Norcantharidin carboxylic acid monofluorobenzyl ester and synthesis method and anti-tumor application thereof

A technology of norcantharidin carboxylic acid and norcantharidin is applied in the synthesis of norcantharidin carboxylate monofluorobenzyl ester and its anti-tumor application field, achieving easy operation and implementation, easy availability of raw materials, and enhanced pharmacokinetics effect of potency

Inactive Publication Date: 2020-06-12
ZUNYI MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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 carboxylic acid monofluorobenzyl ester and synthesis method and anti-tumor application thereof
  • Norcantharidin carboxylic acid monofluorobenzyl ester and synthesis method and anti-tumor application thereof
  • Norcantharidin carboxylic acid monofluorobenzyl ester and synthesis method and anti-tumor application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 15

[0033] The preparation of embodiment 1.5-ene norcantharidin 3:

[0034] 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).

[0035] 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

[0036] Embodiment 2. The preparation of norcantharidin 4:

[0037] 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

[0038] Embodiment 3. Preparation of norcantharidin carboxylic acid-2-fluorobenzyl ester (compound 6-1):

[0039]

[0040]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-fluorobenzyl alcohol 5(2.0 mmol, 215μL), reacted at 60℃ 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 34.7%. 1 H NMR (400MHz, DMSO-d 6 )δ12.30(s,1H),7.40(dd,J=8.4Hz,5.6Hz,2H),7.19(t,J=8.8Hz,2H),5.01(d,J=12.4Hz,1H),4.90 (d,J=12.4Hz,1H),4.75-4.65(m,2H),3.04(dd,J=12.0Hz,10.0Hz,2H),1.58-1.48(m,4H). 19 F NMR (376MHz, DMSO-d 6 )δ-118.92—-119.02(m,1F).

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Abstract

The invention provides synthesis and anti-tumor application of norcantharidin carboxylic acid monofluorobenzyl ester with a structural formula shown as I in the specification. The specific structure of the norcantharidin carboxylic acid monofluorobenzyl ester as shown in the formula I is shown in the specification, and activity tests show that the norcantharidin carboxylic acid monofluorobenzyl ester as shown in the formula I, which is designed and synthesized by the invention, is a suitable anti-tumor candidate drug, especially as an anti-liver cancer candidate drug. Compared with a positivecontrol drug norcantharidin, the norcantharidin sodium salt has the advantage that the water solubility, the stability and the anti-tumor activity are improved. In addition, the synthesis method of norcantharidin carboxylic acid monofluorobenzyl 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, in particular to the synthesis of a class of norcantharidin carboxylic acid monofluorobenzyl 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 only stimula...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/08C07D493/18A61P35/00
CPCC07D493/08C07D493/18A61P35/00
Inventor 贺春阳李晓飞贾佳王乐张建永晏容
Owner ZUNYI MEDICAL UNIVERSITY
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