CN105061453A - 5,6-dihydro demethyl cantharidin oxo mono acetic acid sodium salt and synthetic method and application thereof - Google Patents
5,6-dihydro demethyl cantharidin oxo mono acetic acid sodium salt and synthetic method and application thereof Download PDFInfo
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- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
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Abstract
The invention discloses a novel demethyl cantharidin sodium derivative, a structural formula of the derivative is shown in a formula I. The provided 5,6-dihydro demethyl cantharidin oxo mono acetic acid sodium salt has certain anti-liver cancer effect through active test, and can be taken as a cantharidin antitumor drug with high efficiency and low toxicity. The synthesis technology has the advantages of good selectivity, easily available raw material, low cost, simple synthesis route and convenient operation, and the product after synthesis has the advantages of little toxicity, high yield and high products purity. The technology has the characteristics of high efficiency, convenience and low cost.
Description
Technical field
The present invention relates to Norcantharidin oxo list acetic acid sodium salt and synthetic method thereof and application, belong to cantharidin derivative field.
Background technology
Chinese blister beetle is a kind of insect, also known as " passwind worm ", is the one in China's traditional Chinese medicine material.China uses Chinese blister beetle as the country of medicinal material the earliest, in the medical masterpiece such as Compendium of Material Medica, " Dragon Lord book on Chinese herbal medicine warp ", just once had the record of being used as medicine about Cantharidin.
Cantharidin (cantharidin, C
10h
12o
4) be a kind of more effective cancer-resisting substance extracted in insect body, be the effective constituent of folk therapy malignant tumour, it is compared with other antitumor drug, has many advantages.Such as: it and it analogue can not suppress the immunologic function of human body, in addition, can promote human leukocytes etc.It is to liver cancer, ovarian cancer, and esophagus cancer etc. have good curative effect, and it is the activity by changing protein, and antineoplastic invasion shifts, and causes cell-cycle arrest, and Tumor suppression grows, thus makes it dead.Its antineoplastic mechanism is by reducing cancer cells to amino acid whose picked-up, the synthesis of arrestin matter, stimulate lymphocyte, scavenger cell, polymorphonuclear cell to produce interleukin-, thus improve immunity of organisms, simultaneously killing tumor cell and reach therapeutic purpose.
But Cantharidin has larger toxic side effect to urinary system and gastrointestinal system, Cantharidin is antineoplastic activeconstituents, is also the main component of toxicity simultaneously.Appropriate structural modification is carried out to it, on the basis retaining its anti-tumor activity, greatly can lower the toxic side effect to body, synthesize example with norcantharidin derivative.Norcantharidin not only remains the effect of its stronger anti-tumor activity and leukocyte increasing, and also eliminating its side effect to urinary system, afterwards, take Norcantharidin as the focus that lead compound carries out that structure of modification becomes research.This advantage in antitumor drug or rare, is paid close attention to widely so cause, and synthesized its toxic side effect of many minimizings successively but retained again the similar drugs of its activity simultaneously, the derivative that exploitation upgrades high-efficiency low-toxicity is a good research direction.
The derivative being used for the treatment of cancer after structural modification is carried out to Cantharidin appearance successively in recent years, and start to apply to clinical treatment.As Norcantharidin, it is fewer than Cantharidin two methyl, its toxicity obviously lowers, and therapeutic action is better than canthaxanthin.Also have sodium cantharidinate in addition, Norcantharidin sodium, N-methylcantharidimide etc., these medicines through structure of modification have them
Respective advantage, but these medicines is water-soluble poor, and bioavailability is not high.
At present for (as sodium cantharidinate, Norcantharidin sodium etc.) in the Cantharidin medicine of clinical treatment, exist all in an open-loop manner, chemically structure is seen, its corresponding solubleness of the compound of open loop is comparatively large, and in its body, bioavailability is also high.Therefore the structure of Cantharidin is modified, find the Cantharidin antitumor drug of high-efficiency low-toxicity, there are important industrial application value and market outlook widely.ZL201410163619.4, ZL201410163711.0, ZL201410163705.5 etc. disclose the method preparing cantharidin hydrochlorate.
