl chloride, After the dissolution was complete, 36.6g (0.03mol) of salicylaldehyde in 150mL of dichloroethane was dropped into the reaction solution at 70°C, and after the dropwise addition, the temperature was raised to 80°C for 36 hours of reaction. Slowly pour the reaction solution into 1.0kg of crushed ice under stirring, add 100mL of concentrated hydrochloric acid, separate the organic layer, extract the water layer with 200mL of dichloroethane, combine the dichloroethane layers, wash with water (300mLx2), and saturated salt Wash with water (300 mL), dry over anhydrous sodium sulfate, and concentrate to obtain a yellow oil, which is crystallized with petroleum ether-dichloromethane, filtered, and dried to obtain 58 g of white solid intermediate II...

Embodiment 2

[0046] The intermediate V prepared in Example 1 above was used as a raw material. Add 95g (66.6mmol) boron trifluoride diethyl ether in 40mL tetrahydrofuran solution dropwise into 2.1g (55.5mmol) sodium borohydride suspension in 50mL tetrahydrofuran under the protection of 20 nitrogen, add 1.0g (4mmol) after heating to reflux for 0.5 hours A solution of (R)-diphenylprolinol in 10 mL of tetrahydrofuran was refluxed for 0.5 hours. Cool to 25°C, slowly add 10g (37mmol) intermediate V in 200mL tetrahydrofuran solution dropwise, and the dropwise addition is completed in about 3 hours. Concentrate under reduced pressure to about 50 mL of solvent, add 100 mL of 2N hydrochloric acid, extract with ethyl acetate (100 mL x 2), dry over anhydrous sodium sulfate, and concentrate to obtain (R)-salbutamol as a yellow solid. Dissolve the crude (R)-salbutamol in 100 mL of ethyl acetate, add dropwise 30 mL of 2M ethyl acetate hydrogen chloride solution, a large amount of white solid (R)-salbut...

Embodiment 3

[0048] The intermediate V prepared in Example 1 above was used as a raw material. Under the protection of nitrogen, 95g (66.6mmol) of boron trifluoride diethyl ether in 40mL of dioxane solution was added dropwise to 2.1g (55.5mmol) of sodium borohydride in 50mL of dioxane suspension, heated to reflux for 0.5 hours and then added 1.0 g (4mmol) (R)-diphenylprolinol in 10mL dioxane solution, and then refluxed for 0.5 hours. Cool to 25°C, slowly add 10g (37mmol) intermediate V in 200mL dioxane solution dropwise, and dropwise finish in about 3 hours. Concentrate under reduced pressure to about 50 mL of solvent, add 100 mL of 2N hydrochloric acid, extract with ethyl acetate (100 mL x 2), dry over anhydrous sodium sulfate, and concentrate to obtain (R)-salbutamol as a yellow solid. Dissolve the crude (R)-salbutamol in 100 mL of ethyl acetate, add dropwise 30 mL of 2M ethyl acetate hydrogen chloride solution, a large amount of white solid (R)-salbutamol hydrochloride precipitates, fi...

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Abstract

The invention relates to a novel method for asymmetric syntheses of (R)-salbutamol hydrochloride by using a high-efficiency chiral catalyst. The method comprises the following steps: 1) subjecting salicylaldehyde and halogenoacetyl halide to Friedel-Crafts acylation so as to obtain halogenated ketone; 2) subjecting the obtained halogenated ketone to aminolysis with tert-butylamine and then carrying out hydrolysis and deprotection so as to obtain salicylaldamino ketone; and 3) reducing the salicylaldamino ketone into a crude product of (R)-salbutamol in the presence of a chiral borane catalyst derived from chiral aminoalcohol and carrying out purification and salt formation of hydrochloric acid so as to obtain the high purity (R)-salbutamol hydrochloride.

Description

technical field [0001] The invention relates to a novel asymmetric synthesis method for synthesizing (R)-salbutamol and its hydrochloride with the participation of a high-efficiency chiral borane catalyst. Background technique [0002] (R)-Salbutamol ((R)-Salbutamol), chemical name (R)-α-[[(1,1-Dimethylethyl)-amino]methyl-4-hydroxy-1,3-benzene Dimethanol, a β-2-antagonist used as a bronchodilator, has a good market prospect. Its structural formula is as follows: [0003] [0004] There are many example reports about the chemical methods and physical methods for the preparation of levosalbutamol at present. These methods can be divided into two categories: 1) Synthesize the racemate of albuterol first, and then obtain chiral products by chromatographic separation or chemical resolution, such as patents CN1382685A, CN1927813A, CN1934067A, CN102260179A and literature Chinese Journal of Pharmaceutical Industry, 2006 , 37(6), 376, etc.; 2) Levosalbutamol was directly synthe...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C215/60C07C213/00B01J31/02
Inventor 黄啸王炜陈军
Owner CHENGDU XIANJI BIOCHEM SCI & TECH CO LTD
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