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Salicylic acid amide derivative and preparation method thereof

A technology of salicylic acid amide and compound is applied in the field of salicylic acid amide derivatives and pharmaceutically acceptable salts thereof, and can solve the problems of complicated processing technology, increase of subsequent processes, poor product quality and the like

Active Publication Date: 2015-09-02
SHENZHEN WANHE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

CN1368954A (Chinese Patent Application No. 00811487.0) discloses DHMEQ (that is, DHM2EQ wherein, DHM2EQ and DHMEQ both have the same meaning herein, can be used interchangeably, also can be referred to as formula 1 compound or formula I compound in the present invention ) synthetic method, wherein in step 3, in the solvent tetrahydrofuran, in the presence of hydrogen peroxide and sodium hydroxide, 3-(O-acetylsalicyloylamino)-4,4-dimethoxy- 2,5-cyclohexadienone reacts to generate 5,6-epoxy-4,4-dimethoxy-3-salicyylamino-2-cyclohexenone, and the reactant needs to be processed through a complicated process and The resulting product is of poor quality
Added obstacles to its subsequent process

Method used

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  • Salicylic acid amide derivative and preparation method thereof
  • Salicylic acid amide derivative and preparation method thereof
  • Salicylic acid amide derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0137] Example 1: Preparation of 5,6-epoxy-4-hydroxyl-3-salicyloylamino-2-cyclohexenone (DHM2EQ)

[0138] Step 1: Synthesis of N-(2-acetoxybenzoyl)-2,5-dimethoxyaniline

[0139]

[0140] 2,5-Dimethoxyaniline (10.0 g, 65.3 mmol) was dissolved in pyridine (100 ml). Under ice-cooling, a solution of O-acetylsalicyloyl chloride (13.0 g, 65.3 mmol) in ethyl acetate (50 ml) was added thereto over 15 minutes, followed by stirring at the same temperature for 15 minutes. After adding water (10ml) to the reaction solution to stop the reaction, add ethyl acetate (500ml), then successively add 3 equivalents of hydrochloric acid (500ml), water (500ml), 2% aqueous sodium bicarbonate (500ml) and water (500ml )washing. The ethyl acetate layer was dried over Glauber's salt, concentrated under reduced pressure and dried in vacuo to obtain the title compound (19.8 g) as a pale yellow syrup. The compound was used directly in the following step without further purification. After separati...

Embodiment 2

[0158] Example 2: Synthesis of 5,6-epoxy-4,4-dimethoxy-3-salicyylamino-2-cyclohexenone

[0159] 3-(O-acetylsalicyloylamino)-4,4-dimethoxy-2,5-cyclohexadienone (10.9 g, 33.0 mmol) was dissolved in dimethylformamide (200 ml) Under ice-cooling, add 396mmol hydrogen peroxide (add with 30% hydrogen peroxide aqueous solution form) and the sodium carbonate (165ml) of 1mol / L wherein, stirred reaction 2 hours at same temperature;

[0160] Add ethyl acetate (500ml) to the reaction solution, wash with 1 equivalent of hydrochloric acid (300ml), 10% aqueous sodium thiosulfate solution (300ml×2), 10% saline (300ml) successively, and wash the ethyl acetate layer with Glauber's salt is dried, then vacuum-dried to obtain a light yellow solid powder;

Embodiment 3

[0163] Example 3: Synthesis of 5,6-epoxy-4,4-dimethoxy-3-salicyylamino-2-cyclohexenone

[0164] 3-(O-acetylsalicyloylamino)-4,4-dimethoxy-2,5-cyclohexadienone (10.9 g, 33.0 mmol) was dissolved in dimethylformamide (200 ml) ; Under ice-cooling, add 330mmol hydrogen peroxide (add with 30% hydrogen peroxide aqueous solution form) and the sodium carbonate (165ml) of 1mol / L wherein, stir reaction 2 hours at same temperature;

[0165]Add ethyl acetate (500ml) to the reaction solution, wash with 1 equivalent of hydrochloric acid (300ml), 10% aqueous sodium thiosulfate solution (300ml×2), 10% saline (300ml) successively, and wash the ethyl acetate layer with Glauber's salt is dried, then vacuum-dried to obtain a light yellow solid powder;

[0166] The light yellow solid powder obtained by drying was dissolved in a mixed solvent of acetone-petroleum ether (the volume ratio of the two was 8:1), and an equal volume of saturated saline was added to extract twice, the water layer was di...

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Abstract

The invention discloses a preparation method of salicylamide derivatives shown in the formula 1. The preparation method comprises the following steps that 2,5-dimethoxyaniline is dissolved in an organic solvent and reacts with ethyl acetate of O-alkylacylsalicyloyl chlorine to produce N-(2-alkylacyloxyformoxy)-2,5-dimethoxyaniline; the N-(2-alkylacyloxyformoxy)-2,5-dimethoxyaniline reacts with R3OH in the presence of iodobenzene diacetate to produce 3-(O-alkylacylsalicyloylamino)-4,4-dialkoxy-2,5-cyclohexadienone; in an organic solvent (such as tetrahydrofuran, methanol and dimethyl formamide and especially such as dimethyl formamide), the 3-(O-alkylacylsalicyloylamino)-4,4-dialkoxy-2,5-cyclohexadienone undergoes a reaction in the presence of a hydrogen peroxide aqueous solution and an inorganic base to produce 5,6-epoxy-4,4-dialkoxy-3-salicyloylamido-2-cyclohexenone; the 5,6-epoxy-4,4-dialkoxy-3-salicyloylamido-2-cyclohexenone undergoes a reaction in the presence of a boron trifluoride ether complex to produce 5,6-epoxy-2-salicyloylamido-2-cyclohexenyl-1,4-dione; and the 5,6-epoxy-2-salicyloylamido-2-cyclohexenyl-1,4-dione is reduced into 5,6-epoxy-4-hydroxy-3-salicyloylamido-2-cyclohexenone (DHM2EQ) shown in the formula (1). The invention also relates to a preparation method of the 5,6-epoxy-4-hydroxy-3-salicyloylamido-2-cyclohexenone.

Description

technical field [0001] The present invention relates to a salicylic acid amide derivative represented by formula 1, a pharmaceutically acceptable salt thereof, and a preparation method thereof. The salicylic acid amide derivatives are useful in the treatment of cancer, inflammation, autoimmune disease, diabetes and diabetic complications, infection, cardiovascular disease and defective reperfusion injury. Background technique [0002] NF-κB (Nuclear factor-kappa B) activation is involved in various diseases including cancer, diabetes, cardiovascular disease, autoimmune disease, viral replication, septic shock, neurodegenerative disease, ataxia telangiectasia arthritis (AT), arthritis, asthma, inflammatory bowel disease, and other inflammatory conditions. For example, activation of NF-κB by gram-negative bacterial lipopolysaccharide (LPS) can produce septic shock because NF-κB hyperactivates the transcription of many cytokines and modifying enzymes, whose prolonged expressio...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D303/36A61P35/00A61P29/00A61P37/02A61P3/10A61P31/00A61P9/00A61P9/10
CPCC07D301/00C07D303/36
Inventor 马俊余卫麟
Owner SHENZHEN WANHE PHARMA
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