Summary of the invention
For solving the deficiencies in the prior art, the object of the present invention is to provide a kind of 5,6-dihydro Norcantharidin oxo list acetic acid sodium salt and synthetic method thereof and application, water soluble group is introduced in its structure, increase its bioavailability, reach the object increasing its result for the treatment of, the anti-liver cancer efficacy that 5, the 6-dihydro Norcantharidin oxo list acetic acid sodium salt tools obtained are certain.
In order to realize above-mentioned target, the present invention adopts following technical scheme:
5,6-dihydro Norcantharidin oxo list acetic acid sodium salt, structural formula is formula I:
5, the synthetic method of 6-dihydro Norcantharidin oxo list acetic acid sodium salt, carry out according to following synthetic route: take furans as raw material, 5 are obtained by reacting in organic solvent with MALEIC ANHYDRIDE, 6-dihydro Norcantharidin A, 5, 6-dihydro Norcantharidin obtains 5 through reductive agent reduction reaction in organic solvent, 6-dihydro Norcantharidin glycol B, 5, 6-dihydro Norcantharidin glycol and ethyl bromoacetate obtain 5, 6-dihydro Norcantharidin oxo list ethyl acetate C, finally this ester is hydrolyzed in the basic conditions and generates corresponding 5, 6-dihydro Norcantharidin oxo list acetic acid sodium salt I:
Aforementioned synthetic methods, specifically comprises the following steps:
(1) get MALEIC ANHYDRIDE, porphyrize, add organic solvent dissolution, drip furans until completely dissolved, in 35 DEG C ~ 45 DEG C reaction 24h, suction filtration, obtains white solid product 5,6-dihydro Norcantharidin, drying for standby;
(2), under room temperature, get the white solid product in step (1), dissolve after adding organic solvent, be cooled to 0
oc, more slowly add LiAlH in batches
4, stirring reaction spends the night, and reaction terminates rear suction filtration, abundant with ethyl acetate, water washing, obtains clarified liq 5,6-dihydro Norcantharidin glycol, drying for standby;
(3) be dissolved in organic solvent by 5,6-dihydro Norcantharidin glycol, frozen water is cooled to 0
ounder C, first add 60%NaH, then add ethyl bromoacetate, more under agitation continue reaction spend the night after suction filtration, be spin-dried for, namely residuum obtains 5,6-dihydro Norcantharidin oxo list ethyl acetate through rapid column chromatography.
(4) get 5,6-dihydro Norcantharidin oxo list ethyl acetate to suspend in water, hydrolysis generates corresponding 5,6-dihydro Norcantharidin oxo list acetic acid sodium salt crude products in the basic conditions, after column chromatography purification, obtain sterling.
In aforementioned synthetic methods, in described step (1), organic solvent is any one in ether, toluene, benzene, ethyl acetate, methylene dichloride, chloroform, acetonitrile, tetrahydrofuran (THF).
In aforementioned synthetic methods, in described step (2), organic solvent is tetrahydrofuran (THF) or ether.
In aforementioned synthetic methods, the organic solvent in described step (3) is tetrahydrofuran (THF), DMF, methyl-sulphoxide, any one in acetonitrile.
In aforementioned synthetic methods, described alkali is organic bases or mineral alkali.Wherein organic bases is triethylamine or pyridine etc.Mineral alkali is sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood etc.
5,6-dihydro Norcantharidin oxo list acetic acid sodium salt is preparing the application in medicines resistant to liver cancer.
