CN104478892B - Bromo Norcantharidin mono-acid ethyl ester and its preparation method and application - Google Patents
Bromo Norcantharidin mono-acid ethyl ester and its preparation method and application Download PDFInfo
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- CN104478892B CN104478892B CN201410851794.2A CN201410851794A CN104478892B CN 104478892 B CN104478892 B CN 104478892B CN 201410851794 A CN201410851794 A CN 201410851794A CN 104478892 B CN104478892 B CN 104478892B
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- norcantharidin
- acid ethyl
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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 ethyl ester, i.e. 5,6 dibromo Norcantharidin mono-acid ethyl esters, structural formula is Formulas I.A kind of bromo Norcantharidin mono-acid ethyl ester that the present invention provides, i.e. the 5 of open loop, 6 dibromo Norcantharidin mono-acid ethyl esters, prove that it has good anti-liver cancer efficacy through active testing, can be as the cantharidin antineoplastic of a kind of high-efficiency low-toxicity.The preparation technology of the present invention is selectively 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, safety, and yield is high, and purity is high.Thus this technique has feature efficient, convenient, low cost.
Description
Technical field
The present invention relates to bromo Norcantharidin mono-acid ethyl ester and its preparation method and application, belong to cantharidin derivative neck
Territory.
Background technology
Chinese blister beetle is a kind of insect bodies, is the Chinese medicine of a kind of folk tradition of China.The one extracting in Chinese blister beetle body is called
Cantharidin (cantharidin, C10H12O4) material have very special inhibitory action to certain cancers, for Example Ascites hepatoma or
Person is that primary carcinoma of liver has special inhibitory action, has very high 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 the sub-peaces of cantharidin or hydroxyl Chinese blister beetle etc. have and
Resisting the activity of cancer as cantharidin, the even activity of cantharidin is in contrast lower.Today of development in science and technology, Chinese blister beetle
Element is by extensive understanding application, and the derivative 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 and studied by scientific circles, and one of become important cancer therapy drug further.
Because the toxicity of cantharidin is bigger, can there is certain side effect to clinical treatment.Therefore current many science
Research all uses the method synthesis Norcantharidin of 1,2 methyl of removal.Again because going first spot huge legendary turtle element to be that anticancer effect is preferable
Chinese medicine, therefore may be used for injection in liver cancer.And Norcantharidin is one of medicine of China's relatively early just synthesis in the past.
Li Taihua (Li Taihua, " synthesis of two kinds of cantharidin derivatives,125I mark and animal distribution in vivo thereof ",
Isotope, 1998,11 (2), 95-99) it and is acylated bromine atoms introducing Norcantharidin by bromine addition method for the first time
Derivative.Gained derivative is with external test tube method, with the above-mentioned multiple derivatives of mtt assay screening model detection to oral squamous carcinoma cell
(KB), colorectal cell (HCT), the inhibiting rate of HCC (Bel) three kinds of cancer cells and IC50 value, it is found that this chemical combination
Thing all has certain inhibitory action to cancer cell, all has higher concentration in the heart of small white mouse, liver, lung, kidney and spleen simultaneously.
Consider to have been used to (such as sodium cantharidin, Norcantharidin sodium etc.) in the cantharidin medicine of clinical treatment at present,
All existing in an open-loop manner, chemically seeing in structure, its corresponding solubility of the compound of open loop is relatively big, its vivo biodistribution profit
Expenditure is also high.Therefore the structure of cantharidin is modified, find the cantharidin antineoplastic of high-efficiency low-toxicity, have important
Industrial application value and extensive market prospects.ZL201410163619.4、ZL201410163711.0、
ZL201410163705.5 etc. disclose the method preparing cantharidin hydrochlorate, and prior art also discloses by bromine addition
It is synthesized 5, the method for 6-dibromo Norcantharidin, but not yet have been reported that the 5 of synthesis open loop, 6-dibromo demethylcantharidin monoesters.
