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Method for synthetizing 1,2,4-trioxane compound and purpose

A synthesis method and compound technology, which are applied in the directions of medical preparations containing active ingredients, organic chemistry, drug combinations, etc., to achieve the effect of convenient synthesis and significant in vitro antimalarial activity

Active Publication Date: 2012-06-13
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] Although there are many methods for synthesizing 1,2,4-trioxane in the literature, the synthesis is simple, does not involve photosensitive oxidation or ozonation, etc., requires special equipment / laboratory, and has such high antimalarial activity and UV There is no precedent for chromophore (it is easy to follow if further in vivo experimental research is required)

Method used

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  • Method for synthetizing 1,2,4-trioxane compound and purpose
  • Method for synthetizing 1,2,4-trioxane compound and purpose
  • Method for synthetizing 1,2,4-trioxane compound and purpose

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Experimental program
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Effect test

Embodiment 1

[0038]

[0039] 4 (103 mg, 0.60 mmol) was dissolved in anhydrous THF Chinese name (2 mL), NaH (60% in mineral oil Chinese name, 77 mg, 1.92 mmol) was added, stirred at room temperature for 1 h, and HMPA Chinese name (0.24 mL, 1.2 mmol), after 10 min, a THF solution of 5 (300 mg, 1.2 mmol dissolved in 1 mL of anhydrous THF) was added dropwise. Stir overnight at room temperature, dilute with ether and add saturated NH 4 Cl solution quenched the reaction. Extract with ether, combine the organic phases, wash with saturated sodium chloride solution and dry over anhydrous sodium sulfate. Filtration, concentration and flash column chromatography (EtOAc / PE Chinese name = 1:50) gave 6 (160 mg, 0.47 mmol) as a colorless oily liquid with a yield of 78%. 1 H NMR (300MHz, CDCl 3 )δ7.51(t, J=7.0Hz, 2H), 7.30(t, J=7.3Hz, 1H), 7.13(t, J=7.7Hz, 1H), 5.70-5.82(m, 1H), 5.27( d, J=6.4Hz, 1H), 5.23(s, 1H), 4.61(d, J=13.1Hz, 1H), 4.43(d, J=13.3Hz, 1H), 3.90-3.95(m, 4H), 3.80 (dd, J = 5.3, 7...

Embodiment 2

[0041]

[0042] 6 (200 mg, 0.58 mmol) was dissolved in acetonitrile (12 mL) and PPh was added sequentially 3 (60mg, 0.23mmol), K 2 CO 3 (480mg, 3.50mmol) and Pd(OAc) 2 (26 mg, 0.12 mmol). Heated to reflux in an oil bath at 80°C for 36h under an argon atmosphere. Diluted with ether and washed with water to remove inorganic matter, the organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. Filtration, concentration and flash column chromatography (EtOAc / PE=1:20) gave 7 (114mg, 0.44mmol) as a pale yellow liquid. Yield 76%. 1 H NMR (300MHz, CDCl 3 )δ7.62-7.65 (m, 1H), 7.20-7.26 (m, 2H), 7.00-7.03 (m, 1H), 5.64 (s, 1H), 5.08 (s, 1H), 4.87 (d, J= 15.2Hz, 1H), 4.75(d, J=15.3Hz, 1H), 4.33(t, J=6.2Hz, 1H), 3.89-3.98(m, 4H), 1.72-2.06(m, 4H), 1.37( s, 3H). 13 C NMR (75MHz, CDCl 3 )δ141.7, 134.3, 131.4, 127.7, 126.9, 124.3, 123.8, 109.90, 107.0, 77.0, 65.7, 64.6, 64.6, 34.8, 26.9, 23.9; FT-IR (film) 2980, 2880, 1635, 1485, 1...

Embodiment 3

[0044]

[0045] 7 (35 mg, 0.13 mmol) was dissolved in CH 2 Cl 2 (2mL), add Na under ice-water bath 2 CO 3 (8.0 mg, 0.07 mmol) and m-chloroperoxybenzoic acid (m-CPBA, 34 mg, 0.15 mmol, containing 75% m-CPBA). After stirring at room temperature for 5 h, add saturated NaHCO 3 solution and ether. The organic phase was saturated with Na 2 SO 3 The solution was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. Filtration, concentration and flash column chromatography (EtOAc / PE=1:10) gave 8 (32 mg, 0.115 mmol) as a colorless viscous liquid with a yield of 89%. 1 H NMR (300MHz, CDCl 3 )δ7.21-7.31(m, 2H), 7.13(t, J=3.8Hz, 1H), 7.03(t, J=3.7Hz, 1H), 4.92(s, 2H), 3.82-4.03(m, 5H ), 3.31(d, J=4.4Hz, 1H), 2.92(d, J=4.7Hz, 1H), 1.94-2.08(m, 1H), 1.55-1.78(m, 2H), 1.39-1.54(m, 1H), 1.34(s, 3H). 13 C NMR (75MHz, CDCl 3 )δ137.5, 133.6, 127.7, 127.1, 123.5, 123.2, 109.8, 68.1, 64.7, 64.6, 55.9, 54.0, 35.1, 23.9, 23.7; FT-IR (film) 2979, 2878,...

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Abstract

The invention relates to a method for synthetizing 1,2,4-trioxane compound and a purpose. Hydrogen peroxide is adopted to serve as a peroxy bond source reagent, and a hydroperoxy radical is connected in a target structure through hydroperoxy electrolysis ring-opening reaction of an epoxide. A product has remarkable external anti-malarial activity and can be used as a lead compound to prepare novel anti-malarial drug.

Description

technical field [0001] The invention relates to a series of 1,2,4-trioxane compounds similar to artemisinin, their synthesis method and application. Using hydrogen peroxide as the peroxygen bond source reagent, the hydrogen peroxide group is connected to the precursor of artemisinin through the hydrogen peroxide ring-opening reaction of epoxide, and then the 1,2,4-trioxane with antimalarial activity is synthesized class of compounds. Background technique [0002] Artemisinin (also containing 1,2,4-trioxane partial structure) is an antimalarial natural product discovered by Chinese scientists in the 1970s. Because the mechanism of action of this compound is completely different from that of traditional antimalarial drugs, and it has a very good curative effect on drug-resistant cases, it has received great attention from the scientific community since it came out. At present, compound drugs with artemisinin and its derivatives as the core components are currently the first-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/20A61K31/366A61K31/357A61P33/06
Inventor 伍贻康郝宏东李云
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI