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Bromo-norcantharidin acid-benzyl ester, and synthetic method and application thereof

A technology of norcantharidin and monoacid benzyl ester, which is applied in the direction of drug combination, organic chemistry, antineoplastic drugs, etc., can solve the problems that have not been reported, and achieve the effects of low cost, easy operation and implementation, and easy availability of raw materials

Active Publication Date: 2015-03-25
GUIZHOU BAIQIANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] ZL201410163619.4, ZL201410163711.0, ZL201410163705.5, etc. disclose the method for preparing demethylcantharidin acid salt, and the prior art also discloses a method for synthesizing 5,6-dibromonorcantharidin through bromine addition reaction, However, there is no report on the synthesis of ring-opened 5,6-dibromonorcantharidin monoester

Method used

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  • Bromo-norcantharidin acid-benzyl ester, and synthetic method and application thereof
  • Bromo-norcantharidin acid-benzyl ester, and synthetic method and application thereof
  • Bromo-norcantharidin acid-benzyl ester, and synthetic method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] The preparation of embodiment 1 intermediate A, i.e. 5,6-dihydronorcantharidin: the reaction formula is as follows:

[0025]

[0026] Take out a certain amount of maleic anhydride from the reagent bottle, place it in a dry grinding body and grind it finely, then weigh 12.021g of the finely ground maleic anhydride with an electronic balance, put it in a dry three-necked flask, and plug it Stopper, add diethyl ether and stir, when the amount of diethyl ether is 90mL, the maleic anhydride is completely dissolved. After the maleic anhydride was completely dissolved, 13 mL of furan was slowly added through the dropping funnel for 13 minutes. The temperature was controlled to start the reaction at 38°C. After reacting for 1 h, white solids appeared in the solution, and the longer the time, the more white solids there were. After reacting for 24 hours, it was suction filtered to obtain white solid intermediate A, namely 5,6-dihydronorcantharidin. The dry weight is 17.459...

Embodiment 2

[0028] The preparation of embodiment 2 intermediate B, i.e. 5,6-dibromonorcantharidin: the reaction formula is as follows:

[0029]

[0030] Weigh 5 g of intermediate A obtained in Example 1, place it in a 250 mL two-necked flask, add 20 mL of chloroform and start stirring at room temperature until the reaction solution in the reaction system is stirred into a suspension. At this time, under stirring at room temperature, use a dropping funnel to add dropwise a mixture of 2.5 mL of chloroform and 0.5 mL of liquid bromine. After the addition is complete, rinse the dropping funnel with 2.5 mL of chloroform, and slowly add the rinse , Add the mixed solution and the rinse solution for a total of 20 minutes, and observe the phenomenon. After the reaction was completed, it was suction filtered and washed three times with carbon tetrachloride to obtain white solid intermediate B, namely 5,6-dibromonorcantharidin. The dry weight is 8.330g, and the yield is 85.35%. Melting point: 1...

Embodiment 35

[0031] The preparation of embodiment 35,6-dibromonorcantharidin monoacid benzyl ester: the reaction formula is as follows:

[0032]

[0033] At 0°C, weigh 0.2 g of intermediate B obtained in Example 2, place it in a round bottom flask, add 0.17 mL of triethylamine, 0.13 mL of benzyl alcohol and 4 mL of dichloromethane. After 1 hour of reaction, it was heated to reflux for 5h. Cool and remove the solvent (dichloromethane) under reduced pressure. The residue was subjected to column chromatography to obtain a white solid, namely benzyl 5,6-dibromonorcantharidin monoate. The dry weight was 216mg, and the yield was 81%. Melting point: >240°C. Rf: 0.62 (developing solvent: petroleum ether: ethyl acetate = 10:1). 1 HNMR (DMSO-d6) δ: 3.39 (d, 1H), 3.58 (d, 1H), 4.39-4.44 (m, 2H), 4.69 (s, 1H), 4.79-4.8 (m, 1H), 4.92-4.95 (m, 1H), 5.01-5.05 (m, 1H), 7.29-7.36 (m, 5H), 12.74 (br, 1H).

[0034] The organic base used in the above-mentioned embodiment 3, that is, triethylamine can...

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Abstract

The invention discloses a bromo-norcantharidin acid-benzyl ester shown as a structural formula I. The bromo-norcantharidin acid-benzyl ester is an open-loop 5,6-dibromo-norcantharidin acid benzyl ester, and an active test proves that the bromo-norcantharidin acid-benzyl ester has a good anti-liver-cancer effect and can be used as a high-efficiency and low-toxicity cantharidin anticancer medicine The synthesis process is excellent in selectivity, raw materials are readily available, the cost is low, the synthetic route is simple, operation is easy, a product obtained by the synthesis has low toxicity, high yield and high purity, and the process is high-efficiency, convenient and low in cost.

Description

technical field [0001] The invention relates to bromonorcantharidin monoacid benzyl ester and its synthesis method and application, belonging to the field of cantharidin derivatives. Background technique [0002] Mylabris is a kind of insect body, which is a kind of folk traditional Chinese medicine in my country. A kind of cantharidin (cantharidin, C) extracted in the cantharidin 10 h 12 o 4 ) substances have a very special inhibitory effect on some cancers, and have a special inhibitory effect on ascites liver cancer or primary liver cancer, and have high medicinal value. [0003] Cantharidin can also be modified in structure to synthesize a lot of cantharidin derivatives, which greatly reduces the toxic and side effects and can better inhibit cancer. For example, demethylcantharidin or hydroxycantharidin, etc. have anti-cancer activity similar to cantharidin, and even the activity of cantharidin is lower in comparison. With the development of science and technology t...

Claims

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Application Information

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IPC IPC(8): C07D493/08A61P35/00
CPCC07D493/08
Inventor 张云辉赵长阔张沛李晓飞
Owner GUIZHOU BAIQIANG PHARMA
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