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Artemisinin derivative as well as synthesis and application thereof

A technology for artemisinin and derivatives, which is applied in the field of drug synthesis, can solve the problems of difficulty in producing specific vaccines, threats to human health, and no effective treatment methods, and achieves simple and easy preparation methods, low environmental pollution, and reproducibility. Good results

Active Publication Date: 2017-11-24
贝克诺顿(浙江)制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the extremely rapid mutation of HIV, it is difficult to produce a specific vaccine, and there is no effective treatment so far, which poses a great threat to human health

Method used

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  • Artemisinin derivative as well as synthesis and application thereof
  • Artemisinin derivative as well as synthesis and application thereof
  • Artemisinin derivative as well as synthesis and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Embodiment 1: Preparation of KPC-4000055

[0045]

[0046] Dissolve dihydroartemisinin (300mg, 1.06mmol, 1.0eq) and n-octanol (331mmL, 2.11mmol, 2.0eq) in a 10mL three-necked flask filled with 5mL of dichloromethane, replace nitrogen, and cool to -10 Add boron trifluoride diethyl ether (53mmL, 422μmol, 0.4eq) dropwise at °C and stir at this temperature for 2h. TLC (ethyl acetate:petroleum ether=2:8) showed that the reaction was complete. Slowly pour the reaction solution into water to quench, extract 3 times with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, remove the solvent on the rotary evaporation to obtain the crude product, pass through the column layer Purification by analysis (ethyl acetate:petroleum ether=2:8) gave colorless oily liquid KPC-4000055 (320 mg, yield 76%).

[0047] KPC-4000055: 1 H NMR (800MHz, CHLOROFORM-d) δ: 5.39(s, 1H), 4.78(d, J=3.3Hz, 1H), 3.83(td, J=6.6, 9.6Hz, 1H), 3....

Embodiment 2

[0050] Embodiment 2: Preparation of KPC-4000056

[0051]

[0052] Dihydroartemisinin (1.0g, 3.52mmol, 1.0eq) and 1,4-butanediol (3.11mL, 35.17mmol, 10.0eq) were dissolved in a 25mL three-necked flask containing 10mL of dichloromethane, Nitrogen was replaced, the temperature was lowered to 5°C, and boron trifluoride diethyl ether (442mmL, 3.52mmol, 1.0eq) was added dropwise, and stirred at this temperature for 2h. TLC (ethyl acetate:petroleum ether=4:6) showed that the reaction was complete. Slowly pour the reaction solution into water to quench, extract 3 times with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, remove the solvent on the rotary evaporation to obtain the crude product, pass through the column layer Purification by analysis (ethyl acetate:petroleum ether=4:6) gave white solid KPC-4000056 (1.1 g, yield 88%).

[0053] KPC-4000056: 1 H NMR (800MHz, CHLOROFORM-d) δ: 5.39 (d, J=2.2Hz, 1H), 4.79 (...

Embodiment 3

[0056] Embodiment 3: Preparation of KPC-4000057

[0057]

[0058] Dissolve dihydroartemisinin (399mg, 1.40mmol, 1.0eq) and KPC-4000056 (500mg, 1.40mmol, 1.0eq) in a 25mL three-necked flask filled with 10mL of dichloromethane, replace nitrogen, and cool down to - Boron trifluoride diethyl ether (178mmL, 1.40mmol, 1.0eq) was added dropwise at 20°C and stirred at this temperature for 2h. TLC (ethyl acetate:petroleum ether=4:6) showed that the reaction was complete. Slowly pour the reaction solution into water to quench, extract 3 times with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, remove the solvent on the rotary evaporation to obtain the crude product, pass through the column layer Purification by analysis (ethyl acetate:petroleum ether=4:6) gave white solid KPC-4000057 (650 mg, yield 76%).

[0059] KPC-4000057: 1H NMR (800MHz, CHLOROFORM-d) δ: 5.38(s, 1H), 5.33(s, 1H), 4.77(d, J=3.4Hz, 1H), 4.41(d, J=...

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PUM

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Abstract

The invention belongs to the field of drug synthesis, particularly discloses an artemisinin derivative as well as a preparation method and an application, and more particularly discloses an artemisinin derivative as well as a preparation method and an application thereof in anti-tumor drugs and anti-HIV drugs. The artemisinin derivative disclosed by the invention has a structure as shown in a formula I, wherein R is a residual radical of other compounds. The preparation method of the artemisinin derivative as shown in the formula I is simple and feasible, good in repeatability and small in environmental pollution, and can be used for massively preparing the compound as shown in the formula I. The compound as shown in the formula I has obvious anti-tumor activity and anti-HIV activity.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to an artemisinin derivative, its synthesis and application. Background technique [0002] Artemisia annua, also known as Artemisia annua L, is an annual herb belonging to the family Asteraceae. Artemisinin is a sesquiterpene lactoid antimalarial drug extracted from the traditional Chinese medicine Artemisia annua by Chinese pharmaceutical workers in the early 1970s. Based on this structure, a series of antimalarial actives have been synthesized and semi-synthesized successively. Derivatives of dihydroartemisinin, artesunate, artemether, artether, etc. [0003] The antimalarial activity of artemisinin and its derivatives has been recognized worldwide, and has the advantages of rapid onset of action, high efficacy, and low toxicity and side effects. In addition to being widely used in antimalarial treatment, artemisinin drugs also have various other pharmacological effects...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/18C07D493/20C07D519/00C07H15/26C07H1/00A61K31/357A61K31/7048A61P31/18A61P35/00A61P35/02
Inventor 李剑峰坝德伟杨兆祥
Owner 贝克诺顿(浙江)制药有限公司
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