CN103086975A - 9-hydroxymethyl-10-imidazolanthracenehydrazone, and synthetic method and application thereof - Google Patents
9-hydroxymethyl-10-imidazolanthracenehydrazone, and synthetic method and application thereof Download PDFInfo
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Abstract
The invention discloses a new antharcycline anticancer medicine derivative 9-hydroxymethyl-10-imidazolanthracenehydrazone, and a synthetic method and an application thereof. The synthetic method of 9-hydroxymethyl-10-imidazolanthracenehydrazone comprises the following steps: weighing 9,10-anthracenedicarboxaldehyde and 4,5-dihydroimidazol-2-ylhydrazine hydrobromide having a same molar amount with 9,10-anthracenedicarboxaldehyde, mixing them, dissolving them in an organic solvent, and carrying out an aldehyde-amine condensation reaction to obtain mixed products; carrying out silica gel column chromatography of the mixed products, eluting with a mixed solvent comprising methanol and one of dichloromethane, chloroform and ethyl acetate, concentrating the obtained eluate, and drying to obtain a target intermediate; and carrying out a reducing reaction of the target intermediate and sodium borohydride in the presence of an alcoholic solvent, adding water to the reaction solution, allowing the obtained solution to stand and precipitate, and separating to obtain a solid which is 9-hydroxymethyl-10-imidazolanthracenehydrazone. A case that 9-hydroxymethyl-10-imidazolanthracenehydrazone has substantial in-vitro resistance activities on a plurality of human tumor cells, has substantial propagation inhibition activities on some tested tumor strains, has a good potential medicinal value, and is excepted to be used for the preparation of various antitumor medicines is found in the invention.
Description
Technical field
The present invention relates to medical technical field, be specifically related to 9-methylol-10-miaow anthracene hydrazone and synthetic method and application.
Background technology
Anthracycline anticancer drug is the important antitumor antibiotic of a class.As Zorubicin (Doxorubicin), darubicin (Idarubicin), aclacinomycin (Aclacinomycin), mitoxantrone (Mitoxantrone) and bisantrene (Bisantrene) etc., can suppress the synthetic of DNA or RNA, mostly belong to non-specific cancer therapy drug of cycle.This compounds all is widely used aspect clinical chemotherapy, simultaneously at CEF, has also accounted for very consequence in the Combination chemotherapy such as AC and CAF.
The antitumour activity of anthracene nucleus medicament is based on its anthracene nucleus parent nucleus: anthracene nucleus has good two dimensional structure, therefore effectively intercalation to carrying out irreversible fixation with the duplex of DNA between the base pair of DNA, and finally causes the DNA splitting of chain and causes death of neoplastic cells; In addition, the side chain on anthracene nucleus also has certain impact to the antitumour activity of anthracycline compound.Side chain as bisantrene is the imidazoles hydrazone, and when the anthracene nucleus intercalation was arrived between the DNA base pair, side-chain radical can further be stablized this combination by hydrogen bond and electrostatic interaction.But yet there are no the relevant reports such as relevant 9-methylol-10-miaow anthracene hydrazone and synthetic method thereof.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of new anthracycline anticancer drug derivative, i.e. 9-methylol-10-miaow anthracene hydrazone, and its synthetic method and application.
9-methylol of the present invention-10-miaow anthracene hydrazone, its structural formula is shown below:
The synthetic thinking of 9-methylol of the present invention-10-miaow anthracene hydrazone is: get 9,10-anthracene dicarbaldehyde and 4,5-dicyan imidazoles-2-hydrazine hydrogen bromide, carry out the aldimine condensation reaction, obtain the by product-bisantrene of the two condensations of 9-formaldehyde-10-miaow anthracene hydrazone and 9,10-, then separate through silica gel column chromatography and remove bisantrene, obtain single target intermediate product, i.e. 9-formaldehyde-10-miaow anthracene hydrazone; Again with 9-formaldehyde-10-miaow anthracene hydrazone sodium borohydride (NaBH
4) reduction, obtaining at last 9-methylol-10-miaow anthracene hydrazone, synthetic route is as follows:
Concrete synthetic method is: take 9 of Isoequivalent weight, and 10-anthracene dicarbaldehyde and 4,5-dicyan imidazoles-2-hydrazine hydrogen bromide, mixing is dissolved in organic solvent, carries out the aldimine condensation reaction, obtains mix products; Mix products carries out wash-out through silica gel column chromatography with methyl alcohol and the mixed solvent that is selected from a kind of composition in methylene dichloride, chloroform and ethyl acetate, and elutriant is concentrated, dry, obtains the target intermediate; Get target intermediate and sodium borohydride and carry out reduction reaction under the alcoholic solvent existence condition, add water in reaction solution, standing, separate out, isolate solid, namely obtain 9-methylol-10-miaow anthracene hydrazone.