Usefulness of the present invention is: through active testing, 5,6-dihydro Norcantharidin oxo list acetic acid sodium salts provided by the invention, prove that it has certain anti-liver cancer efficacy, can be used as a kind of Cantharidin antitumor drug of high-efficiency low-toxicity.Synthesis technique selectivity of the present invention is good, and raw material is easy to get, with low cost, and synthetic route is simple, and convenient operation is implemented, and it is little to synthesize products therefrom toxicity, and yield is high, and product purity is high, and thus this technique has feature that is efficient, convenient, low cost.
Embodiment
Below in conjunction with specific embodiment, the present invention is further introduced.
The furans used in the present invention, MALEIC ANHYDRIDE, LiAlH
4, NaH(60%), ethyl bromoacetate is all from Shanghai traditional Chinese medicines group.Solvent for use is from Zun Yi Shuan Ju Chemical Co., Ltd..Unless otherwise indicated, agents useful for same is chemical pure.
The synthetic method of embodiment 15,6-dihydro Norcantharidin oxo list acetic acid sodium salt I.
The preparation of step (1) intermediate A, i.e. 5,6-dihydro Norcantharidins: reaction formula is as follows:
From reagent bottle, take out a certain amount of MALEIC ANHYDRIDE, be placed in dry grinding body porphyrize, then take the MALEIC ANHYDRIDE 12.021g of porphyrize with electronic balance, be placed in dry there-necked flask, cap, then the stirring that adds diethyl ether, when ether amount is 90mL, MALEIC ANHYDRIDE is dissolved completely.After MALEIC ANHYDRIDE is dissolved completely, slowly add 13mL furans with dropping funnel, used time 13min.Control temperature starts reaction at 38 DEG C.After reaction 1h there is white solid in solution, and time longer white solid is more.React suction filtration to 24h, obtain white solid intermediate A, i.e. 5,6-dihydro Norcantharidins.Drying is weighed as 17.459g, yield 85.75%.Fusing point: 122 ~ 123 DEG C, R
f: 0.52 (developping agent: sherwood oil: ethyl acetate=3: 1);
1hNMR (CDCl
3): δ: 3.18 (s, 2H), 5.47 (s, 2H), 6.58 (s, 2H).
For dissolving the organic solvent of MALEIC ANHYDRIDE except ether in above-mentioned steps (1), any one also in available toluene, benzene, ethyl acetate, methylene dichloride, chloroform, acetonitrile, tetrahydrofuran (THF) etc. replaces; Described temperature of reaction can between 35 DEG C ~ 45 DEG C.
Step (2) intermediate
b, i.e. 5,6-dihydro Norcantharidin glycol preparation:
Take the compd A 2.0g generated, in the clean flask of 25ml, add the THF that 25ml dewaters, ice bath is stirred to solution clarification.Add LiAlH in four batches lentamente
4(689mg), reaction 24h, some plate.Add ethyl acetate, shrend is gone out reaction, makes stable reaction.Suction filtration, with the diafiltration three times repeatedly of ethyl acetate, water, merging filtrate is also spin-dried for, and obtains 5,6-dihydro Norcantharidin glycol
bcrude product 2.05g.Yield >100%, R
f: 0.21 (developping agent is ethyl acetate);
1hNMR (CDCl
3): δ: 6.38 (s, 2H), 4.68 (s, 2H), 3.76-3.85 (m, 4H), 1.94 (t, 2H).
In above-mentioned steps (2), organic solvent is tetrahydrofuran (THF) or ether.
The preparation of step (3) intermediate C, i.e. 5,6-dihydro Norcantharidin oxo list ethyl acetate.
