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Dihydroartemisinin oxime-containing phenol derivatives as well as synthesis method and application thereof

A technology of dihydroartemisinin and synthesis method, which is applied in the field of chemical medicine, can solve problems such as unreported, achieve good application prospects, high synthesis yield, and the effect of inhibiting interleukin-17

Active Publication Date: 2019-11-22
SOUTHWEST UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Literature survey found that there are many derivatives of DHA, but the dihydroartemisinin-containing oxime phenol derivatives of DHA have not been reported so far

Method used

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  • Dihydroartemisinin oxime-containing phenol derivatives as well as synthesis method and application thereof
  • Dihydroartemisinin oxime-containing phenol derivatives as well as synthesis method and application thereof
  • Dihydroartemisinin oxime-containing phenol derivatives as well as synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Embodiment 1, preparation of dihydroartemisinin-containing oxime phenol derivatives

[0030] (1) The preparation method of intermediate IM1 is as follows:

[0031]

[0032] Dihydroartemisinin (DHA), diethyl ether (Et 2 O) and bromoalcohol, add boron trifluoride-ether (BF 3 ·Et 2 O), under stirring reaction 5 ~ 20h, after the completion of the reaction, add saturated NaHCO 3 The reaction was terminated, the layers were left to stand, the aqueous layer was extracted with ethyl acetate (EtOAc or EA), the organic phases were combined, washed with saturated brine, anhydrous MgSO 4 Dry, filter with suction, and remove the solvent by rotating the filtrate under reduced pressure to obtain a crude product, which is recrystallized with petroleum ether (PE)-EA mixed solvent to obtain intermediate IM1.

[0033] (2) DHA and carbonyl-containing phenol conjugates, we use TM4 to represent in this application, and its preparation method is as follows:

[0034]

[0035] In a 1...

Embodiment 2

[0039] Example 2, Preparation of dihydroartemisinin-containing oxime phenol derivatives TM8-1~TM8-58

[0040] According to the preparation method described in Example 1 when n=2 or 3, R 1 H or -OCH 3 , R 2 H, -CH 3 or -CH 2 CH 3 , R 3 for H, CH 3 or CH 2 CO 2 H, m=0 or 2, a series of products TM8-1 to TM8-58 were prepared, and the respective reaction conditions, yields, product yields, and product melting points are shown in Table 1.

[0041] Table 1 Experimental results of synthesis of TM8 series compounds

[0042]

[0043]

[0044]

[0045]

Embodiment 3

[0046] Example 3, Test and Characterization of TM8-1~TM8-58

[0047] Carried out to embodiment 2TM8-1~TM8-58 series products 1 H NMR (AV-300), 13 C NMR (AV-75) and HRMS (Varian7.0T) testing and characterization, the data are as follows:

[0048]

[0049] TM8-1(E)-2-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2] dioxepino [4,3-i]isochromen-10-yl)oxy)propoxy)benzaldehyde

[0050] 1 H NMR (300MHz, CDCl 3 )δ: 8.51(1H, s), 7.70(1H, d, J=6.6Hz), 7.32(1H, t, J=7.2Hz), 6.97-6.88(2H, m), 5.33(1H, s), 4.83(1H, d, J=3.3Hz), 4.15-4.08(3H, m), 3.59-3.52(1H, m), 2.65-2.60(1H, m), 2.39-2.28(1H, m), 2.13- 1.04(12H, m), 1.43(3H, s), 0.89(3H, d, J=7.5Hz), 0.86(3H, d, J=6.3Hz). 13 C NMR (75MHz, CDCl 3 )δ:156.95,146.36,131.15,126.88,120.85,111.90,104.19,101.90,87.84, 81.12,65.16,64.33,52.50,44.40,37.28,36.44,34.58,30.95,29.29,26.19,24.65,24.60,20.42, 13.0 .HRMScalcdforC 25 h 35 NO 7 [M+Na] + 484.2311, found 484.2310.

[0051] TM8-2(E)-3-(3-(((3R,6R,8...

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Abstract

The invention discloses dihydroartemisinin oxime-containing phenol derivatives as well as a synthesis method and application thereof, and belongs to the technical field of chemical medicines. The derivatives or racemates, stereoisomers, tautomers and pharmaceutically acceptable salts thereof have the following general formula shown in the specification. The invention also discloses the synthesis method of the derivatives, and the application of the derivatives in antituberculotic, antidiabetic, lipid-lowering and interleukin-17 inhibition drugs.

Description

technical field [0001] The invention relates to the technical field of chemistry and medicine, in particular to a dihydroartemisinin-containing oxime phenol derivative, a synthesis method and an application. Background technique [0002] Artemisinin is a terpenoid found in the plant Artemisia annua. Dihydroartemisinin (DHA) is the first-generation derivative of artemisinin. It not only has a unique structure, but also shows better pharmaceutical properties than artemisinin. It is an important clinical antimalarial drug. Based on the special structure and excellent activity of DHA, the research on DHA at home and abroad continues. At present, it mainly focuses on the design and synthesis of new DHA derivatives, the exploration of new activities of old molecules of DHA or the activity research of new molecules. So far, many new derivatives of DHA have been synthesized, and some artemisinin derivatives have been used in clinical trials against breast cancer, colorectal cancer,...

Claims

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Application Information

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IPC IPC(8): C07D493/20A61P3/06A61P3/10A61P31/06A61K31/357
CPCC07D493/20A61P3/06A61P3/10A61P31/06Y02P20/55
Inventor 杨大成唐雪梅潘建芳范莉周福委李平杨艳
Owner SOUTHWEST UNIVERSITY
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