Synthetic method of 8-epi-puupehedione

A synthesis method and technology for skeleton compounds, which are applied in the field of synthesis of marine natural product 8-epi-puupehedione, can solve the problems of low yield, high cost, increased cost and the like, and achieve good product selectivity, high total yield, high reaction The effect of fewer steps

Active Publication Date: 2017-10-20
威海创惠环保科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In 1999, Barrero et al. reported an acid-catalyzed ring-closing method for phenolic hydroxyl groups to attack alkenes, and obtained a mixture with different orientations of the 8-position methyl groups, resulting in low yields (A. F. Barrero, E. J. Alvarez-Manzaneda, R. Chahboun , M. Cortés and V. Armstrong, Tetrahedron, 1999, 55, 15181.)
In 2003, Armstrong et al. used natural (-)-drimenol as a starting material and used a similar acid-catalyzed cyclization method to obtain a mixture with different methyl orientations. Not only the yield was low, but the starting material was expensive. greatly contributes to the production costs of this method (Armstrong, A. F.Barrero, E. J. Alvarez-Manzaneda, M. Corte´s, and B. Sepulveda, J. Nat.Prod., 2003, 66, 1382.)
Yamamoto et al. reported in 2004 that the compound 8-epi-puupehedione was synthesized by Brönsett acid-promoted polyene tandem cyclization method. It greatly increases the cost and is not conducive to industrial production (H. Ishibashi, K. Ishihara and H. Yamamoto, J. Am. Chem. Soc., 2004, 126, 11122.)
The above methods all have unfavorable factors such as high cost or extremely low yield, and are not suitable for industrial production.

Method used

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  • Synthetic method of 8-epi-puupehedione

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1: Synthesis of Perilla Hydrazone (2, see accompanying drawing)

[0024] Dissolve 2.38 g (1, 10.0 mmol) of sclarealdehyde in 30 ml of anhydrous methanol, add 1.86 g (10.0 mmol) of p-toluenesulfonyl hydrazide, stir and react at room temperature for 3 hours, and TLC detects that the reaction is complete. After concentration, 3.98 g of white solid (+) clarylasulfonylhydrazone was obtained, with a yield of 98%.

Embodiment 2

[0025] Embodiment 2: the synthesis of skeleton compound (4, see accompanying drawing)

[0026] Dissolve 2.03 g (2, 5.0 mmol) of clarylar sulfonylhydrazone in 25 ml of anhydrous tetrahydrofuran, add 144 mg (0.125 mmol) of tetrakistriphenylphosphine palladium, and 2.07 g (15 mmol) of potassium carbonate to repeatedly fill and exhaust argon Exhale three times to exhaust the air. Another 1.47 g (3.5 mmol) of iodo-1,2,4-trimethoxybenzene was dissolved in 5 ml of anhydrous tetrahydrofuran, slowly added dropwise to the above reaction system, heated to 110 oC, and stirred for 10 hours. TLC detects that the reaction is complete. Add 50 ml of water to the reaction system, extract with ethyl acetate (30 mL x 3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography to obtain 1.64 g of white solid, The yield was 85%.

Embodiment 3

[0027] Embodiment 3: the synthesis of reductive isomerization intermediate (5, see accompanying drawing)

[0028] Dissolve 622 mg (4, 1.6 mmol) of the skeleton compound in 15 mL of dry dichloromethane, add 0.38 mL (3.2 mmol) of triethylsilane and stir for 5 minutes at 0 °C, then add dropwise 0.12 mL (1.6 mmol) of trifluoroacetic acid ) continued to react for 3 hours, and TLC detected that the reaction was complete. Add 20 ml of water, extract with ethyl acetate (20 mL x 3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography to obtain 542 mg of light yellow liquid with a yield of 91%.

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Abstract

The invention relates to a synthetic method of a sea natural product 8-epi-puupehedione, which belongs to the field of chemical synthesis. According to the invention, salvia sclarea aldehyde and 1-iodine-2,4,5-trialkoxy benzene are used as starting materials, salvia sclarea aldehyde and p-toluenesulfonhydrazide generate salvia sclarea hydrazone 2, the salvia sclarea hydrazone 2 and 1-iodine-2,4,5-trialkoxy benzene form a framework compound 4 of puupehedione under the catalysis of palladium in a coupling manner, the framework compound 4 is subjected to one-step hydroxyl reduction and double-bond isomerization under the action of a reducing agent to obtain an intermediate 5, the intermediate 5 is oxidized into an intermediate quinone compound 6 under the action of an oxidizing agent, and isomerization and Diels-Alder ring closure are realized for the quinone compound 6 under alkaline condition, then an intermediate 7 is obtained, and the intermediate 7 is further oxidized to obtain the final product 8-epi-puupehedione. The method has the characteristics of less reaction step, simple operation, and good products selectivity, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a synthesis method of marine natural product 8-epi-puupehedione. Background technique [0002] The compound 8-epi-puupehedione is the epimer with the opposite orientation of the methyl group at the 8-position of the marine natural product puupehedione, and it is a derivative of the active marine natural product puupehedione. In 2004, Quesada et al. reported that the compound 8-epi-puupehedione is a very active angiogenesis inhibitor. (M. E. Castro, M.González-Iriarte, A. F. Barrero, N. Salvador-Tormo, R. Muñoz-Chápuli , M. Á. Medina and A. R. Quesada, Int. J. Cancer, 2004, 110, 31.). [0003] There are few reports on the synthetic methods of 8-epi-puupehedione, and the yields are low. In 1999, Barrero et al. reported an acid-catalyzed ring-closing method for phenolic hydroxyl groups to attack alkenes, and obtained a mixture with different orientations of the 8-position methyl groups, resulting in low yields (A. F. Barrero, E....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/78
CPCC07D311/78
Inventor 吴彦超王洪双李惠静
Owner 威海创惠环保科技有限公司
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