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Polysubstituted aromatic diketone compounds as well as preparation method and application thereof

A technology for aromatic diketones and compounds, which is applied in the fields of polysubstituted aromatic diketones and their preparation and application, can solve problems such as limiting the application of HAART, toxic and side effects, and achieve the effects of mild reaction conditions and simple steps

Inactive Publication Date: 2014-05-21
BEIJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, mutations in the HIV-1 gene have led to the emergence of drug-resistant viruses, and some patients have been ineffective with this conventional treatment.
In addition, some toxic and side effects of antiviral drugs also limit the application of HAART
Because the first two types of drugs are easy to induce HIV drug resistance and have strong toxic and side effects on the human body, more and more patients cannot continue to receive these anti-HIV drug treatments

Method used

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  • Polysubstituted aromatic diketone compounds as well as preparation method and application thereof
  • Polysubstituted aromatic diketone compounds as well as preparation method and application thereof
  • Polysubstituted aromatic diketone compounds as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1: Preparation of 1-(4-hydroxybenzo[1,2-b:3,4-b']difuran-5-yl)propyl-1,3-dione (1a)

[0054] (1) Preparation of 1-(2,4-(2,2-diethoxyethoxy)-6-hydroxyphenyl)ethanone

[0055]

[0056] Add 2,4,6-trihydroxyacetophenone (3g, 17.9mmol) into a 50mL two-necked flask, add 20mL of dry DMF and stir to dissolve, add K 2 CO 3 (9.84g, 71.3mmol), bromoacetaldehyde ethylene acetal (3mL, 18.8mmol), after stirring uniformly at room temperature, the reaction mixture was heated to reflux for 8h, poured into ice, stirred and cooled, extracted with ethyl acetate, and the organic phase was separated And with anhydrous MgSO 4 dry. The organic solvent was evaporated to dryness to obtain a dark brown oily liquid, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 8:1 as the eluent.

[0057] The pure product is a white solid, melting point: 60-62°C, yield: 60%.

[0058] 1 H NMR (400MHz, CDCl 3 ,δppm):1.19(t,12H,J=7.2Hz),2.58(s,1H),3...

Embodiment 2

[0079] Example 2: 1-(4-chlorophenyl)-3-(4-hydroxybenzo[1,2-b:3,4-b']difuran-5-yl)propyl-1,3- Preparation of diketone (2a)

[0080] (1), (2), (3) steps are with embodiment 1.

[0081] (4) 1-(4-chlorophenyl)-3-(4-hydroxybenzo[1,2-b:3,4-b']difuran-5-yl)propyl-1,3-di Preparation of ketone (2a)

[0082]

[0083] Add 2-acetylbenzodifuran-4-chlorobenzoate (0.846g, 2.39mmol) into a 50mL round bottom flask, add 15mL of acetone and stir to dissolve, add KOH (0.335g, 5.98mmol) and stir evenly, then Heated to reflux for 7 h under the protection of argon, cooled to room temperature, adjusted to pH=6 with 1M HCl, extracted with EtOAc, separated the organic phase and washed with anhydrous MgSO 4 dry. The organic solvent was evaporated to dryness to obtain a yellow solid, which was recrystallized from ethanol to obtain a pure product.

[0084] Melting point: 220-221°C, yield: 40%.

[0085] 1 H NMR (400MHz, CDCl 3 ,δppm):7.03(d,1H,J=2.0Hz),7.07(d,1H,J=2.0Hz),7.48(d,2H,J=8.8Hz),7.60(...

