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Synthetic method of deuterium-labeled D9-clenbuterol hydrochloride

A technology of clenbuterol hydrochloride and its synthetic method, which is applied in the direction of organic chemical methods, chemical instruments and methods, and the preparation of organic compounds, can solve problems such as poor stability, and achieve advanced process selection, simple operation, and mild reaction conditions Effect

Active Publication Date: 2018-12-28
东莞暨南大学研究院 +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

which uses D 9 - more tert-butylamine, and D 9 - The total conversion rate of tert-butylamine is only 4%, so Chinese publication CN 104387284 A replaces D with other organic bases 9 - tert-butylamine, thereby significantly improving D 9 - The conversion rate of tert-butylamine, but when other organic bases are added to form salts and precipitate products, it will bring the added organic bases to form salts and precipitates
And they are all 4-amino-α-bromo-3,5-dichloroacetophenone and D 9 - tert-butylamine reacts, and 4-amino-α-D 9 - Tert-butylamino-3,5-dichloroacetophenone is poorly stable

Method used

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  • Synthetic method of deuterium-labeled D9-clenbuterol hydrochloride
  • Synthetic method of deuterium-labeled D9-clenbuterol hydrochloride
  • Synthetic method of deuterium-labeled D9-clenbuterol hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043]In a 250ml three-neck flask, add 4.8g of 3,5-dichloro-4-aminoacetophenone, 10.8g of copper bromide, 48ml of ethyl acetate and 48ml of chloroform, and reflux for 4 hours after the addition. Filter, wash the filter cake with ethyl acetate, combine the filtrates, wash twice with water, wash twice with saturated brine, dry over sodium sulfate, recrystallize with chloroform under reduced pressure, filter, and dry to obtain solid 3,5-dichloro-4-amino- 4.0 g of α-bromoacetophenone, the yield is about 62%.

[0044] The proton nuclear magnetic spectrum data of gained solid is as follows: 1 H NMR (CDCl 3 )δ7.85(s, 2H), 5.06 (s, 2H), 4.31(s, 2H). It shows that 3,5-dichloro-4-amino-α-bromoacetophenone was successfully synthesized in this example.

Embodiment 2

[0046] In a 50ml pressure bottle, add 2.8g of 3,5-dichloro-4-amino-α-bromoacetophenone, D 9 - tert-butylamine 1.2g, 45ml tetrahydrofuran, stirred and reacted at room temperature for 6 hours, and filtered to remove D generated during the reaction 9 - tert-butylamine hydrobromide, the filter cake was washed with 10ml THF, the filtrate was combined, about half of the THF was concentrated, and 4mol / L hydrogen chloride / ethanol solution was added to adjust the pH value of the solution to 4, filtered, and dried to obtain 4-amino-α- D. 9 - tert-butylamino-3,5-dichloroacetophenone hydrochloride 3.0g, yield 93%, D 9 - 63% conversion of tert-butylamine.

[0047] The proton nuclear magnetic spectrum data of gained solid is as follows: 1 H NMR (MeOD) δ8.00 (s, 2H), 4.59 (s, 2H), indicating that Example 2 successfully synthesized 4-amino-α-D 9 - tert-butylamino-3,5-dichloroacetophenone hydrochloride.

Embodiment 3

[0049] In a 25ml pressure bottle, add 1.0g of 3,5-dichloro-4-amino-α-bromoacetophenone, D 9 - 0.46g of tert-butylamine, 15ml of acetonitrile, stirred and reacted at room temperature for 6 hours, filtered, washed the filter cake with 5ml of acetonitrile, combined the filtrate, concentrated about half of the acetonitrile, added 4mol / L hydrogen chloride / ethanol solution until the solution was acidic (pH = 4), filtered and dried to obtain 4-amino-α-D 9 - tert-butylamino-3,5-dichloroacetophenone hydrochloride 1.1g, yield 96%, D 9 - The conversion of tert-butylamine is 61%. Wherein the proton nuclear magnetic spectrum data of drying gained solid is as follows: 1 H NMR (MeOD) δ8.00 (s, 2H), 4.59 (s, 2H), indicating that Example 3 also successfully synthesized 4-amino-α-D 9 - tert-butylamino-3,5-dichloroacetophenone hydrochloride.

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Abstract

The invention belongs to the field of food safety and standard substance synthesis, and discloses a synthetic method of deuterium-labeled D9-clenbuterol hydrochloride. According to the method, 4-amino-3,5-dichloroacetophenone is taken as a raw material and subjected to three-step reaction including bromination, D9 tert-butyl amination and reduction, and deuterium-labeled D9-clenbuterol hydrochloride is generated. The method is simple to operate, reaction conditions are mild (most reactions are performed at room temperature), reaction routes are reasonable, the process is advanced, the processing method is simple, and a product is easy to purify. Meanwhile, the total conversion rate of D9-tert-butylamine as the core raw material in the synthesis process of D9-clenbuterol hydrochloride is increased to 40% from 4.2%, yield is increased to 64%, and the method has good economic value and social value.

Description

technical field [0001] The invention belongs to the field of food safety and standard product synthesis, in particular to a deuterium-labeled D 9 -The synthetic method of clenbuterol hydrochloride. Background technique [0002] Clenbuterol hydrochloride, the chemical name is α-[(tert-butylamino)methyl]-4-amino-3,5-dichlorobenzyl alcohol hydrochloride, and the drug name is dichlorohydrin hydrochloride, ammonia Asthmaline, Ambitux, Salbutamol, Ketanin, etc., its appearance is white or off-white crystalline powder, melting point 174-175.5°C, odorless, bitter, soluble in water, ethanol, slightly soluble in acetone, insoluble in ether. It is a potent selective adrenergic β2 receptor agonist, can relax bronchial smooth muscle, and is used for the treatment of bronchial asthma, asthmatic bronchitis and bronchitis with emphysema. A convenient, effective, high-sensitivity technical method is needed to detect it. [0003] At present, there are gas chromatography-mass spectrometry ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/08C07C215/68
CPCC07B2200/05C07C213/00C07C213/08C07C221/00C07C215/68C07C225/22
Inventor 蒋杰郑成麦丽谊罗淑雯
Owner 东莞暨南大学研究院
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