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An improved synthesis process of bardoxolone lactone derivatives

A synthesis process and derivative technology, applied in the direction of steroids, organic chemistry, etc., can solve the problems of long synthesis route of Bardoxolone lactone derivatives, heavy synthesis and purification workload, unsuitable for industrial production, etc., to reduce synthesis cost , avoid water pollution, repeatable effect

Active Publication Date: 2018-01-12
泰州学院
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] However, the existing synthetic route of this Bardoxolone lactone derivative is relatively long (11 steps, references are the same as above), and the workload of synthesis and purification is large, which is not conducive to the development of later biological activity evaluation, and is also not suitable for industrial production.

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  • An improved synthesis process of bardoxolone lactone derivatives
  • An improved synthesis process of bardoxolone lactone derivatives
  • An improved synthesis process of bardoxolone lactone derivatives

Examples

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Embodiment 1

[0040] Example 1: Preparation and structural confirmation of the compound shown in Chemical Formula II

[0041] Dissolve OA (500 mg, 1.1 mmol) and mCPBA (377 mg, 2.2 mmol) in 50 mL of anhydrous CH 2 Cl 2 , stirred at room temperature for 5 hours. The reaction solution was mixed with 200ml CH 2 Cl 2 After dilution, the organic layer was washed three times with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and a white solid (440mg, 85%) was obtained by silica gel column chromatography. 1 H-NMR (300MHz, CDCl 3 ,303K,TMS),δ(ppm):3.883(s,1H,C 12 -H),3.20-3.24(m,1H,C 3 -H),2.14(d,1H,C 18 -H),1.305,1.256,1.197,0.987,0.902,0.882,0.779(s,each3H); 13 C-NMR (75MHz, CDCl 3, 303K, TMS), δ (ppm): 179.977 (C 28 ), 90.642 (C 13 ), 78.859 (C 3 ), 76.323 (C 12 ),55.194,51.107,49.731,44.710,44.568,42.053,41.936,39.391,38.896,36.951,34.142,33.965,33.270,31.563,30.629,29.685,28.769,27.991,27.4...

Embodiment 2

[0042] Embodiment 2: Preparation and structure confirmation of the compound shown in chemical formula III

[0043] The compound represented by chemical formula II (450 mg, 1 mmol) and IBX (1.4 g, 5 mmol) were dissolved in 15 ml of anhydrous DMSO, heated to 105° C., and stirred for 6 hours. Cool to room temperature, terminate the reaction with 100ml of water, and extract 3 times with 100ml of ethyl acetate respectively. The organic layers were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was subjected to silica gel column chromatography to obtain a white solid (364 mg, 81%). 1 H-NMR (300MHz, CDCl 3 ,303K,TMS):,δ7.31,7.28,7.26(t,1H,C 1 -H),6.23(s,1H,C 11 -H),5.95,5.92(d,1H,C 2 -H),2.97,2.93(d,1H,C 18 -H),1.51,1.48,1.19,1.12,1.01,0.95(s,each 3H),0.95(s,6H); 13 C-NMR (75MHz, CDCl 3 ,303K,TMS),δ(ppm):202.61(C 3 ), 191.15 (C 12 ), 177.85 ...

Embodiment 3

[0044] Embodiment 3: Preparation and structural confirmation of the compound shown in chemical formula IV

[0045] The compound represented by chemical formula III (1.0 g, 2.2 mmol), simple iodine (1.7 g, 6.7 mmol) and pyridine (0.7 g, 8.6 mmol) were dissolved in 30 ml THF, and stirred at reflux for 24 hours. The solvent was distilled off from the reaction solution under reduced pressure, the black residue was dissolved in 50ml of ethyl acetate, the organic layer was washed with 10% sodium bicarbonate solution, 5% HCl solution and saturated brine respectively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated The amber crude product was obtained, and a white solid (0.97 g, 76%) was obtained by silica gel column chromatography with dichloromethane / petroleum ether=1:1. 1 H-NMR (300MHz, CDCl3, 303K, TMS): δ8.09(s, 1H, C1-H), 6.23(s, 1H, C11-H), 2.99, 2.95(d, 1H, C18-H), 1.51,1.50,1.24,1.19,1.04(s,each 3H),0.97(s,6H); 13C-NMR(75MHz,CDCl3,303K,TMS)...

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Abstract

The invention discloses an improved Bardoxolone lactone derivative synthetic process. Oleanolic acid is adopte as an original raw material, and the improved Bardoxolone lactone derivative synthetic process comprises the steps of a, obtaining a compound shown in the formula II by lactonizing oleanolic acid, and introducing a lactonic ring; b, oxidizing the compound shown in the formula II to obtain a compound shown in the formula III, and introducing an alpha, beta-unsaturated ketone group; c, iodinating the compound show in the formula III to obtain a compound shown in the formula IV; d, conducting nitrile grouping on the compound shown in the formula IV to obtain the Bardoxolone lactone derivative shown in the formula I. The improved Bardoxolone lactone derivative synthetic process is fewer in synthetic procedures, and manpower cost is effectively reduced; the synthetic process is high in raw material utilization ratio, excessive intermediate impurities and remaining solvents cannot be introduced in the final product, the synthetic process is suitable for industrialized production, and the Bardoxolone lactone derivative is high in yield and purity and easy for quality control.

Description

technical field [0001] The invention belongs to the field of drug synthesis and relates to the synthesis of Bardoxolone lactone derivatives, in particular to an improved synthesis process of Bardoxolone lactone derivatives. Background technique [0002] α,β-unsaturated ketones are pharmacophore in many active natural products and chemically synthesized small molecules, which can act as Michael acceptors and nucleophilic groups of various biomacromolecules in vivo (such as the sulfhydryl group of cysteine ​​residues ) undergoes an addition reaction, through covalent binding, regulates numerous signaling pathways in the cell, and exerts a wide range of biological activities and therapeutic effects on diseases. [0003] The introduction of α,β-unsaturated ketone groups into the pentacyclic triterpene structure of natural products can significantly improve its anti-inflammatory and anti-tumor activities. Honda et al. modified the structure of oleanolic acid (OA), synthesized an...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J71/00
CPCC07J71/0005
Inventor 牟伊
Owner 泰州学院
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