Embodiment 3

[0088]Example 3: Preparation of 1-(3-acetyl-2-hydroxyl-4,6-dimethoxyphenyl)-3-phenylpropane-1,3-dione (3a)

[0089] (1) Preparation of 1,3,5-trimethoxybenzene

[0090]

[0091] Phloroglucinol (0.162g, 1mmol) was dissolved in 20mL of acetone, adding K 2 CO 3 (0.55g, 4mmol), stirred for a while, then added dropwise dimethyl sulfate (0.2mL, 2mmol), stirred at room temperature for 6h, the raw material disappeared, the reaction solution was poured into water, extracted with ethyl acetate, the organic phase was separated and washed with anhydrous MgSO 4 dry. The solvent was spin-dried to obtain pure product;

[0092] The pure product is a white solid, melting point: 50-52°C, yield: 80%.

[0093] 1 H NMR (CDCl 3 ,400MHz,δppm):6.08(s,3H),3.77(s,9H).

[0094] (2) Preparation of 1,1'-(2-hydroxy-4,6-dimethoxy-1,3-phenylene) diethyl ketone

[0095]

[0096] 1,3,5-Trimethoxybenzene (2.02g, 12mmol) was dissolved in 150mL of dichloromethane, anhydrous AlCl was added 3 (5g, 37m...

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Abstract

The invention relates to polysubstituted aromatic diketone compounds as shown in the formula (I) as well as a preparation method and application thereof. R1 in the formula (I) is a substituent group expressed by the formula (I-1), (I-2) or (I-3), and R2 is -H, -F, -Cl, -Br, -CH3 or -OCH3. When R1 is the formula (I-1), the preparation method comprises the following steps: with 2,4-dihydroxyacetophenone as the raw material, enabling the 2,4-dihydroxyacetophenone to be reacted with bromoacetaldehyde ethylene acetal to obtain 1-(4-(2,2-methoxyethoxy)-2-hydroxyphenyl) ethyl ketone; then, cyclizing and enabling the 1-(4-(2,2-methoxyethoxy)-2-hydroxyphenyl) ethyl ketone to be reacted with aryl chloride; finally, rearranging under an alkaline condition to obtain the polysubstituted aromatic diketone compounds. When R1 is the formula (I-2), the method disclosed by the invention is basically same as the method adopted when R1 is the formula (I-1). When R1 is the formula (I-3), the method comprises the following steps: with phloroglucinol as the raw material, methylating to obtain 1,3,5-trimethoxybenzene; then, enabling the 1,3,5-trimethoxybenzene to be reacted with acetyl chloride to obtain 1,1'-(2-hydroxy-4,6-dimethoxy-1,3-phenylene) diethyl ketone; next, enabling the 1,1'-(2-hydroxy-4,6-dimethoxy-1,3-phenylene) diethyl ketone to be reacted with aryl chloride; finally, rearranging under an alkaline condition to obtain the polysubstituted aromatic diketone compounds. The polysubstituted aromatic diketone compounds have an inhibiting effect for HIV-1 (Human Immunodeficiency Virus-1) integrase. The formula (I) is shown in the specification.

Description

technical field [0001] The invention relates to multi-substituted aromatic diketone compounds, their preparation method and their application as HIV-1 integrase inhibitors. Background technique [0002] AIDS (Acquired immunodeficiency syndrome, AIDS) is an autoimmune disease caused by human immunodeficiency virus (Human immunodeficiency virus-1, HIV-1) infection. Since the disease was first reported in 1981, it has rapidly developed into a major infectious disease that seriously threatens human health and survival, and is one of the main infectious diseases that cause death. According to the 2013 United Nations AIDS Statistics Table, in 2012 there were about 34 million HIV-infected and AIDS-related people in the world, of which 2.7 million were newly infected in 2011, and 1.8 million people died of AIDS-related diseases. [0003] So far, 25 single anti-HIV-1 drugs and 5 compound preparations composed of these drugs have been approved by the US FDA for clinical use. Accordi...

Claims

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Application Information

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IPC IPC(8): C07D493/04C07C49/84C07C45/54C07D307/79A61P31/18
CPCC07C45/54C07C49/84C07D307/79C07D493/04
Inventor 胡利明王占洋王雨捷曾程初
Owner BEIJING UNIV OF TECH
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