By the compound generated
bcrude product gets the flask that 1.3g is placed in 50ml cleaning, adds the THF that 25ml dewaters, and ice bath stirs, then adds 60%NaH513mg, finally adds ethyl bromoacetate (1.4ml), reaction 24h, and some plate, suction filtration, is spin-dried for, and obtains crude product 1.7g.Crude product is utilized column chromatogram chromatography principle, be separated with silicagel column, obtain compound
c(0.45g, yield: 45%).R
f: 0.67 (developping agent is sherwood oil: ethyl acetate=5:1);
1hNMR (CDCl
3) δ: 6.36-6.42 (m, 2H), 4.76 (t, 2H), 4.21-4.23 (m, 2H), 4.12-4.19 (m, 2H), 3.76-3.85 (m, 2H), 3.63-3.65 (m, 2H), 1.93-2.08 (m, 2H), 1.29 (t, 3H);
Organic solvent in above-mentioned steps (3) is tetrahydrofuran (THF), DMF, methyl-sulphoxide, any one in acetonitrile.
The preparation of step (4) 5,6-dihydro Norcantharidin oxo list acetic acid sodium salt I: reaction formula is as follows:
Get Compound C 0.45g, in the flask of 25ml cleaning, add 9ml water, stir, then add NaOH148mg, reaction 24h.Add 10%HCl and adjust PH4-5, be spin-dried for.Utilize column chromatogram chromatography principle, with silicagel column be separated Compound I (0.31g, yield: 78%), Rf:0.25 (ethyl acetate: ethanol=5:1).
1hNMR(D
2o) δ: 6.3 (s, 2H), 3.81 (s, 2H), 3.32-3.63 (m, 6H), 1.77-1.90 (m, 2H).
13cNMR(D
2o) δ: 177.71,135.23,80.75,80.72,70.08,69.68,60.59,41.17,38.84.
Alkali used in above-mentioned steps (4) is organic bases or mineral alkali.Wherein organic bases is triethylamine or pyridine etc.Mineral alkali is sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood etc.TLC(thin-layer chromatography) also available vapor-phase chromatography or liquid phase chromatography replace.
The resisting liver cancer activity test of experimental example 25,6-dihydro Norcantharidin oxo list acetic acid sodium salt
Sulforhodamine (sulforhodamineB, SRB) staining
During inoculating cell, often kind of parallel inoculation of cell two piece of 96 orifice plate, one piece is control board (T0), and another block is brassboard.After cultivating 20h in CO2 incubator, control board (T0) is taken out, fix with 50% trichoroacetic acid(TCA) (TCA), to be measured.Add testing compound (final concentration is respectively 5,2.5,1.25,0.625,0.313 μ gmL-1) in brassboard, and establish negative control group (C), experimental group (T), solvent control group.Often group establishes 5 multiple holes, culture plate is taken out after continuing to cultivate 48h, fix (final concentration is for 10%) with precooling 50%TCA, after 1h placed by 4 DEG C of refrigerators, with deionized water rinsing, naturally dry, dye with the SRB of 100 μ L0.4%, rinse with 0.1% acetic acid, dry after 10min, finally use the buffering Tris alkali lye (pH10.5) of 200 μ L10mmolL-1 to dissolve, microplate reader is selected 530nm place survey absorbance (OD value).
This test is according to SRB method, with canthaxanthin, sodium cantharidinate for positive control, carry out 5,6-dihydro Norcantharidin oxo list acetic acid sodium salt is tested the inhibit activities of human liver cancer cell HepG2, found that it is 65% to the inhibiting rate of human liver cancer cell HepG2, demonstrates 5 as concentration c=5 μ g/ml, 6-dihydro Norcantharidin oxo list acetic acid sodium salt has certain inhibition to human liver cancer cell HepG2, can use it for the medicine preparing anti-liver cancer.