More specifically synthetic method comprises the following steps:
1) take 9 of Isoequivalent weight, 10-anthracene dicarbaldehyde and 4,5-dicyan imidazoles-2-hydrazine hydrogen bromide mixes and to be dissolved in organic solvent, and back flow reaction is to fully under 70～150 ℃ of conditions, and reaction solution is standing, separate out, and obtains mix products;
2) mix products through silica gel column chromatography, carries out wash-out with methyl alcohol and the mixed solvent that is selected from a kind of composition in methylene dichloride, chloroform and ethyl acetate, and thin-layer chromatography is followed the tracks of and detected, and collects the elutriant that contains the purpose composition, and is concentrated, dry, obtains the target intermediate;
3) getting target intermediate and sodium borohydride is dissolved in respectively in alcoholic solvent, under 0～30 ℃ of condition, the alcoholic solution of sodium borohydride is dripped in the alcoholic solution of target intermediate, stirring reaction is to complete, add water in reaction solution, standing, separate out, isolate solid, namely obtain 9-methylol-10-miaow anthracene hydrazone.
In above-mentioned synthetic method,
Step 1) in, described organic solvent is dehydrated alcohol or anhydrous methanol, or the combination of dehydrated alcohol and anhydrous methanol or propyl carbinol.When organic solvent be chosen as the combination of dehydrated alcohol and anhydrous methanol or propyl carbinol the time, their proportioning can be any proportioning.The consumption of described organic solvent is can dissolve 9,10-anthracene dicarbaldehyde and 4,5-dicyan imidazoles-2-hydrazine hydrogen bromide is advisable, generally, 0.01mol anthracene dialdehyde and 0.01mol4,5-dicyan imidazoles-2-hydrazine hydrogen bromide dissolves with 50～200mL organic solvent, and preferably the organic solvent with 50～100mL dissolves.
Step 1) in, the temperature of back flow reaction is preferably 70～100 ℃.
Step 2) in, be used for the mixed solvent of wash-out, the volume ratio of methyl alcohol and methylene dichloride or chloroform or ethyl acetate is 1:20～100, is preferably 1:30～70.
Step 3) in, the consumption of sodium borohydride is usually excessive with respect to the target intermediate, in order to the target intermediate is fully reduced, preferably, the mol ratio of target intermediate and sodium borohydride is 1:1.5～10.In this step, the temperature of described reaction is preferably 0～15 ℃; Described alcoholic solvent is dehydrated alcohol and/or anhydrous methanol, when alcoholic solvent be chosen as the combination of dehydrated alcohol and anhydrous methanol the time, their proportioning can be any proportioning; The consumption of described alcoholic solvent is product B or sodium borohydride dissolving can be got final product.In this step, the purpose that described water adds is to make separating out of target product 9-methylol-10-miaow anthracene hydrazone, and the add-on of water can not lower than the amount of the required organic solvent of reaction, be generally 2～5 times of reaction organic solvent usually.
In above-mentioned synthetic method, whether various reactions can adopt thin-layer chromatography to follow the tracks of is fully detected, under above-mentioned qualifications, and step 1) in, back flow reaction approximately needs 4～6h to fully approximately needing 2～8h under optimum condition; Step 3) in, stirring reaction approximately needs 4～8h to fully approximately needing 4～24h under optimum condition.Described standingly usually carry out under 0～25 ℃ of condition preferably carries out under 0～4 ℃ of condition, and the standing time is generally 1～12h.
The organic solvent that uses in above-mentioned synthetic method, alcoholic solvent etc. are preferably first used before use
Molecular sieve dehydration is with the carrying out that is conducive to react.
The present invention also comprises the application of above-mentioned 9-methylol-10-miaow anthracene hydrazone in the preparation antitumor drug.
The present invention also comprises the antitumor drug of the preparation take above-mentioned 9-methylol-10-miaow anthracene hydrazone as effective constituent.
Be 30%～70% by the synthetic productive rate that obtains 9-methylol-10-miaow anthracene hydrazone of aforesaid method.
Compared with prior art, the present invention is take the chemical structure of typical anthracycline anticancer drug as the basis, side substitution group by changing anthracene nucleus is (in the imidazoles hydrazone side chain that keeps similar bisantrene, increase methylol groups at the anthracene nucleus opposite side, water-soluble to improve it, reduce its liver renal toxicity), synthetic new anthracene nucleus antineoplastic active compound---the 9-methylol-10-miaow anthracene hydrazone that obtains.By investigating it to the proliferation inhibition activity of various human tumour cell, find that its anti tumor activity in vitro is remarkable, proliferation inhibition activity to certain tested tumor line wherein is remarkable, demonstrates good potential pharmaceutical use, is expected to the preparation for various antitumor drugs.
