Asymmetric synthesis method of dihydroartemisinic acid from arteannuinic acid

A technology of dihydroartemisinic acid and synthesis method, which is applied in the direction of ozone oxidation to prepare carboxylic acid, organic chemistry, etc., can solve the problems of destroying the environment and ecological balance, resource depletion, time-consuming and labor-intensive, etc., and achieve good industrial application prospects and cost advantages Obvious, simple synthetic process effect

Active Publication Date: 2016-04-13
SHANGHAI JIAO TONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since the purchase and harvest of Artemisia annua is processed and extracted in the factory, there are many links, which are time-consuming and labor-intensive, and the quality of Artemisia annua varies greatly in

Method used

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  • Asymmetric synthesis method of dihydroartemisinic acid from arteannuinic acid
  • Asymmetric synthesis method of dihydroartemisinic acid from arteannuinic acid
  • Asymmetric synthesis method of dihydroartemisinic acid from arteannuinic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] 1.1 Synthesis of chiral catalysts

[0047] Tris(triphenylphosphine)ruthenium dichloride (3.8 mg, 4 μmol) and chiral ligand L11b (1.76 mg, 2 μmol) were dissolved in methanol (3 mL), heated and stirred at 30° C. for 1 hour. Cool to room temperature, remove the solvent under reduced pressure, and separate by column chromatography (using silica gel column, eluent: ethyl acetate / petroleum ether=1 / 5) to obtain 3.21 mg of a dark green solid with a yield of 92%.

[0048] 1.2 Asymmetric synthesis of dihydroartemisinic acid

[0049]

[0050] Under nitrogen atmosphere, artemisinic acid (0.4mmol), methanol (2.6mL), potassium hydroxide in methanol (0.4mL, 0.05M) and catalyst 0.69mg (TON=1000). The reaction system was placed in an autoclave at 25 °C and H 2 (20atm) and stirred for 6 hours. The solvent was removed under reduced pressure and separated by column chromatography (using silica gel column, eluent: ethyl acetate / petroleum ether = 1 / 1) to obtain 0.091 g of pure product,...

Embodiment 2

[0053] 2.1 Synthesis of chiral catalysts

[0054] Tris(triphenylphosphine)ruthenium dichloride (3.8 mg, 4 μmmol) and chiral ligand L11a (2.3 mg, 2.8 μmmol) were dissolved in ethanol (3 mL), heated and stirred at 70° C. for 3 hours. Cool to room temperature, remove the solvent under reduced pressure, and separate by column chromatography (using a silica gel column, eluent: ethyl acetate / petroleum ether=1 / 5) to obtain 3.31 mg of a dark green solid with a yield of 94.8%.

[0055] 2.2 Asymmetric synthesis of dihydroartemisinic acid

[0056] Under nitrogen atmosphere, artemisinic acid (0.4mmol), ethanol (2.6mL) and ethanol solution of potassium hydroxide (0.4mL, 0.07M) and catalyst 0.63mg (TON=1000) were added. The reaction system was placed in an autoclave at 25 °C and H 2 (20atm) and stirred for 12 hours. The solvent was removed under reduced pressure and separated by column chromatography (using silica gel column, eluent: ethyl acetate / petroleum ether = 1 / 1) to obtain 0.092 g...

Embodiment 3

[0059] 3.1 Synthesis of chiral catalysts

[0060] Tris(triphenylphosphine)ruthenium dichloride (3.8 mg, 4 μmmol) and chiral ligand L2a (1.8 mg, 2.6 μmmol) were dissolved in toluene (3 mL), heated and stirred at 100° C. for 4 hours. Cool to room temperature, remove the solvent under reduced pressure, and separate by column chromatography (using a silica gel column, eluent: ethyl acetate / petroleum ether=1 / 5) to obtain 3.56 mg of a dark green solid with a yield of 96.1%.

[0061] 3.2 Asymmetric synthesis of dihydroartemisinic acid

[0062] Under nitrogen atmosphere, artemisinic acid (0.4mmol), toluene (2.6mL), potassium hydroxide methanol solution (0.4mL, 0.1M) and the above catalyst 0.32mg (TON=2000) were added. The reaction system was placed in an autoclave at 25 °C and H 2 (20atm) and stirred for 12 hours. The solvent was removed under reduced pressure and separated by column chromatography (using silica gel column, eluent: ethyl acetate / petroleum ether = 1 / 1) to obtain 0.0...

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Abstract

The invention discloses an asymmetric synthesis method of dihydroartemisinic acid from arteannuinic acid. The asymmetric synthesis method comprises the following steps: in the presence of a solvent and alkali and under the action of a chiral catalyst, performing asymmetric catalytic hydrogenation on the arteannuinic acid, so that the dihydroartemisinic acid is generated. According to the asymmetric synthesis method, the final conversion rate of arteannuinic acid is up to 100% and the diastereoselectivity is higher than 99.0%. The asymmetric synthesis method is easy to operate, good in selectivity, high in yield and very good in industrial application prospect.

Description

technical field [0001] The invention relates to a method for synthesizing a key intermediate in the field of chemical pharmacy, in particular to an asymmetric synthesis method from artemisinic acid to dihydroartemisinic acid. Background technique [0002] Artemisinin, a sesquiterpene lactone antimalarial drug with peroxy groups extracted from the traditional Chinese medicine Artemisia annua, is the first internationally recognized natural medicine discovered in China. The antimalarial mechanism of artemisinin is different from other antimalarial drugs. Its main function is to interfere with the membrane-mitochondrion function of Plasmodium, rather than interfere with folic acid metabolism, resulting in the complete collapse of parasite structure. In addition, artemisinin can be used as raw material to synthesize a variety of its derivatives, such as dihydroartemisinin, artemether, artesunate and so on. These artemisinin drugs have low toxicity and strong anti-masochistic pr...

Claims

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Application Information

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IPC IPC(8): C07C57/26C07C51/36
Inventor 张万斌申杰峰刘德龙
Owner SHANGHAI JIAO TONG UNIV
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