Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Synthesis and anti-tumor application of norcantharidin carboxylic acid difluorobenzyl ester

A technology of methylcantharidin carboxylate difluorobenzyl ester and methylcantharidin carboxylic acid is applied in the synthesis of norcantharidin carboxylate difluorobenzyl ester and its anti-tumor application field, achieving easy operation and implementation and improving water solubility. , the effect of easy availability of raw materials

Active Publication Date: 2020-06-19
ZUNYI MEDICAL UNIVERSITY
View PDF5 Cites 0 Cited by
  • 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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Synthesis and anti-tumor application of norcantharidin carboxylic acid difluorobenzyl ester
  • Synthesis and anti-tumor application of norcantharidin carboxylic acid difluorobenzyl ester
  • Synthesis and anti-tumor application of norcantharidin carboxylic acid difluorobenzyl ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 15

[0035] The preparation of embodiment 1.5-ene norcantharidin 3:

[0036] Take a certain amount of maleic anhydride 1 (26mmol, 2.6g), put it in a round-bottomed flask, add 20mL of ether into the bottle to completely dissolve the maleic anhydride, and after it is completely dissolved, slowly add 2.9mL of furan 2 (39mmol), reacted at room temperature for 24h, suction filtered, and dried to obtain white solid compound 3, namely 5-enenorcantharidin, which weighed 2.1g after drying, and the yield was 48%. 1 H NMR (400Hz, DMSO-d 6 ): δ6.58(s, 2H), 5.35(s, 2H), 3.31(d, J=4.0Hz, 2H).

[0037] The organic solvent used to dissolve maleic anhydride in step 1 of the above-mentioned embodiment 1 can be replaced by any one of dichloromethane, chloroform and tetrahydrofuran in addition to diethyl ether.

Embodiment 2

[0038] Embodiment 2. The preparation of norcantharidin 4:

[0039]At room temperature, take the compound 3 (10mmol, 1.7g) in step (1), and add 10% palladium carbon (0.16g, 15mmol%) into a 100mL three-necked bottle in turn, stopper and vacuumize, pass in hydrogen, and then add acetic acid Ethyl ester 30mL, stirred at room temperature for 24h. Suction filtration after the reaction was completed, the filter cake was rinsed 2-3 times with ethyl acetate, and the obtained filtrate was concentrated under reduced pressure to obtain white solid intermediate 4 (1.6 g), i.e. norcantharidin, with a yield of 97%. 1 H NMR (400Hz, DMSO-d 6 ): 4.86(s,2H), 3.39(s,2H), 1.65(s,4H).

Embodiment 3

[0040] Example 3. Preparation of norcantharidin carboxylic acid-2,3-difluorobenzyl ester (compound 6-1):

[0041]

[0042] Add norcantharidin 4 (1.0mmol, 168mg) and 4-DMAP (1.0mmol, 244mg) to the 25mL sealed tube respectively, after argon replacement three times, then add DCM 2.5mL, 2,3-difluorobenzyl alcohol in sequence 5 (2.0mmol, 225μL), reacted at 60°C for 14h. 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 phase was dried with anhydrous sodium sulfate, flash column chromatography gave the white solid product 6-1. The yield was was 40.5%. 1 H NMR (400MHz, DMSO-d 6 )δ12.29(s,1H),7.46-7.39(m,1H),7.28-7.19(m,2H),5.13(d,J=12.4Hz,1H),4.99(d,J=12.4Hz,1H ), 4.70(d, J=2.0Hz, 2H), 3.05(dd, J=12.4Hz, 9.6Hz, 2H), 1.58-1.50(m, 4H). 19 F NMR (376MHz, DMSO-d 6 )δ-139.14—-139.23(m,1F),-143.60—-143.67(m,1F).

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention provides synthesis and anti-tumor application of norcantharidin carboxylic acid difluorobenzyl ester with a structural formula shown as I in the specification. The specific structure ofthe norcantharidin carboxylic acid difluorobenzyl ester as shown in the formula I is shown in the specification, and activity tests show that the norcantharidin carboxylic acid difluorobenzyl ester asshown in the formula I, which is designed and synthesized by the invention, is a suitable anti-tumor candidate drug, especially as a candidate anti-liver-cancer drug. Compared with positive control drugs norcantharidin and sodium norcantharidate, the water solubility, the stability and the anti-tumor activity are improved. In addition, the synthesis method of norcantharidin carboxylic acid difluorobenzyl ester has the advantages that the raw materials are easy to obtain, and the operation and the implementation are very easy.

Description

technical field [0001] The invention belongs to the field of new drug design and synthesis, and specifically relates to the synthesis of a class of norcantharidin carboxylic acid difluorobenzyl ester and its antitumor application. Background technique [0002] Cantharidin (cantharidin, CA) is an anti-cancer substance extracted from the body of Cantharis, an insect of the family Melanthaceae. It has good curative effects on liver cancer, ovarian cancer, esophageal cancer, etc., and 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, so it has certain limitations in its clinical application. The artificially synthesized cantharidin derivative norcantharidin (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. It can not onl...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07D493/08A61P35/00
CPCC07D493/08A61P35/00
Inventor 贺春阳贾佳朱二林王乐李晓飞刘云
Owner ZUNYI MEDICAL UNIVERSITY
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com