Bromo-norcantharidin mono-methyl ester, as well as synthesizing method and application thereof

A technology of norcantharidin and methyl monoacid, which is applied in drug combination, organic chemistry, antineoplastic drugs, etc., can solve the problems that have not been reported, and achieve the effect of low cost, good selectivity and high yield

Active Publication Date: 2015-04-22
GUIZHOU BAIQIANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

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 mono-methyl ester, as well as synthesizing method and application thereof
  • Bromo-norcantharidin mono-methyl ester, as well as synthesizing method and application thereof
  • Bromo-norcantharidin mono-methyl ester, as well as synthesizing method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] The preparation of embodiment 1 intermediate A, i.e. 5,6-dihydronorcantharidin: the reaction formula is as follows:

[0028]

[0029] 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

[0031] The preparation of embodiment 2 intermediate B, i.e. 5,6-dibromonorcantharidin: the reaction formula is as follows:

[0032]

[0033] 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

[0034] Preparation of embodiment 35,6-dibromonorcantharidin monoacid methyl ester: the reaction formula is as follows:

[0035]

[0036] Weigh 0.5 g of intermediate B obtained in Example 2, place it in a round-bottomed flask, add 5 mL of anhydrous methanol, start stirring while heating to 45 ° C, and continue to slowly add 5 mL of anhydrous methanol during the stirring process. The reaction started to become turbid, and after 5 hours, it was filtered with suction to obtain a white solid, ie methyl 5,6-dibromonorcantharidin monoate. The dry weight was 472 mg, and the yield was 86%. Melting point: >240°C. Rf: 0.62 (developing solvent: petroleum ether: ethyl acetate = 10:1). 1 HNMR (DMSO-d6) δ: 12.61 (br, 1H), 4.76 (d, 2H), 4.68 (s, 2H), 3.51 (s, 3H), 3.12 (s, 2H).

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Abstract

The invention discloses bromo-norcantharidin mono-methyl ester with a structural formula as shown in a formula I in the specification. The bromo-norcantharidin mono-methyl ester is ring-opened 5,6-dibromo-norcantharidin mono-methyl ester. Activity tests prove that the bromo-norcantharidin mono-methyl ester has a good liver cancer resistance, and can be used as an efficient low-toxicity cantharidin anti-tumor medicine. The synthesis process has good selectivity, easily available raw materials, low cost and simple synthesizing route, and is convenient to operate and implement; and the synthesized product has small toxicity, high yield and high purity. Therefore, the process has the characteristics of high efficiency, convenience and low cost.

Description

technical field [0001] The invention relates to bromonorcantharidin monoacid methyl 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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Patent Type & Authority Applications(China)
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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