Preparation method for doxorubicin13-position hydrazone derivative

A technology for doxorubicin and derivatives, which is applied in the field of preparation of doxorubicin derivatives, can solve the problems of large solvent consumption, difficult removal, and large solvent consumption, so as to simplify the post-processing procedure, reduce the amount of reaction solvent, and reduce the The effect of production costs

Inactive Publication Date: 2012-09-19
SITAOLI TECH DEV TIANJIN +1
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Problems solved by technology

[0006] The yield of this synthetic method is relatively low (especially the step that obtains maleimido caproic acid 2), and the total yield is no more than 20%, and the solvent consumption is very large, and on average every gram of doxorubicin hydrazone product consumes about The reaction solvent is 70 mL of acetic acid, 300 mL of tetrahydrofuran, and 40 mL of trifluoroacetic acid, and since tert-butyl 2-(6-maleimidocaproyl)carbazate needs to be purified by column chromatography, a large amount of solvent will be consumed
This results in complex post-processing processes and cumbersome operations.
And because the synthesis of final product doxorubicin hydrazone has used trifluoroacetic acid, there will inevitably be trifluoroacetic acid impurities in the product, which is not easy to remove.
Based on the shortcomings of such routes, such as high cost, low yield and production efficiency, and complex operation of the process route, it is obviously not suitable for large-scale production. It is necessary to improve the process or explore other synthetic methods

Method used

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  • Preparation method for doxorubicin13-position hydrazone derivative
  • Preparation method for doxorubicin13-position hydrazone derivative
  • Preparation method for doxorubicin13-position hydrazone derivative

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Experimental program
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Embodiment

[0042] Reagents and Instruments

[0043] Tert-butyl carbazate was purchased from Zhangjiagang Bomai Chemical Co., Ltd.

[0044] Adriamycin hydrochloride was purchased from Beijing Huafeng Lianbo Technology Co., Ltd.

[0045] Butenedioyl chloride, dry chloroform, anhydrous potassium carbonate, 6-aminocaproic acid, thionyl chloride, triethylamine, anhydrous ether, trichloroacetic acid, acetonitrile and other reagents were purchased from Shanghai Sinopharm Group.

[0046] 1 The H NMR nuclear magnetic resonance data was obtained by using a Mercury-300BB nuclear magnetic resonance instrument (Varian company) with deuterated methanol (CD 3 OD) was obtained as solvent.

[0047] Synthesis of 6-maleimidocaproylhydrazone from doxorubicin

[0048]

[0049] Dissolve 15.2 g (0.1 mol) of butenedioyl chloride in 25 mL of dry chloroform, add 27.6 g (0.2 mol) of anhydrous potassium carbonate, and add 13.2 g (0.1 mol) in chloroform (50 mL), reacted at room temperature for 3 hours after ...

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Abstract

The invention relates to a preparation method for a doxorubicin derivative, in particular to the preparation method for a doxorubicin13-position hydrazone derivative through fumaryl chloride and amino-alkyl-carboxylic acid.

Description

technical field [0001] The present invention relates to a method for preparing doxorubicin derivatives. Specifically, the present invention relates to a method for preparing doxorubicin 13-position hydrazone derivatives by means of butenedioyl chloride and aminoalkylcarboxylic acid. Background technique [0002] The anticancer drug doxorubicin is widely used due to its strong side effects. Studies have shown that derivatizing the 13-position acylhydrazone of doxorubicin can reduce its side effects. [0003] According to literature reports, (see, for example, David Willner et al., "(6-Maleimidocaproyl)hydrazone of Doxorubicin-A New Derivative for the Preparation of Immunoconjugates of Doxorubicin," Bioconjugate Chem.1993, 4, 521-527; J.K. Tota Hill et al. People, "the method for preparing thioether conjugates," CN1109886A, etc.), the synthetic method and main process of adriamycin 13-position hydrazone derivatives are as follows: [0004] [0005] First, maleic anhydride...

Claims

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Application Information

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IPC IPC(8): C07H15/252C07H1/00
Inventor 韩绪儒李子意李凌燕覃玲莉张广良徐峰
Owner SITAOLI TECH DEV TIANJIN
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