Content 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 ethyl ester and
Its preparation method and application, obtained bromo Norcantharidin mono-acid ethyl 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 ethyl ester, i.e. 5,6-dibromo Norcantharidin mono-acid ethyl ester, structural formula is Formulas I:
The preparation method of bromo Norcantharidin mono-acid ethyl ester, is carried out according to following synthetic route: with furans as raw material, with
Maleic anhydride reacts in organic solvent and obtains 5, and 6-dihydro Norcantharidin, 5,6-dihydro Norcantharidins are at three chloromethanes
Reacting with bromine in alkane and obtaining 5,6-dibromo Norcantharidin, 5,6-dibromo Norcantharidins and ethanol synthesis obtain 5,6-dibromo
Norcantharidin mono-acid ethyl ester I,
Aforementioned preparation process, specifically includes following steps:
(1) take maleic anhydride, finely ground, add organic solvent dissolve, until completely dissolved drip furans, in 35 DEG C～
45 DEG C of reaction 24h, suction 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 to stir into suspension, stir with back
Mixing limit and instilling the mixed liquor of chloroform and bromine, be slow added into chloroform rinse liquid, stirring reaction, reaction is taken out after terminating
Filter, with carbon tetrachloride washing, obtains white solid 5,6-dibromo Norcantharidin, drying for standby；
(3) 5 are taken, 6-dibromo Norcantharidin, it is initially charged part 95% ethanol, stirring is warming up to when 78 DEG C start backflow,
Adding dropwise 95% ethanol, until solution clarification, suction filtration obtains filtrate while hot, seals filtrate, freezing and crystallizing, overnight, and suction filtration,
Obtain white solid 5,6-dibromo Norcantharidin mono-acid ethyl ester.
Aforementioned preparation process, it is also possible to comprise the following steps:
(1) take maleic anhydride, finely ground, add organic solvent dissolve, until completely dissolved drip furans, in 35 DEG C～
45 DEG C of reaction 24h, suction 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 to stir into suspension, stir with back
Mixing limit and instilling the mixed liquor of chloroform and bromine, be slow added into chloroform rinse liquid, stirring reaction, reaction is taken out after terminating
Filter, with carbon tetrachloride washing, obtains white solid 5,6-dibromo Norcantharidin, drying for standby；
(3) 5 are taken, 6-dibromo Norcantharidin, add absolute ethyl alcohol, organic base and organic solvent, heating reflux reaction,
After TLC monitoring reaction completes, being cooled to room temperature, removal of solvent under reduced pressure, residue obtains 5 through column chromatography, 6-dibromo Norcantharidin
Mono-acid ethyl ester.
In aforementioned preparation process, described organic solvent is DMF, dimethyl sulfoxide (DMSO), dichloromethane, chlorine
Imitative, acetonitrile, oxolane or ether.
In aforementioned preparation process, the organic base in described step (3) is triethylamine or pyridine.
Application in preparing medicines resistant to liver cancer for the bromo Norcantharidin mono-acid ethyl ester.
The invention have benefit that: a kind of bromo Norcantharidin mono-acid ethyl ester that the present invention provides, i.e. open loop
Through active testing, 5,6-dibromo Norcantharidin mono-acid ethyl esters, prove that it has good anti-liver cancer efficacy, can be as a kind of height
The cantharidin antineoplastic of effect low toxicity.The preparation technology of the present invention is selectively 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, safety, yield is high, and 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.
