CN104447782B - Bromo norcantharidin mono-acid benzyl ester and synthetic method thereof and application - Google Patents
Bromo norcantharidin mono-acid benzyl ester and synthetic method thereof and application Download PDFInfo
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- CN104447782B CN104447782B CN201410842554.6A CN201410842554A CN104447782B CN 104447782 B CN104447782 B CN 104447782B CN 201410842554 A CN201410842554 A CN 201410842554A CN 104447782 B CN104447782 B CN 104447782B
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- norcantharidin
- acid benzyl
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/08—Bridged systems
Abstract
The invention discloses a kind of bromo norcantharidin mono-acid benzyl ester, structural formula is Formulas I.A kind of bromo norcantharidin mono-acid benzyl ester that the present invention provides, is the 5 of open loop, and through active testing, 6 dibromo norcantharidin mono-acid benzyl esters prove that it has good anti-liver cancer efficacy, can be as the cantharidin antitumor drug of a kind of high-efficiency low-toxicity.The synthesis technique selectivity of the present invention is good, and raw material is easy to get, with low cost, and synthetic route is simple, it is simple to operation is implemented, and it is little to synthesize products therefrom toxicity, and yield is high, and product purity is high, thus this technique has efficient, convenient, the feature of low cost.
Description
Technical field
The present invention relates to bromo norcantharidin mono-acid benzyl ester and synthetic method thereof and application, belong to cantharidin derivative neck
Territory.
Background technology
Mylabris is a kind of insect bodies, is the Chinese medicine of a kind of folk tradition of China.The one extracted in Mylabris body is called
Cantharidin (cantharidin, C10H12O4) material certain cancers is had very particularly inhibitory action, for Example Ascites hepatoma or
Person is that primary hepatocarcinoma has special inhibitory action, has the highest medical value.
Cantharidin may also pass through the modification of structure, thus synthesis obtains a lot of cantharidin derivatives so that it is poison is secondary to be made
With being substantially reduced, and can also preferably suppress cancer.Such as cantharidin or hydroxyl Mylabris Asia peace etc. have and
The activity resisting the activity of cancer, even cantharidin as cantharidin is the lowest.Today of development in science and technology, Mylabris
Element is extensively recognized application, and the derivant of the cantharidin after optimization not only maintains the active anticancer of cantharidin but also makes its poison
Property be substantially reduced, start to be paid attention to by scientific circles and study, and one of become important cancer therapy drug further.
Because the toxicity of cantharidin is bigger, clinical treatment can there be is certain side effect.Therefore current many science
Research all uses the method synthesis norcantharidin of 1,2 methyl of removal.Again because nor-speckle huge legendary turtle element is that anticancer effect is preferable
Chinese medicine, therefore may be used for injection in hepatocarcinoma.And norcantharidin is one of medicine of China's relatively early the most just synthesis.
Li Taihua (Li Taihua, the synthesis of two kinds of cantharidin derivatives,125I labelling and animal distribution in vivo thereof, with
Position element, 1998,11 (2), 95-99) for the first time by bromine addition method, bromine atoms introduced norcantharidin and carry out being acylated and spread out
Raw.Gained derivant, with external test tube method, detects above-mentioned multiple derivant to oral squamous carcinoma cell with mtt assay screening model
(KB), colorectal cell (HCT), the suppression ratio of hepatoma carcinoma cell (Bel) three kinds of cancerous cell and IC50 value, found that this chemical combination
Thing all has certain inhibitory action to cancerous cell, all has higher concentration in the heart, liver, lung, kidney and the spleen of white mice simultaneously.
Have been used to (such as sodium cantharidinate, sodium norcantharidate etc.) in the cantharidin medicine of clinical treatment at present, all to open
The mode of ring exists, and chemically sees in structure, and its corresponding dissolubility of the compound of open loop is relatively big, and its vivo biodistribution availability is also
High.Therefore modifying the structure of cantharidin, find the cantharidin antitumor drug of high-efficiency low-toxicity, having important industry should
With being worth and market prospect widely.
