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Method for preparing Dolastatin 10 having high anticancer activity

A technology of dolastatin and anti-cancer activity, applied in the direction of peptides, etc., can solve the problems that hinder the research on the structure of dolastatin 10, the synthesis is difficult, and there are not many routes

Active Publication Date: 2018-12-18
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to its remarkable activity, the research on dolastatin 10 has never stopped in the past 30 years. There are only a few reports on the synthesis of Dill and Dap trichiral fragments in Dolastatin 10, and in these reported synthetic routes, due to factors such as route operability, stereochemical control, and synthetic costs, they can be used to develop large-scale preparations There are not many technological routes, which seriously hinder the research on the structure of dolastatin 10. Therefore, it is of great significance to establish a high-efficiency and low-cost synthetic route of dolastatin 10

Method used

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  • Method for preparing Dolastatin 10 having high anticancer activity
  • Method for preparing Dolastatin 10 having high anticancer activity
  • Method for preparing Dolastatin 10 having high anticancer activity

Examples

Experimental program
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Embodiment 1

[0034] Synthesis of compound 3: Dissolve compound 2 (5.00g, 41.61mmol) in 150mL of dichloromethane, add (S)-tert-butylsulfinamide (5.55g, 45.77mmol), anhydrous copper sulfate (13.28g, 83.22mmol) and pyridine p-toluenesulfonate (1.05g, 4.16mmol), stirred at room temperature for 36 hours, concentrated by filtration, and purified by silica gel column to obtain light yellow liquid 3 (7.43g, 80%);

[0035] Synthesis of compound 4: Dissolve 2-bromothiazole (2.42mL, 26.87mmol) in 90mL of toluene, lower to -78 degrees Celsius, slowly add n-butyllithium in hexane (1.6M in hexane, 22.39mmol), stir for 30 Minutes later, compound 3 was dissolved in 10 mL of toluene and added slowly, and reacted at -78 degrees Celsius for three hours, quenched by saturated ammonium chloride solution, extracted with ethyl acetate, dried, concentrated, and purified on a silica gel column to obtain a colorless liquid 4 (3.66g, 53%), 1 H NMR (CDCl 3 ,400MHz):δ7.76(d,J=3.2Hz,1H),7.28-7.19(m,5H),7.13-7.10(m,2H...

Embodiment 2

[0053] Synthesis of compound 18: Dissolve compound 17 (8.00g, 18.41mmol) and 10% palladium carbon (800mg) in 500mL methanol, stir for 5 hours under the action of hydrogen, filter, concentrate and dissolve in 70mL tetrahydrofuran, add chloroformic acid Ethyl ester (2.00g, 18.41mmol), stirred at room temperature for 2 hours and then set aside; Benzyl acetate (8.43mL, 58.91mmol) was dissolved in 70mL tetrahydrofuran, cooled to -78 degrees Celsius, slowly added lithium diisopropylamide ( 27.62mL, 55.23mmol), after stirring for 30 minutes, add the activated ester prepared above, stir at -78 degrees Celsius for 3 hours, add saturated ammonium chloride solution to quench, extract with ethyl acetate, dry, filter, concentrate, and Silica gel column purification gave colorless liquid 18 (1.76 g, 20%).

Embodiment 3

[0055] Synthesis of compound 18: Dissolve compound 17 (8.00g, 18.41mmol) and 10% palladium carbon (800mg) in 500mL of methanol, stir for 5 hours under the action of hydrogen, filter, concentrate and dissolve in 70mL of tetrahydrofuran, add N, N'-carbonyldiimidazole (2.99g, 18.41mmol), stirred at room temperature for 2 hours and then set aside; Benzyl acetate (8.43mL, 58.91mmol) was dissolved in 70mL of tetrahydrofuran, cooled to -78 degrees Celsius, slowly added diisopropyl Lithium amide (27.62mL, 55.23mmol), after stirring for 30 minutes, the activated ester prepared above was added, stirred at -78°C for 3 hours, then quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate, dried, filtered, Concentrate and purify by silica gel column to give colorless liquid 18 (7.02 g, 80%).

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Abstract

The invention belongs to the technical field of chemical synthesis, and relates to a preparation method of Dolastatin 10 having anticancer activity and represented by the following formula. Accordingto the present invention, in the technical route for preparing the dolastatin 10, the used reagents are all commonly used reagents; the method has advantages of simple operation, high yield, low cost,convenient enlargement production and the like; and the experiment results confirm that the cost of the Dolastatin 10 preparation technical route is significantly reduced, the preparation of the 1-10g Dolastatin 10 can be conveniently achieved in the laboratory, and the method is suitable for large-scale preparation. The formula is defined in the specification.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and relates to a preparation method of dolastatin10, a marine natural product with high anticancer activity. Background technique [0002] According to reports, at present, chemical drug therapy is one of the most important means in cancer treatment, but because there are only small differences between cancer cells and healthy cells, this makes the phenomenon of "killing a thousand enemies and harming oneself" appear in chemical drug therapy. 800" serious side effects. Therefore, the research of developing new high-efficiency and low-toxic antitumor drugs is a challenging and significant research field in today's life sciences. [0003] The prior art discloses that an antibody drug conjugate (antibody drug conjugate, ADC) is a drug for targeted therapy, consisting of an antibody, a conjugate bond, and a cytotoxic drug. It combines the efficiency of the cytotoxin with the target of the antibody....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/027
CPCC07K5/0205
Inventor 魏邦国周雯司长梅韩盼周祝孙逊
Owner FUDAN UNIV
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