The furans using in the present invention, maleic anhydride, bromine is 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:
Take out a certain amount of maleic anhydride from reagent bottle, 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.It after maleic anhydride is completely dissolved, is slowly added to dropping funel
13mL furans, used time 13min.Control temperature starts reaction at 38 DEG C.After reaction 1h, there is white solid in solution, and the time is longer
White solid is more.React suction filtration to 24h, obtain white solid intermediate A, i.e. 5,6-dihydro Norcantharidin.It is dried and weigh
For 17.459g, yield 85.75%.Fusing point: 122～123 DEG C, Rf:0.52 (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 formamide, dimethyl sulfoxide (DMSO), 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 obtaining 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.Now under stirring at room temperature, leak with dropping liquid
Bucket dropping 2.5mL chloroform and the mixed liquor of 0.5mL bromine, drip and use 2.5mL chloroform rinse dropping funel after finishing,
And rinse liquid is slowly added to, add mixed liquor to amount to used time 20min with rinse liquid, observe phenomenon.After question response terminates, take out
Filter, is washed three times by carbon tetrachloride, obtains white solid intermediate B, i.e. 5,6-dibromo Norcantharidin.It is dried and be weighed as
8.330g, yield 85.35%.Fusing point: 157～159 DEG C, Rf:0.65 (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 ethyl ester: reaction equation is as follows:
Weigh intermediate B 0.500g of gained in embodiment 2, be placed in round-bottomed flask, add 1.5mL 95% ethanol,
Start stirring liter high-temperature to solution when 78 DEG C and start backflow, then slowly dropwise drip 95% ethanol, treat that solution becomes clarification.
The filtrate of gained is sealed, inserts refrigerator by then suction filtration while hot, starts crystallization.Overnight, second day, conical flask occur a large amount of
White crystal, suction filtration, obtain white solid, i.e. 5,6-dibromo Norcantharidin mono-acid ethyl ester.It is dried and be weighed as 469mg, yield
82%.Fusing point: > 240 DEG C.Rf:0.63 (solvent: petroleum ether: ethyl acetate=10: 1).1HNMR(DMSO-d6)δ:12.64
(s, 1H), 4.77 (d, 2H), 4.41 (d, 1H), 4.01 (q, 2H), 3.34 (s, 2H), 3.21 (s, 1H), 1.13 (t, 3H).
The preparation of embodiment 45,6-dibromo Norcantharidin mono-acid ethyl ester: reaction equation is as follows:
Weigh intermediate B 1g of gained in embodiment 2, be placed in round-bottomed flask, add 2mL absolute ethyl alcohol, 1mL tri-second
Amine and 10mL dichloromethane, heating reflux reaction, it after TLC (thin-layer chromatography) monitoring reaction completes, is cooled to room temperature, decompression removes
Solvent, residue, through column chromatography, obtains product, i.e. 5,6-dibromo Norcantharidin mono-acid ethyl ester.It is dried and is weighed as 0.98g, receive
Rate 84%.Fusing point: > 240 DEG C.Rf:0.63 (solvent: petroleum ether: ethyl acetate=10: 1).1HNMR(DMSO-d6)δ:
12.64 (s, 1H), 4.77 (d, 2H), 4.41 (d, 1H), 4.01 (q, 2H), 3.34 (s, 2H), 3.21 (s, 1H), 1.13 (t,
3H)。
Organic base, i.e. triethylamine used in above-described embodiment 4 can be replaced by pyridine；Organic solvent dichloromethane used
Any one in available N,N-dimethylformamide, dimethyl sulfoxide (DMSO), chloroform, acetonitrile, oxolane, ether replaces.TLC is (thin
Layer chromatography) can also be used with gas chromatography or liquid chromatography replacement.
The resisting liver cancer activity test of experimental example 15,6-dibromo Norcantharidin mono-acid ethyl ester
Sulforhodamine (sulforhodamine B, SRB) decoration method
During inoculating cell, every kind of cell two piece of 96 orifice plate of parallel inoculation, one piece is control board (T0), and another block is experiment
Plate.After 20h cultivated by CO2 incubator, control board (T0) is taken out, fixed by 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 precooling 50%TCA, after 1h placed by 4 DEG C of refrigerators, with deionized water
Rinse, naturally dry, with the SRB dyeing of 100 μ L 0.4%, rinse with 0.1% acetic acid, dry after 10min, finally use 200 μ
L10mmol·L-1Buffering Tris alkali lye (pH=10.5) dissolve, on ELIASA 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 cantharidin as positive control, has carried out 5,6-dibromo demethylcantharidin
The inhibitory activity to human liver cancer cell Hep G2 for the element mono-acid ethyl ester is tested, and result is as shown in table 1:
Table 1
| Sample | C (test concentrations) | Inhibiting rate (Inhibitionratio) | IC50 |
| Cantharidin | 15.75μmol/L | 73.5% | 7.98μmol/L |
| Sodium Cantharidinate | 15.75μmol/L | 71.3% | 8.22μmol/L |
| Compound I | 15.75μmol/L | 97.2% | 5.05μmol/L |
As shown in Table 1,5,6-dibromo Norcantharidin mono-acid ethyl ester has well suppression to human liver cancer cell Hep G2
Effect, can use it for preparing the medicine of anti-liver cancer and anti-.