ZL201410163619.4, ZL201410163711.0, ZL201410163705.5 etc. disclose and prepare demethyl
The method of cantharidin hydrochlorate, prior art also disclose by bromine additive reaction synthesize 5, the method for 6-dibromo norcantharidin,
But not yet have been reported that the 5,6-dibromo demethylcantharidin monoesters of synthesis open loop.
Summary of the invention
For solving the deficiencies in the prior art, it is an object of the invention to provide a kind of bromo norcantharidin mono-acid benzyl ester and
Its synthetic method and application, obtained bromo norcantharidin mono-acid benzyl ester has good anti-liver cancer efficacy.
In order to realize above-mentioned target, the present invention adopts the following technical scheme that:
Bromo norcantharidin mono-acid benzyl ester, i.e. 5,6-dibromo norcantharidin mono-acid benzyl ester, structural formula is Formulas I:
The synthetic method of bromo norcantharidin mono-acid benzyl ester, is carried out according to following synthetic route: with furan as raw material, with
Maleic anhydride reacts in organic solvent and obtains 5, and 6-dihydro norcantharidin, 5,6-dihydro norcantharidin are at three chloromethanes
Reacting with bromine in alkane and obtain 5,6-dibromo norcantharidin, 5,6-dibromo norcantharidin and benzyl alcohol are at organic base and organic
In solvent, reaction obtains 5,6-dibromo norcantharidin mono-acid benzyl ester I,
Aforementioned synthetic methods, specifically includes following steps:
(1) take maleic anhydride, finely ground, add organic solvent and dissolve, drip furan until completely dissolved, in 35 DEG C～
45 DEG C of reaction 24h, sucking filtration, obtain white solid product 5,6-dihydro norcantharidin, drying for standby；
(2) under room temperature, take the white solid product in step (1), add chloroform and stir into suspension, stir with back
Mixing limit and instill the mixed liquor of chloroform and bromine, be slow added into chloroform rinse liquid, stirring reaction, reaction is taken out after terminating
Filter, washs with carbon tetrachloride, obtains white solid 5,6-dibromo norcantharidin, drying for standby；
(3) at 0 DEG C, 5 are taken, 6-dibromo norcantharidin, add benzyl alcohol, organic base and organic solvent, after reaction 1h,
It is heated to reflux 5h, cooling, removal of solvent under reduced pressure, obtain white solid 5,6-dibromo norcantharidin mono-acid benzyl ester through column chromatography.
In aforementioned synthetic methods, described organic solvent is DMF, dimethyl sulfoxide, dichloromethane, chlorine
Imitative, acetonitrile, oxolane or ether.
In aforementioned synthetic methods, described organic base is triethylamine or pyridine.
The application in preparing medicines resistant to liver cancer of the bromo norcantharidin mono-acid benzyl ester.
The invention have benefit that: a kind of bromo norcantharidin mono-acid benzyl ester that the present invention provides, i.e. open loop
Through active testing, 5,6-dibromo norcantharidin mono-acid benzyl esters, prove that it has good anti-liver cancer efficacy, can be as a kind of high
The cantharidin antitumor drug of effect low toxicity.The synthesis technique selectivity of the present invention is good, and raw material is easy to get, with low cost, synthetic route
Simply, it is simple to operation is implemented, and it is little to synthesize products therefrom toxicity, yield is high, and product purity is high, thus this technique has height
Effect, convenient, the feature of low cost.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is further introduced.
In the present invention, the furan of use, maleic anhydride, bromine are all from Shanghai traditional Chinese medicines group.Solvent for use is from abiding by
Yi Shuanju Chemical Co., Ltd..Unless otherwise indicated, agents useful for same is chemical pure.
Embodiment 1 intermediate A, the i.e. preparation of 5,6-dihydro norcantharidin: reaction equation is as follows:
From reagent bottle, take out a certain amount of maleic anhydride, be placed in dry grinding body finely ground, then use electronic balance
Weigh finely ground maleic anhydride 12.021g, be placed in dry there-necked flask, cap, then the stirring that adds diethyl ether, in second
When ether amount is 90mL, maleic anhydride is completely dissolved.After maleic anhydride is completely dissolved, it is slowly added to Dropping funnel
13mL furan, used time 13min.Control temperature and start reaction at 38 DEG C.After reaction 1h, there is white solid in solution, and the time is the longest
White solid is the most.React sucking filtration to 24h, obtain white solid intermediate A, i.e. 5,6-dihydro norcantharidin.It is dried and weighs
For 17.459g, yield 85.75%.Fusing point: 122～123 DEG C, Rf:0.52 (developing solvent: petroleum ether: ethyl acetate=3: 1)；1HNMR(CDCl3) δ: 3.18 (s, 2H), 5.47 (s, 2H), 6.58 (s, 2H).
