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Synthesis method of 5-(2-bromoacetyl)-2-hydroxybenzaldehyde

A technology of hydroxybenzaldehyde and bromoacetyl group is applied in the synthesis field of 5--2-hydroxybenzaldehyde, can solve the problems of high price of bromoacetyl bromide, poor selectivity, restricting industrial production and the like, and achieves reduction of purification difficulty and improvement of yield. efficiency and purity, and the availability of raw materials

Inactive Publication Date: 2019-05-21
UNIV OF JINAN
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

Among them (Li Lichan, Liu Juntao, Zhao Xuan. Synthesis of new chiral ligands and their application in the synthesis of key intermediates of salmeterol [J]. Chinese Journal of Medicinal Chemistry, 2008(3):175-179.), The yield is 81%, but it needs to be purified by column chromatography, which limits its industrial production, and bromoacetyl bromide is expensive and has poor selectivity

Method used

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  • Synthesis method of 5-(2-bromoacetyl)-2-hydroxybenzaldehyde

Examples

Experimental program
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Effect test

Embodiment 1

[0019] Preparation of 2-(acetoxy)-benzaldehyde:

[0020] Add glacial acetic acid (50 mL) into a 500 mL three-necked flask, add salicylaldehyde (24.4 g, 0.2 mol) and acetic anhydride (22.5 g, 0.22 mol) dropwise into glacial acetic acid under stirring, Under reflux for 2 h, the TLC control reaction was completed. The reaction solution was added to 100 mL of ice water, cooled to 5°C, stirred for 1-2 h, and separated by filtration after solid precipitation. Finally, it was dissolved in 125 mL of ethyl acetate, dried over anhydrous magnesium sulfate, and the ethyl acetate was concentrated in vacuo to obtain 32.6 g of solid 2-(acetoxy)-benzaldehyde with a yield of 99.4%.

[0021] Preparation of 5-acetyl-2-hydroxy-benzaldehyde:

[0022] Add dichloromethane (250 mL) into a 500 mL three-necked flask, add anhydrous aluminum trichloride (36 g, 0.27 mol) under stirring, raise the temperature to 25 °C, and then add 2-(acetoxy)-benzaldehyde ( 29.5 g, 0.18 mol), kept at 25°C, reacted for ...

Embodiment 2

[0026] Preparation of 2-(acetoxy)-benzaldehyde:

[0027] Add glacial acetic acid (50 mL) into a 500 mL three-necked flask, and add salicylaldehyde (24.4 g, 0.2 mol) and acetyl chloride (18.8 g, 0.24 mol) dropwise into glacial acetic acid under stirring. Under reflux for 2 h, the TLC control reaction was completed. The reaction solution was added to 100 mL of ice water, cooled to 5°C, stirred for 1-2 h, and separated by filtration after solid precipitation. Finally, it was dissolved in 125 mL of ethyl acetate, dried over anhydrous magnesium sulfate, and the ethyl acetate was concentrated in vacuo to obtain 32.2 g of solid 2-(acetoxy)-benzaldehyde with a yield of 98.2%.

[0028] Preparation of 5-acetyl-2-hydroxy-benzaldehyde:

[0029] Add dichloromethane (250 mL) into a 500 mL three-necked flask, add zinc chloride (34.1 g, 0.25 mol) while stirring, raise the temperature to 30 °C, and then add 2-(acetoxy)-benzaldehyde (29.5 g, 0.18 mol), kept at 30°C, reacted for 10 h, and the...

Embodiment 3

[0033] Preparation of 2-(acetoxy)-benzaldehyde:

[0034] Add glacial acetic acid (50 mL) into a 500 mL three-necked flask, and add dropwise salicylaldehyde (24.4 g, 0.2 mol) and acetic anhydride (24.5 g, 0.24 mol) into glacial acetic acid under stirring. Under reflux for 2 h, the TLC control reaction was completed. The reaction solution was added to 100 mL of ice water, cooled to 5°C, stirred for 1-2 h, and separated by filtration after solid precipitation. Finally, it was dissolved in 125 mL of ethyl acetate, dried with anhydrous magnesium sulfate, and the ethyl acetate was concentrated in vacuo to obtain 32.3 g of solid 2-(acetoxy)-benzaldehyde with a yield of 98.5%.

[0035] Preparation of 5-acetyl-2-hydroxy-benzaldehyde:

[0036] Add dichloromethane (250 mL) into a 500 mL three-necked flask, add anhydrous ferric chloride (40.6 g, 0.25 mol) while stirring, raise the temperature to 25 °C, and then add 2-(acetoxy)-benzaldehyde (29.5 g, 0.18 mol), kept at 25°C, reacted for 10...

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Abstract

The invention discloses a synthesis method of 5-(2-bromoacetyl)-2-hydroxybenzaldehyde, and belongs to the field of medicine synthesis. According to the method, the acylation reaction is conducted withsalicylaldehyde as the raw material to obtain 2-(acetoxyl)-benzaldehyde, then the rearrangement reaction is conducted, and finally the bromination reaction is conducted to obtain 5-(2-bromoacetyl)-2-hydroxybenzaldehyde. The preparing method has the advantages of being high in product purity and high in yield.

Description

technical field [0001] The invention belongs to the field of medicine synthesis and relates to a synthesis method of 5-(2-bromoacetyl)-2-hydroxybenzaldehyde. Background technique [0002] Vilanterol triphenylacetate is a long-acting β2-adrenoceptor agonist developed by GlaxoSmithKline (GSK) with bronchodilation for chronic obstructive pulmonary disease (COPD) and asthma Treatment. The molecular formula of vilanterol is C 24 h 33 Cl 2 NO 5 , molecular weight 486.4, CAS: 503068-34-6, Chinese name: Chemical name: (R)-4-[2-[[6-[(2,6-dichlorobenzyl)oxy]-ethoxy Base] ethyl] amino] -1-hydroxyethyl] -2-hydroxyethyl] -2-hydroxymethylphenol, the chemical structural formula is as follows: [0003] . [0004] Among them, 5-(2-bromoacetyl)-2-hydroxybenzaldehyde is an important intermediate for the synthesis of vilanterol, salmeterol, etc. Document Synthesis, 1988,8 (12), 966 relates to a kind of vilanterol intermediate: the synthetic method of 5-(2-bromoacetyl)-2-hydroxybenzald...

Claims

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Application Information

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IPC IPC(8): C07C45/63C07C49/86C07C45/78
Inventor 朱臣析郑庚修高令峰陈胜男张启龙
Owner UNIV OF JINAN
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