Claims (6)
1. bromo Norcantharidin mono-acid ethyl ester, i.e. 5,6-dibromo Norcantharidin mono-acid ethyl ester, it is characterised in that: structural formula is
Formulas I:
2. the preparation method of bromo Norcantharidin mono-acid ethyl ester as claimed in claim 1, it is characterised in that: close according to following
Become route to carry out: with furans as raw material, react in organic solvent with maleic anhydride and obtain 5,6-dihydro Norcantharidin,
5,6-dihydro Norcantharidins react with bromine in chloroform and obtain 5, and 6-dibromo Norcantharidin, 5,6-dibromos remove first spot
Chinese blister beetle element obtains 5 with ethanol synthesis, 6-dibromo Norcantharidin mono-acid ethyl ester I, described organic solvent be DMF,
Dimethyl sulfoxide (DMSO), dichloromethane, chloroform, acetonitrile, oxolane or ether；
3. the preparation method of bromo Norcantharidin mono-acid ethyl ester according to claim 2, it is characterised in that: include following
Step: (1) takes maleic anhydride, finely ground, adds organic solvent to dissolve, and drips furans until completely dissolved, in 35 DEG C～45
DEG C reaction 24h, suction 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 to stir into suspension, while stirring subsequently
Instilling the mixed liquor of chloroform and bromine, being slow added into chloroform rinse liquid, stirring reaction, reaction terminates rear suction filtration,
With carbon tetrachloride washing, obtain white solid 5,6-dibromo Norcantharidin, drying for standby；
(3) 5 are taken, 6-dibromo Norcantharidin, it is initially charged part 95% ethanol, stirring is warming up to when 78 DEG C start backflow, then by
Dropping 95% ethanol, until solution clarification, suction filtration obtains filtrate while hot, seals filtrate, freezing and crystallizing, overnight, and suction filtration, to obtain final product
White solid 5,6-dibromo Norcantharidin mono-acid ethyl ester.
4. the preparation method of bromo Norcantharidin mono-acid ethyl ester according to claim 2, it is characterised in that: include following
Step:
(1) maleic anhydride is taken, finely ground, add organic solvent to dissolve, drip furans until completely dissolved, in 35 DEG C～45 DEG C
Reaction 24h, suction 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 to stir into suspension, while stirring subsequently
Instilling the mixed liquor of chloroform and bromine, being slow added into chloroform rinse liquid, stirring reaction, reaction terminates rear suction filtration,
With carbon tetrachloride washing, obtain white solid 5,6-dibromo Norcantharidin, drying for standby；
(3) taking 5,6-dibromo Norcantharidin, addition absolute ethyl alcohol, organic base and organic solvent, heating reflux reaction, TLC supervises
After measured reaction completes, being cooled to room temperature, removal of solvent under reduced pressure, residue obtains 5 through column chromatography, 6-dibromo Norcantharidin mono-acid second
Ester.
5. the preparation method of bromo Norcantharidin mono-acid ethyl ester according to claim 4, it is characterised in that: described step
(3) organic base in is triethylamine or pyridine.
6. application in preparing medicines resistant to liver cancer for the bromo Norcantharidin mono-acid ethyl ester as claimed in claim 1.
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