For dissolving the organic solvent of maleic anhydride in addition to ether in above-described embodiment 1, can also be used with N, N-diformazan
Any one in base Methanamide, dimethyl sulfoxide, dichloromethane, chloroform, acetonitrile, oxolane replaces；Described reaction temperature can
Between 35 DEG C～45 DEG C.
Embodiment 2 intermediate B, the i.e. preparation of 5,6-dibromo norcantharidin: reaction equation is as follows:
Weigh intermediate A 5g obtained in embodiment 1, be placed in two mouthfuls of flasks of 250mL, add 20mL chloroform
At room temperature start stirring, until reaction solution stirs into suspension in reaction system.The most under stirring at room temperature, leak with dropping liquid
Bucket dropping 2.5mL chloroform and the mixed liquor of 0.5mL bromine, use 2.5mL chloroform rinse Dropping funnel after dropping,
And rinse liquid is slowly added to, add mixed liquor and amount to used time 20min with rinse liquid, observe phenomenon.After question response terminates, take out
Filter, washs three times with carbon tetrachloride, obtains white solid intermediate B, i.e. 5,6-dibromo norcantharidin.It is dried and is weighed as
8.330g, yield 85.35%.Fusing point: 157～159 DEG C, Rf:0.65 (developing solvent: petroleum ether: ethyl acetate=2: 1).1HNMR
(DMSO-d6) δ: 5.18 (d, 1H), 4.49-4.54 (m, 2H), 3.86 (s, 2H).
The preparation of embodiment 35,6-dibromo norcantharidin mono-acid benzyl ester: reaction equation is as follows:
At 0 DEG C, weigh intermediate B 0.2g of gained in embodiment 2, be placed in round-bottomed flask, add 0.17mL tri-second
Amine, 0.13mL benzylalcohol and 4mL dichloromethane.After reacting 1 hour, it is heated to reflux 5h.Cooling, removal of solvent under reduced pressure (dichloromethane
Alkane).Residue obtains white solid through column chromatography, is 5,6-dibromo norcantharidin mono-acid benzyl ester.It is dried and is weighed as
216mg, yield 81%.Fusing point: > 240 DEG C.Rf:0.62 (developing solvent: petroleum ether: ethyl acetate=10: 1).1HNMR(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).
Organic base, i.e. triethylamine used in above-described embodiment 3 can replace with pyridine；Organic solvent dichloromethane used
Any one in available N,N-dimethylformamide, dimethyl sulfoxide, chloroform, acetonitrile, oxolane, ether replaces.
The resisting liver cancer activity test of experimental example 15,6-dibromo norcantharidin mono-acid benzyl ester
Sulforhodamine (sulforhodamine B, SRB) staining
During inoculating cell, two piece of 96 orifice plate of every kind of parallel inoculation of cell, one piece is control board (T0), and another block is experiment
Plate.CO2After incubator cultivates 20h, control board (T0) is taken out, fix with 50% trichloroacetic acid (TCA), to be measured.Brassboard
(final concentration is respectively 5 μ g mL to middle addition testing compound-1、2.5μg·mL-1、1.25μg·mL-1、0.625μg·mL-1、
0.313μg·mL-1), and set negative control group (C), and experimental group (T), solvent control group.Often group sets 5 multiple holes, continues to cultivate
Take out culture plate after 48h, fix (final concentration of 10%) with pre-cooling 50%TCA, after 1h placed by 4 DEG C of refrigerators, with deionized water
Rinse, naturally dry, dye with the SRB of 100 μ L 0.4%, rinse with 0.1% acetic acid, dry, finally with 200 μ L after 10min
10mmol·L-1Buffering Tris alkali liquor (pH=10.5) dissolve, in microplate reader select 530nm place survey absorbance (OD value),
Calculate growth inhibition ratio (Inhibition ratio, IR) according to the following formula.
