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Synthetic method of deuterium-labeled phenylethanolamine beta receptor stimulants

A technology of phenylethanolamine and synthesis method, applied in chemical instruments and methods, formation/introduction of hydroxyl groups, preparation of organic compounds, etc., can solve problems such as difficulty in using phenylethanolamine compounds, cumbersome steps, long synthesis route, etc., and achieve synthesis The method is simple and efficient, and the effect of high deuterium substitution rate

Inactive Publication Date: 2015-01-21
SHANGHAI INST OF MEASUREMENT & TESTING TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, the synthesis of deuterium-labeled phenylethanolamines has not been reported, and the synthesis of naturally abundant phenylethanolamines can be obtained through multi-step reactions such as acylation, halogenation, nucleophilic substitution, and reduction of aryl compounds (Gonzalez-Antuna et al. Tetrahedron, 2011), this method not only synthetic route is longer, the steps are loaded down with trivial details, and is difficult to obtain multiple different phenylethanolamine compounds using general route

Method used

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  • Synthetic method of deuterium-labeled phenylethanolamine beta receptor stimulants
  • Synthetic method of deuterium-labeled phenylethanolamine beta receptor stimulants
  • Synthetic method of deuterium-labeled phenylethanolamine beta receptor stimulants

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Embodiment 1: six deuterium labeled salbutamol

[0027] (1) The synthetic method of 5-(2-bromoacetyl)-2-hydroxybenzaldehyde

[0028]

[0029] Add anhydrous aluminum trichloride (33.3g, 250mmol) and 35mL of dichloromethane into a 100mL three-necked flask, add 7.5mL of a dichloromethane solution of bromoacetyl chloride (9.9g, 63mmol) dropwise under reflux, stir for 0.5h and slowly 7.5 mL of a solution of salicylaldehyde (6.1 g, 50 mmol) in dichloromethane was added dropwise. Refluxed for 16h, poured into ice water to quench, and separated. The aqueous phase was extracted three times with dichloromethane, and the combined organic phases were washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was spin-dried, and the solid was washed with dichloromethane and diethyl ether to obtain ω-bromo-acetophenone intermediate 5-(2-bromoacetyl)-2-hydroxybenzaldehyde (8.3 g, 70%). 1 H NMR (300MHz, CDCl 3 )δ10.36(1H,s),8.05(...

Embodiment 2

[0037] Embodiment 2: Nine deuterium-labeled salbutamol

[0038] (1) Synthesis of nonadeuterium-labeled 5-(2-tert-butylaminoacetyl)-2-hydroxybenzaldehyde hydrochloride from 5-(2-bromoacetyl)-2-hydroxybenzaldehyde

[0039]

[0040] Add 5-(2-bromoacetyl)-2-hydroxybenzaldehyde (10.8g, 44.4mmol) and 40mL isopropanol into a 100mL flask, stir and add tert-butylamine-d under nitrogen 9 (10.5g, 133mmol), refluxed for 2h. Add 11.1mL of 12mol / L hydrochloric acid and 9mL of isopropanol, and continue to reflux for 18h. Cool to room temperature and filter. The filter cake was stirred in 100 mL of isopropanol for 18 h and then filtered to obtain the nine-deuterium-labeled acetophenone amine intermediate 5-(2-tert-butylaminoacetyl)-2-hydroxybenzaldehyde hydrochloride (5.8 g, 47%) . 1 H NMR (300MHz, CDCl 3 )δ10.36(1H,s),8.05(1H,d,J=7.2Hz),7.58(1H,s),7.25(1H,d,J=7.2Hz),5.35(1H,br),3.65( 2H, s).

[0041] (2) Synthesis of nonadeuterium-labeled albuterol from nonadeuterium-labeled 5-(2-t...

Embodiment 3

[0045] Example 3: Hexadeuterium Labeled Clenbuterol

[0046] (1) The synthetic method of 5-(2-bromoacetyl)-2,5-dichloroaniline

[0047]

[0048] Add anhydrous aluminum trichloride (33.3g, 250mmol) and 35mL of dichloromethane into a 100mL three-necked flask, add 7.5mL of a dichloromethane solution of bromoacetyl chloride (9.9g, 63mmol) dropwise under reflux, stir for 0.5h and slowly 7.5 mL of a dichloromethane solution of 2,5-dichloroaniline (8.0 g, 50 mmol) was added dropwise. Refluxed for 16h, poured into ice water to quench, and separated. The aqueous phase was extracted three times with dichloromethane, and the combined organic phases were washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was spin-dried, and the solid was washed with dichloromethane and ether to obtain ω-bromo-acetophenone intermediate 5-(2-bromoacetyl)-2,5-dichloroaniline (9.1g, 64% ). 1 H NMR (300MHz, CDCl 3 )δ7.51 (2H, s), 6.30 (2H, br), ...

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Abstract

The invention discloses a method of synthesizing deuterium-labeled phenylethanolamine beta receptor stimulants with high efficiency and a high deuterated ratio. The synthetic method comprises the following steps: performing Friedel-Crafts acylation, performing nucleophilic substitution and performing reduction to prepare pure deuterium-labeled phenylethanolamine beta receptor stimulants. The synthetic method disclosed by the invention is simple and efficient; the synthesized products have chemical purity greater than 99% and labeled point isotope abundance greater than 99%, and can be used for detecting residues of forbidden veterinary drugs such as clenbuterol in the food safety field as well as researching a metabolic mechanism of the forbidden veterinary drugs.

Description

technical field [0001] The invention belongs to the technical field of chemical industry and relates to a method for synthesizing a deuterium-labeled phenylethanolamine beta receptor agonist. Background technique [0002] Beta agonists include nonselective beta agonists such as isoproterenol and selective cardiac beta 1 Agonists such as dobutamine, selective beta 2 Receptor agonists such as salbutamol, etc. A β2 receptor agonist with a phenylethanolamine structure that excites β on the surface of airway smooth muscle and mast cell membranes 2 Receptors, relax airway smooth muscle, reduce mast cell and basophil degranulation and the release of their mediators, reduce microvascular permeability, increase the swing of airway epithelial cilia, etc. to relieve asthma symptoms. In addition, adding it to the feed can increase the amount of lean meat of animals, reduce the use of feed, make the meat products go on the market earlier, and reduce the cost. Therefore, this kind of c...

Claims

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Application Information

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IPC IPC(8): C07B41/02C07C213/00C07C215/60C07C215/68C07C253/30C07C255/59
Inventor 李杰于瑞祥许卓妮陈鹰王虎
Owner SHANGHAI INST OF MEASUREMENT & TESTING TECH
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