Preparation method for total synthesis of 4'-demethylepipodophyllotoxin

A demethylated epipodophyllin and total synthesis technology, applied in the direction of asymmetric synthesis, organic chemical methods, chemical instruments and methods, etc., can solve the problems of complex reaction operations and difficult purification of crude products, and achieve environmental friendliness and save steps And the effect of low processing and production costs

Active Publication Date: 2020-05-12
SHANGHAI JINHE BIO TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Even so, there are still many problems in the industrial synthesis of podophyllotoxin so far, such as complex reaction operations, the use of many sensitive reagents, and the difficulty in purification of crude products. Therefore, it is of great significance to develop a simple and efficient synthetic route

Method used

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  • Preparation method for total synthesis of 4'-demethylepipodophyllotoxin
  • Preparation method for total synthesis of 4'-demethylepipodophyllotoxin
  • Preparation method for total synthesis of 4'-demethylepipodophyllotoxin

Examples

Experimental program
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Effect test

Embodiment 1

[0042] Synthesis of compound 2:

[0043] Dissolve 18.1 g of compound 1 syringaldehyde in a three-necked reaction flask filled with 180 mL of tetrahydrofuran, control the temperature at 25-30° C., and stir. Add 19.5g of benzyl chloroformate into the reaction flask in the previous step, stir and drop 115mL of 1N sodium hydroxide solution, the dropping time is controlled at 1.5-2 hours, the temperature is controlled at 25-30°C, after the dropping is completed, stir for 30 minute. After the reaction was completed, the liquids were separated, the organic phase was washed with salt water until neutral, the organic phase was concentrated to dryness, and dried under vacuum at 45° C. by adding phosphorus pentoxide for 8 hours to obtain the product compound 2: 30.9 g, Y=98%.

[0044] Synthesis of compound 4:

[0045] Add 12.1g of compound 3 into a three-necked reaction flask containing 210mL of tetrahydrofuran, under nitrogen protection, freeze the reaction solution to -20~-15°C, slow...

Embodiment 2

[0057] figure 1 HNMR and its analysis of the product prepared for the present invention.

[0058] figure 2 Obtain high performance liquid phase chromatograms for the product prepared by the present invention.

[0059] Adopt conventional high performance liquid phase to detect the product prepared by the present invention, such as figure 2 shown.

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Abstract

The invention discloses a preparation method for total synthesis of 4'-demethylepipodophyllotoxin (also named as epipodophyllotoxin). The preparation method comprises the following steps: (1) syringaldehyde (compound 1) used as an initial material and benzyl methoxyacyl used as a protective group are in favor of a chemical reaction of finally removing the protective group to obtain a target compound; (2) a chiral target object is produced by adopting an asymmetric hydrogenation reduction reaction in which a chiral ligand (s-BINAN Ru (II)) participates; and (3) a reaction of hydrogenating and deprotecting groups is also carried out in parallel while chiral catalytic hydrogenation is carried out. The reaction steps and treatment are saved, the route selection is targeted to the target compound, the production cost is low, and the environment is friendly.

Description

technical field [0001] The present invention relates to a process method of anti-tumor drug mother nucleus, relates to a preparation method of epipodophyllotoxin, in particular to a preparation method of total synthesis of 4'-desmethyl epipodophyllotoxin. Background technique [0002] Since the beginning of the 1950s, a lot of work has been done on the structural transformation of podophylloid compounds at home and abroad. Etoposide (Etoposide), Teniposide (Teniposide) and Etopophos (Etopophos) ( Structural formula 1) has been clinically used for the treatment of diseases such as gastric cancer, lung cancer, breast cancer, bladder cancer, testicular cancer and ovarian cancer. The core of these three antineoplastic drugs is 4'-epipodophyllotoxin (4'-Demethylepipodophyllotoxin, also known as: epipodophyllotoxin) (structural formula 2), the main method of obtaining epipodophyllotoxin at present is from podophyllotoxin The natural podophyllotoxin (structural formula 3) is extra...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/04C07B53/00
CPCC07D493/04C07B53/00C07B2200/07Y02P20/55
Inventor 张伟中王权勇袁道博石迪升庄凤凤
Owner SHANGHAI JINHE BIO TECH
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