This test is according to SRB method, with Cantharidin, sodium cantharidinate as positive control, has carried out 5,6-dibromo demethylcantharidin
The inhibitory activity of human liver cancer cell Hep G2 is tested by element mono-acid benzyl ester, and result is as shown in table 1:
Table 1
| Sample | C (test concentrations) | Suppression ratio (Inhibitionratio) | IC50 |
| Cantharidin | 12.92μmol/L | 70% | 8.52μmol/L |
| Sodium Cantharidinate | 12.92μmol/L | 65% | 9.41μmol/L |
| Compound I | 12.92μmol/L | 95% | 5.53μmol/L |
As shown in Table 1,5,6-dibromo norcantharidin mono-acid benzyl esters have certain suppression to human liver cancer cell Hep G2
Effect, can use it for preparing the medicine of anti-liver cancer and anti-.
Claims (5)
1. bromo norcantharidin mono-acid benzyl ester, i.e. 5,6-dibromo norcantharidin mono-acid benzyl ester, it is characterised in that: structural formula is
Formulas I:
2. the synthetic method of the bromo norcantharidin mono-acid benzyl ester described in a claim 1, it is characterised in that: according to as follows
Synthetic route is carried out: with furan as raw material, reacts in organic solvent with maleic anhydride and obtains 5,6-dihydro demethylcantharidin
Element, 5,6-dihydro norcantharidin react with bromine in chloroform and obtain 5, and 6-dibromo norcantharidin, 5,6-dibromos go
Norcantharidin and benzyl alcohol react in organic base and organic solvent and obtain 5,6-dibromo norcantharidin mono-acid benzyl ester I,
Comprise the following steps: (1) takes maleic anhydride, finely ground, add organic solvent and dissolve, drip furan until completely dissolved
Mutter, react 24h, sucking filtration in 35 DEG C～45 DEG C, obtain white solid product 5,6-dihydro norcantharidin, drying for standby；
(2) under room temperature, take the white solid product in step (1), add chloroform and stir into suspension, the most while stirring
Instilling the mixed liquor of chloroform and bromine, be slow added into chloroform rinse liquid, stirring reaction, reaction terminates rear sucking filtration,
Wash with carbon tetrachloride, obtain white solid 5,6-dibromo norcantharidin, drying for standby；
(3) at 0 DEG C, 5 are taken, 6-dibromo norcantharidin, add benzyl alcohol, organic base and organic solvent, after reaction 1h, heating
Backflow 5h, cooling, removal of solvent under reduced pressure, obtain white solid 5,6-dibromo norcantharidin mono-acid benzyl ester through column chromatography.
The synthetic method of bromo norcantharidin mono-acid benzyl ester the most according to claim 2, it is characterised in that: described organic
Solvent is N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, acetonitrile, oxolane or ether.
The synthetic method of bromo norcantharidin mono-acid benzyl ester the most according to claim 2, it is characterised in that: described organic
Alkali is triethylamine or pyridine.
5. the application in preparing medicines resistant to liver cancer of the bromo norcantharidin mono-acid benzyl ester described in claim 1.
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| CN105061453A (en) * | 2015-08-06 | 2015-11-18 | 贵州柏强制药有限公司 | 5,6-dihydro demethyl cantharidin oxo mono acetic acid sodium salt and synthetic method and application thereof |
| CN111253414A (en) * | 2020-03-17 | 2020-06-09 | 遵义医科大学 | Synthesis of perfluorobenzyl norcantharidinate carboxylate and anti-tumor application thereof |
| CN111362962B (en) * | 2020-03-17 | 2022-08-09 | 遵义医科大学 | Tetrafluorobenzyl norcantharidin carboxylate and synthesis method thereof |
| CN111269242A (en) * | 2020-03-17 | 2020-06-12 | 遵义医科大学 | Norcantharidin carboxylic acid monofluorobenzyl ester and synthesis method and anti-tumor application thereof |
| CN111303179B (en) * | 2020-03-17 | 2022-12-02 | 遵义医科大学 | Synthesis of norcantharidin carboxylic acid difluoro benzyl ester and anti-tumor application thereof |
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