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Dibromobenzyl derivative, stereoisomer or salt thereof, and preparation method and application thereof

A stereoisomer, dibromobenzyl technology, applied in the field of its stereoisomer, dibromobenzyl derivatives, can solve problems such as unsatisfactory expectorant effect and reduced metabolic stability

Active Publication Date: 2021-01-29
CHENGDU SHIBEIKANG BIOLOGICAL MEDICINE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Ambroxol hydrochloride freeze-dried powder injections, small water injections and large infusions are already on the market in China, and ambroxol hydrochloride has been on the market worldwide for more than 30 years. It is an older generation of expectorant. When ambroxol enters the human body, the hydroxyl group on the cyclohexane will combine with glucuronic acid and become invalid. Therefore, its metabolic stability in the body is reduced, and it needs to be administered 2 to 3 times a day, and clinical patients often report that the expectorant effect is not good. do one's best

Method used

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  • Dibromobenzyl derivative, stereoisomer or salt thereof, and preparation method and application thereof
  • Dibromobenzyl derivative, stereoisomer or salt thereof, and preparation method and application thereof
  • Dibromobenzyl derivative, stereoisomer or salt thereof, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] This example discloses the preparation of compound 1: 3-((2-amino-3,5-dibromobenzyl)amino)adamantan-1-ol, whose structure is as follows:

[0046]

[0047] Add 3 g (0.018 mol) of 3-amino-1-adamantanol, 10 g (0.036 mol) of 2-amino-3,5-dibromobenzaldehyde and 100 ml of tetrahydrofuran (THF) into the reaction flask, reflux overnight, and monitor the reaction with TCL , until the raw material drug basically disappeared, cooled to room temperature, added 2.5g (0.066mol) of sodium borohydride to react for 24 hours, then added about 250ml of water, then extracted with 300ml of ethyl acetate, concentrated under reduced pressure to obtain compound 1, a total of 6.60g, HPLC The purity is 98.70%, and the yield is 86%.

[0048] MS m / z(ES):429.01

[0049] 1H NMR (400MHz,D 2 O)δ7.81(d,1H),7.21(d,1H),3.76(s,2H),1.76(s,2H),1.68-1.66(m,6H),1.46-1.55(m,4H), 1.34-1.38 (m, 4H).

Embodiment 2

[0051] This example discloses the preparation of compound 2: 3-((2-amino-3,5-dibromobenzyl)amino)adamantan-1-ol hydrochloride, whose structure is as follows:

[0052]

[0053] Compound 1 was prepared according to the method of Example 1, and then (0.018mol) Compound 1 was washed with 100ml of saturated sodium chloride, acidified with hydrochloric acid, and concentrated to dryness under reduced pressure to obtain Compound 2, a total of 7.06g, HPLC purity 98.65%, yield 85%.

[0054] MS m / z(ES):429.02

[0055] 1H NMR (400MHz,D 2O)δ7.80(d,1H),7.22(d,1H),3.76(s,2H),1.77(s,2H),1.68-1.67(m,6H),1.46-1.56(m,4H), 1.34-1.38 (m, 4H).

Embodiment 3

[0057] This example discloses the preparation of compound 3: (1R,2R)-2-((2-amino-3,5-dibromobenzyl)amino)-cyclopentanol, whose structure is as follows:

[0058]

[0059] Add 3 g (0.029 mol) of trans (1R, 2R)-2-aminocyclopentanol, 10 g (0.036 mol) of 2-amino-3,5-dibromobenzaldehyde and 100 ml of THF into the reaction flask, reflux overnight, and TCL Monitor the reaction until the raw material drug basically disappears, cool to room temperature, add 2.5g (0.066mol) of sodium borohydride to react for 24 hours, then add about 250ml of water, then extract with 300ml of ethyl acetate, and concentrate under reduced pressure to obtain compound 3, a total of 8.90g , HPLC purity 98.76%, yield 86%.

[0060] MS m / z(ES):362.95

[0061] 1H NMR (400MHz,D 2 O)δ7.81(d,1H),7.28(d,1H),3.45(s,2H),4.22(m,1H),3.59(m,1H),2.09-2.34(m,2H),1.53- 1.72 (m, 4H).

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Abstract

The invention discloses a dibromobenzyl derivative with a structure shown as formula I, a stereoisomer or pharmaceutically acceptable salt thereof, and a preparation method and application of the dibromobenzyl derivative. The dibromobenzyl derivative and the stereoisomer thereof have better in-vivo pharmacokinetic stability and better drug effect, and can be used for preparing respiratory system treatment drugs, especially phlegm eliminating drugs.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to dibromobenzyl derivatives, stereoisomers or pharmaceutically acceptable salts thereof, preparation methods and applications. Background technique [0002] Ambroxol (Ambroxol) is a metabolite of bromhexine in vivo, which can promote the secretion of pulmonary surfactant and airway fluid, break the mucopolysaccharide protein fibers in sputum, promote the dissolution of mucus sputum, significantly reduce sputum viscosity, and enhance The movement of bronchial mucous membrane and cilia can promote the discharge of sputum, which can effectively improve the ventilation function and the condition of dyspnea. Because the expectorant effect of ambroxol is significantly higher than that of bromhexine, and the toxicity is small and the tolerance is good, so it has become a commonly used expectorant drug at present. Ambroxol was used clinically in the form of hydrochloride in 1984. It is ...

Claims

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Application Information

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IPC IPC(8): C07C211/52C07C215/44C07C249/02C07C251/24C07C209/52C07C213/02A61K31/137A61P11/10
CPCC07C211/52C07C215/44C07C249/02C07C209/52C07C213/02A61P11/10C07C2601/08C07C2603/74C07C251/24A61K31/137C07B2200/07
Inventor 岑国栋杨茂廷谭少军
Owner CHENGDU SHIBEIKANG BIOLOGICAL MEDICINE TECH CO LTD
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