Meta-disubstituted phenol compound and its preparation method and anti-tuberculosis application

A phenol compound and a disubstituted technology, applied in the field of medicinal chemistry, can solve the problems of large side effects, unsuitable for long-term medication and the like

Active Publication Date: 2020-04-17
SUN YAT SEN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Clinically, the proportion of patients resistant to the first-line anti-tuberculosis drugs isoniazid, rifampin, pyrazinamide and streptomycin is close to 15%, while the second-line drugs are not suitable for long-term medication due to their side effects

Method used

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  • Meta-disubstituted phenol compound and its preparation method and anti-tuberculosis application
  • Meta-disubstituted phenol compound and its preparation method and anti-tuberculosis application
  • Meta-disubstituted phenol compound and its preparation method and anti-tuberculosis application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Embodiment 1 Synthetic N-(3-benzyl-5-hydroxyl phenyl)-2-phenylacetamide

[0079]

[0080] In a 100mL two-necked flask, sodium borohydride (1.6g, 42mmol) and redistilled tetrahydrofuran (20mL) were added under the protection of argon, and 3-nitro-5-methoxybenzoic acid (3.94 g, 20mmol), and then add boron trifluoride ether solution 6.7mL. After reacting at room temperature for 4 h, the reaction solution was quenched with dilute hydrochloric acid under ice cooling, and then extracted with dichloromethane (30 mL×2). The solvent of the extract was removed under reduced pressure to obtain 3.6 g of crude product 3-nitro-5-methoxybenzyl alcohol, which was directly used in the next reaction.

[0081] In a 100mL round bottom flask, add anhydrous aluminum trichloride (5.58g, 42mmol), 20mL of anhydrous benzene and 10mL of dichloromethane, slowly add 3-nitro-5-methoxybenzyl alcohol under ice-bath conditions (3.6g, 20mmol), and then reflux at 80°C for 5h. After cooling, the rea...

Embodiment 2

[0086] Embodiment 2 Synthetic N-(3-benzyl-5-hydroxyl phenyl) cyclohexyl formamide

[0087]

[0088] Refer to Example 1 for the synthesis of 1-benzyl-3-aminophenol. In a 50mL round bottom flask, add 1-benzyl-3-aminophenol (99.5mg, 0.5mmol), cyclohexanecarbonyl chloride (74μL, 0.55mmol), triethylamine (76μL, 0.55mmol) under ice cooling and redistilled tetrahydrofuran 2mL, reacted at room temperature for 12h, the reaction solution was extracted with ethyl acetate (15mL×2), and the solvent was removed from the extract under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate Ester gradient elution) to obtain 75 mg of white solid N-(3-benzyl-5-hydroxyphenyl)cyclohexanecarboxamide with a yield of 49%.

[0089] 1 H NMR(400MHz,DMSO)δ9.59(s,1H),9.24(s,1H),7.28(m,2H),7.19(m,3H),7.04(m,1H),6.84(m,1H) ,6.28(m,1H),3.77(s,2H),2.27(t,J=11.4Hz,1H),1.73(d,J=9.2Hz,4H),1.63(d,J=9.6Hz,1H) ,1.37(m,2H),1.30–1.14(m,...

Embodiment 3

[0090] Example 3 Synthesis of N-(3-benzyl-5-hydroxyphenyl)-2-(4,4-dimethylcyclohexyl)acetamide

[0091]

[0092] Refer to Example 1 for the synthesis of 1-benzyl-3-aminophenol. In a 25 mL round bottom flask, add 1-benzyl-3-aminophenol (160 mg, 0.8 mmol), 2-(4,4-dimethylcyclohexyl) acetic acid (204 mg, 1.2 mmol), triphenyl phosphite (314μL, 1.2mmol) and redistilled toluene 5mL were reacted at 110°C for 12h. The solvent was removed from the reaction solution under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / dichloromethane gradient elution) to obtain a white solid, namely N-(3-benzyl-5-hydroxyphenyl)-2-(4 , 4-dimethylcyclohexane) acetamide 127mg, yield 45%.

[0093] 1 H NMR(400MHz,DMSO)δ9.60(s,1H),9.21(s,1H),7.28(m,2H),7.18(m,3H),7.06(m,1H),6.79(m,1H) ,6.28(m,1H),3.78(s,2H),2.15(d,J=7.1Hz,2H),1.64(m,1H),1.49(m,2H),1.33(m,2H),1.19– 1.10(m,4H),0.87(s,3H),0.86(s,3H). 13C NMR (101MHz, DMSO) δ170.89, 157.99, 142.94, 141...

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Abstract

The invention provides an m-di-substituted phenol compound with a general formula (I) as well as a preparation method and application thereof. The m-di-substituted phenol compound provided by the invention has a novel tubercle bacillus resistance drug parent nucleus structure and excellent tubercle bacillus resistance activity and especially has very strong inhibition activity on a drug-resistantvariant tubercle bacillus strain. The invention further provides the preparation method of the m-di-substituted phenol compound; the preparation method has the advantages that raw materials are cheapand easy to obtain, a high-toxicity and high-pollution reagent are not needed, reaction steps are simple and industrialized production can be realized; the m-di-substituted phenol compound has a goodmedicinal prospect.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a class of m-disubstituted phenol compounds, a preparation method thereof and an anti-tuberculosis application. Background technique [0002] Tuberculosis is a chronic and fatal disease caused by Mycobacterium tuberculosis. Its annual death toll exceeds that of AIDS and seriously endangers human health. At present, due to the emergence of multidrug-resistant and extensively drug-resistant mutant tuberculosis, as well as the emergence of tuberculosis patients co-infected with HIV, the difficulty of treating tuberculosis has been greatly increased. Clinically, the proportion of patients who are resistant to the first-line anti-tuberculosis drugs isoniazid, rifampicin, pyrazinamide and streptomycin is close to 15%, while the second-line drugs are not suitable for long-term medication due to their side effects. [0003] Therefore, the discovery of new anti-tuberculosis...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C233/29C07C233/26C07D309/08C07C233/75C07C235/56C07D213/82C07D333/38C07D285/06C07C271/38C07C271/28C07C233/80C07D213/74C07D241/20A61K31/167A61K31/351A61K31/44A61K31/381A61K31/433A61K31/27A61K31/4402A61K31/4965A61P31/06
CPCC07C233/26C07C233/29C07C233/75C07C233/80C07C235/56C07C271/28C07C271/38C07D213/74C07D213/82C07D241/20C07D285/06C07D309/08C07D333/38
Inventor 鄢明张天宇张妞妞刘志永钱露唐运祥程亚娟张学景
Owner SUN YAT SEN UNIV
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