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The synthetic method of levalbuterol intermediate and levalbuterol hydrochloride

A technology of levalbuterol and hydrochloride, which is applied in the field of preparation of levalbuterol intermediate and levalbuterol hydrochloride, can solve the problems of high production cost, many synthesis steps, low product yield and the like, and achieves short synthetic route and high yield. The effect of high rate and simple post-processing steps

Active Publication Date: 2017-02-22
SHANGHAI DINGYA PHARM CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The technical problem to be solved by this invention is to provide an improved new process for synthesizing levosalbutamol hydrochloride, which overcomes the low product yield in the prior art, many synthetic steps and high production costs

Method used

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  • The synthetic method of levalbuterol intermediate and levalbuterol hydrochloride
  • The synthetic method of levalbuterol intermediate and levalbuterol hydrochloride
  • The synthetic method of levalbuterol intermediate and levalbuterol hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] The synthesis of embodiment one bromoacetyl salicylaldehyde

[0042] .

[0043]Add anhydrous aluminum trichloride (20 g, 0.15 mol) to a 250 mL three-necked flask, add 15 mL of dichloromethane dropwise under stirring, raise the temperature to 50°C, add dropwise 7 g (0.045 mol) of dichloromethane bromoacetyl chloride Methane solution 10 mL, stirred for 30 minutes. Dissolve 3.66 g (0.03 mol) of salicylaldehyde in 10 mL of dichloromethane, drop into the reactant at 40°C, and react under reflux for 12 hours. Slowly pour the reaction solution into 120 g of crushed ice under stirring, adjust the pH value to 4, stir for 30 minutes, then add dichloromethane, separate the organic layer, and wash the aqueous layer with dichloromethane (30 mL×3) , combined the organic phases, and the organic phases were washed with distilled water and saturated brine successively, then dried with anhydrous magnesium sulfate, filtered, concentrated, and vacuum-dried to obtain a purple-black oil,...

Embodiment 2

[0045] Example 2 2-bromo-1-(4-hydroxyl-3-(hydroxymethyl)phenyl)ethanone

[0046] .

[0047] Dissolve 12 g of bromoacetyl salicylaldehyde in 50 mL of acetic acid, then cool to 0 °C, add 2.3 g of sodium borohydride in batches under nitrogen protection, slowly warm up to room temperature after the addition, and continue stirring until the reaction is complete. Adjust the pH value of the reaction solution to neutral with saturated sodium carbonate aqueous solution at 0°C, then add 100 mL of distilled water, back-extract the mixed solution with ethyl acetate three times, combine the organic phases, and use distilled water and saturated salt for the organic phases in turn Wash with water, then dry with anhydrous sodium sulfate, filter, concentrate, and dry in vacuo to obtain the crude product, which is a red oily substance. g 2-bromo-1-(4-hydroxy-3-(hydroxymethyl)phenyl)ethanone, the property is light yellow solid, the yield is 88%.

[0048] 1 H-NMR ( DMSO-d 6 ): 4.36 (s, 2H),...

Embodiment 3

[0049] Example 3 Synthesis of 2-bromo-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)ethanone

[0050] .

[0051] 10 g of 2-bromo-1-(4-hydroxyl-3-(hydroxymethyl)phenyl)ethanone prepared in Example 2 and 0.14 g of p-toluenesulfonic acid in a catalytic amount were added to a 250 mL three-port In the flask, then add 100 mL of dichloromethane and stir to form a light yellow suspension. At room temperature, the solution formed by 8.5 g of 2,2-dimethoxypropane and 40 mL of dichloromethane is slowly added dropwise to the reaction solution. Continue to stir the reaction until the reaction solution becomes clear, add saturated potassium bicarbonate solution to the reaction solution to adjust the reaction system to weak alkalinity, let stand to separate the layers, separate the organic layer, and wash the organic phase with saturated sodium chloride aqueous solution and water respectively , and then dried with anhydrous magnesium sulfate, filtered to remove magnesium sulfate, concentrated,...

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Abstract

The invention provides a levalbuterol intermediate and a levalbuterol hydrochloride synthesis method, and relates to a levalbuterol intermediate and a method for preparing levalbuterol hydrochloride from the intermediate. The method comprises steps as follows: 2-halogenate-1-(2,2-dimelthyl-4-hydrogen-benzo [d][1,3] dioxane)-butanone and organic amine have a Hoffman alkylation reaction to prepare a compound in the formula 2, the structural formula of the compound is shown in the specification, and the compound in the formula 2 is subjected to a reduction reaction, optically pure organic acid resolution and deprotection by hydrochloric acid to obtain levalbuterol hydrochloride. The method does not need processes of protection or deprotection and the like of hydroxyl groups on a benzene ring, protection, deprotection and purification processes are reduced, the synthesis route is short, operation is simple, meanwhile, borane-thioether does not need to be used as a reduction agent, and safety and environmental protection are realized.

Description

technical field [0001] The invention relates to the preparation of carbocyclic compounds of amino and hydroxyl groups connected to the same carbon frame, in particular to the preparation of levalbuterol intermediates and levosalbutamol hydrochloride. Background technique [0002] Salbutamol was discovered by British scholars in 1962 and developed by British Glaxo Company. It is a β-adrenergic receptor agonist and is widely used in the treatment of asthma. Its chemical structure is express: [0003] . [0004] Comprehensive literature report, the synthetic method of salbutamol mainly contains following two classes. The first synthetic method is the formula The compound is used as the raw material to obtain the diol compound formula by bromination hydrolysis , diol compound formula Reaction with an organic amine through hydroxime to generate a compound of formula IV, using borane-thioether as a reducing agent to reduce the compound of formula IV, and finally hydrol...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C215/60C07C213/06C07D319/08
Inventor 不公告发明人
Owner SHANGHAI DINGYA PHARM CHEM CO LTD
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