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Norcantharidin carboxylate trifluorobenzyl ester and its synthesis method and application

A technology of cantharidin carboxylic acid and trifluorobenzyl ester, which is applied in the field of medicine to achieve the effects of improving water solubility, readily available raw materials, and easy operation and implementation

Active Publication Date: 2022-08-09
ZUNYI MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, there are few studies on the introduction of fluorine-containing groups into cantharidin. At the same time, in order to find anti-tumor drug candidates with better efficacy and less toxicity, and to expand the types of cantharidin anti-tumor drugs, we designed a fluorine-containing group The fluorine-containing derivatives of norcantharidin were synthesized, which laid the foundation for the subsequent screening of anticancer activity

Method used

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  • Norcantharidin carboxylate trifluorobenzyl ester and its synthesis method and application
  • Norcantharidin carboxylate trifluorobenzyl ester and its synthesis method and application
  • Norcantharidin carboxylate trifluorobenzyl ester and its synthesis method and application

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Preparation of 5-enenorcantharidin 3:

[0040] Take 2.6 g of maleic anhydride 1 (26 mmol), put it in a round-bottomed flask, add 20 mL of diethyl ether to the flask to completely dissolve the maleic anhydride, and after it is completely dissolved, slowly add furan 22.9 mL (39 mmol) dropwise, The reaction was carried out at room temperature for 24 h, filtered with suction, and dried to obtain a white solid compound 3, namely 5-enenorcantharidin, which was dried and weighed to 2.1 g, and the yield was 48%. 1 HNMR(400Hz, DMSO-d 6 ): δ6.58(s, 2H), 5.35(s, 2H), 3.31(d, J=4.0Hz, 2H).

[0041] In addition to diethyl ether, the organic solvent used for dissolving maleic anhydride in step 1 of the above embodiment 1 can also be replaced by any one of dichloromethane, chloroform and tetrahydrofuran.

Embodiment 2

[0043] Preparation of Norcantharidin 4:

[0044]At room temperature, the white solid compound 3 (10mmol, 1.7g) obtained in step 1 was taken, and 10% palladium carbon (0.16g, 15mmol%) was successively added to a 100mL three-necked flask, plugged and evacuated, passed into hydrogen, and then added with acetic acid Ethyl ester 30mL, stirred at room temperature for 24h. After the reaction is completed, suction filtration, the filter cake is washed with ethyl acetate for 2-3 times, and the obtained filtrate is concentrated under reduced pressure to obtain white solid intermediate 4 (1.6 g), namely norcantharidin, with a yield of 97%. 1 HNMR(400Hz, DMSO-d 6 ): 4.86(s, 2H), 3.39(s, 2H), 1.65(s, 4H).

Embodiment 3

[0046] Preparation of norcantharidin carboxylate-2,3,4-trifluorobenzyl ester (compound 6-1):

[0047]

[0048] Norcantharidin 4 (1.0 mmol, 168 mg) and 4-DMAP (1.0 mmol, 244 mg) were added to a 25 mL sealed tube, and after three times of argon replacement, 2.5 mL of DCM, 2,3,4-trifluorocarbon were added successively. Benzyl alcohol 5 (2.0 mmol, 232 μL) was reacted at 60 °C for 14 h. After the reaction was completed, it was cooled to room temperature, washed three times with HCl (1mol / L) and saturated brine respectively, and the organic phases were combined. After the organic phases were dried with anhydrous sodium sulfate, the white solid product 6-1 was obtained by flash column chromatography. The yield was was 33.5%. 1 H NMR (400MHz, DMSO-d 6 )δ12.26(s,1H),7.37-7.27(m,2H),5.09(d,J=12.8Hz,1H),4.97(d,J=12.8Hz,1H),4.69(d,J=2.4 Hz,2H),3.04(s,2H),1.60-1.50(m,4H). 19 F NMR (376MHz, DMSO-d 6 )δ-139.35,-143.11(d,J=15.0Hz,1F),-166.16(t,J=18.8Hz,1F).

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Abstract

Norcantharidin carboxylate trifluorobenzyl ester, whose structural formula is shown in formula I The specific structure of norcantharidin carboxylate trifluorobenzyl ester shown in formula I includes: Activity test shows that the synthesis of the present invention is shown in I The norcantharidin carboxylate trifluorobenzyl ester is a suitable antitumor drug candidate, especially as an anticancer drug candidate. Compared with the positive control drugs norcantharidin and norcantharidin sodium, the water solubility, stability and antitumor activity are improved. In addition, the method for synthesizing trifluorobenzyl norcantharidin carboxylate of the present invention has easily available raw materials and is very easy to operate and implement.

Description

technical field [0001] The invention belongs to the technical field of medicine, and particularly relates to a class of norcantharidin carboxylate trifluorobenzyl ester and a synthesis method and application thereof. Background technique [0002] Cantharidin (CA) is an anti-cancer substance extracted from Cantharidaceae, an insect of the family Corianaceae. It has good curative effect on liver cancer, ovarian cancer, esophageal cancer, etc., especially it has a special inhibitory effect on primary liver cancer. However, due to the severe toxicity of cantharidin, it can seriously stimulate the human urinary system and digestive system, and it has certain limitations in its clinical application. The synthetic cantharidin derivative norcantharidin (NCTD) has the same configuration as cantharidin, but the 2 and 3 methyl groups are replaced by hydrogen, and the toxic and side effects are significantly reduced. However, due to the short residence time of norcantharidin in the hum...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/08C07D493/18A61P35/00
CPCC07D493/08C07D493/18A61P35/00
Inventor 贾佳贺春阳朱二林王乐李晓飞张建永
Owner ZUNYI MEDICAL UNIVERSITY
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