Claims (8)
1.5,6-dihydro Norcantharidin oxo list acetic acid sodium salt, is characterized in that: structural formula is formula I:
。
2. as claimed in claim 15, the synthetic method of 6-dihydro Norcantharidin oxo list acetic acid sodium salt, it is characterized in that: carry out according to following synthetic route: take furans as raw material, 5 are obtained by reacting in organic solvent with MALEIC ANHYDRIDE, 6-dihydro Norcantharidin, 5, 6-dihydro Norcantharidin obtains 5 through reductive agent reduction reaction in organic solvent, 6-dihydro Norcantharidin glycol, 5, 6-dihydro Norcantharidin glycol and ethyl bromoacetate obtain 5, 6-dihydro Norcantharidin oxo list ethyl acetate, finally this ester is hydrolyzed in the basic conditions and generates corresponding 5, 6-dihydro Norcantharidin oxo list acetic acid sodium salt:
。
3. the synthetic method of 5,6-dihydro Norcantharidin oxo list acetic acid sodium salts according to claim 2, is characterized in that: comprise the following steps:
(1) get MALEIC ANHYDRIDE, porphyrize, add organic solvent dissolution, drip furans until completely dissolved, in 35 DEG C ~ 45 DEG C reaction 24h, suction filtration, obtains white solid product 5,6-dihydro Norcantharidin, drying for standby;
(2), under room temperature, get the white solid product in step (1), dissolve after adding organic solvent, be cooled to 0
oc, more slowly add LiAlH in batches
4, stirring reaction spends the night, and reaction terminates rear suction filtration, with the diafiltration three times repeatedly of ethyl acetate, water, obtains clarified liq 5,6-dihydro Norcantharidin glycol, drying for standby;
(3) be dissolved in organic solvent by 5,6-dihydro Norcantharidin glycol, frozen water is cooled to 0
ounder C, first add 60%NaH, then add ethyl bromoacetate, more under agitation continue reaction spend the night after suction filtration, be spin-dried for, namely residuum obtains 5,6-dihydro Norcantharidin oxo list ethyl acetate through rapid column chromatography;
(4) get 5,6-dihydro Norcantharidin oxo list ethyl acetate to suspend in water, hydrolysis generates corresponding 5,6-dihydro Norcantharidin oxo list acetic acid sodium salt crude products in the basic conditions, after column chromatography purification, obtain sterling.
4. according to claim 35, the synthetic method of 6-dihydro Norcantharidin oxo list acetic acid sodium salt, is characterized in that: in described step (1), organic solvent is any one in ether, toluene, benzene, ethyl acetate, methylene dichloride, chloroform, acetonitrile, tetrahydrofuran (THF).
5. the synthetic method of 5,6-dihydro Norcantharidin oxo list acetic acid sodium salts according to claim 3, is characterized in that: in described step (2), organic solvent is tetrahydrofuran (THF) or ether.
6. the synthetic method of 5,6-dihydro Norcantharidin oxo list acetic acid sodium salts according to claim 3, is characterized in that: the organic solvent in described step (3) is tetrahydrofuran (THF), DMF, methyl-sulphoxide, any one in acetonitrile.
7. according to claim 35, the synthetic method of 6-dihydro Norcantharidin oxo list acetic acid sodium salt, it is characterized in that: described alkali is organic bases or mineral alkali, wherein organic bases is triethylamine or pyridine, and mineral alkali is any one in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood.
8. 5,6-dihydro Norcantharidin oxo list acetic acid sodium salts as claimed in claim 1 are preparing the application in medicines resistant to liver cancer.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447782A (en) * | 2014-12-30 | 2015-03-25 | 贵州柏强制药有限公司 | Bromo-norcantharidin acid-benzyl ester, and synthetic method and application thereof |
| CN104817568A (en) * | 2015-05-11 | 2015-08-05 | 遵义医学院 | 5, 6-bidehydronorcantharides alcohol derivative and application thereof to tumor resistance |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447782A (en) * | 2014-12-30 | 2015-03-25 | 贵州柏强制药有限公司 | Bromo-norcantharidin acid-benzyl ester, and synthetic method and application thereof |
| CN104817568A (en) * | 2015-05-11 | 2015-08-05 | 遵义医学院 | 5, 6-bidehydronorcantharides alcohol derivative and application thereof to tumor resistance |
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