Description of drawings
Fig. 1 is the infrared spectra spectrogram of the final product that makes of the embodiment of the present invention 1;
Fig. 2 is the UV spectrum spectrogram of the final product that makes of the embodiment of the present invention 1;
Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram of the final product that makes of the embodiment of the present invention 1;
Fig. 4 is the carbon-13 nmr spectra figure of the final product that makes of the embodiment of the present invention 1
Fig. 5 is the electrospray ionization mass spectrum figure of the final product that makes of the embodiment of the present invention 1.
Embodiment
The invention will be further described with embodiment for the below, but the present invention is not limited to these embodiment.
Below the organic solvent, the alcoholic solvent that use in each embodiment all first use before use
Molecular sieve dehydration.
1) get 9 of 0.01mol, 4 of 10-anthracene dicarbaldehyde and 0.01mol, 5-dicyan imidazoles-2-hydrazine hydrogen bromide is dissolved in the dehydrated alcohol of 50mL, under 78 ℃ of conditions, back flow reaction is to (TLC follows the tracks of detection fully, about 3h), stopped reaction is cooled to room temperature with reaction solution, standing 1h, separate out orange solids, filter, the gained solid is vacuum-drying 10h under room temperature condition, obtain mix products, productive rate 55%;
2) product A is advanced silica gel column chromatography, using by volume ratio is the anhydrous methanol of 1:50 and the mixed solvent wash-out that methylene dichloride forms, and thin-layer chromatography is followed the tracks of and detected, and collects the elutriant that contains the purpose composition, and the gained elutriant is concentrated, dry, obtains the target intermediate;
3) getting the target intermediate of 0.01mol, is settled solution with 30mL anhydrous methanol heating for dissolving; Get the NaBH of 0.05mol
4, be dissolved as settled solution with the 10mL anhydrous methanol, slowly be added drop-wise in the methanol solution of target intermediate stirring at room 2h, add 80mL distilled water in reaction solution, then standing under 4 ℃ of conditions, separate out yellow solid, isolate solid, drying obtains yellow solid product, and productive rate is 70%.
To yellow solid product obtained above carry out respectively infrared spectra, UV spectrum,
1The H nuclear magnetic resonance spectrum,
13C nuclear magnetic resonance spectrum and electrospray ionization mass spectrum evaluation, as shown in Fig. 1,2,3,4 and 5, concrete Spectral Characteristic data are as follows respectively for their spectrogram:
Infrared spectra: (KBr, cm
-1) 3313.18 (ν
N-H), 3050 (ν
Ar-H), 1636.0(ν
C=N), 1577.52 (ν
C=C), 1053.53 (ν
C-N);
UV spectrum (H
2O): ε
max=2.01 * 10
4Lmol
-1Cm
-1(256nm);
Nuclear magnetic resonance spectrum (hydrogen spectrum):
1H NMR (500MHz, DMSO) δ 9.10 (s, 1H, CH=N), 8.55 (d, J=8.4Hz, 2H, Ar-H), 8.48 (d, J=8.5Hz, 2H, Ar-H), 7.63 – 7.48 (m, 4H, Ar-H), (6.65 s, 1H, CH2), 6.52 (s, 1H, CH2), 5.45 (s, 2H, NH), 3.42 (s, 4H, CH
2CH
2), 2.50 (s, 1H ,-OH);
Nuclear magnetic resonance spectrum (carbon spectrum):
13C NMR (125MHz, DMSO) δ 165.97,143.90,133.75,130.05,129.78,126.64,126.00,125.58,55.96,42.97,42.17.
The positive ion peak of electrospray ionization mass spectrum: m/z=319[M+H]
+.
Therefore, can determine that above-mentioned yellow solid product is 9-methylol-10-miaow anthracene hydrazone, molecular formula is C
19H
18N
4O, molecular weight are 318g/mol, and its chemical structural formula is as follows:
1) get 9 of 0.01mol, 4 of 10-anthracene dicarbaldehyde and 0.01mol, 5-dicyan imidazoles-2-hydrazine hydrogen bromide is dissolved in the anhydrous methanol of 100mL, under 70 ℃ of conditions, back flow reaction is to (TLC follows the tracks of detection fully, about 3h), stopped reaction is cooled to 20 ℃ with reaction solution, standing 2h, separate out orange solids, filter the vacuum-drying of gained solid, obtain product A, productive rate 65%;
2) product A is advanced silica gel column chromatography, using by volume ratio is the anhydrous methanol of 1:70 and the mixed solvent wash-out that chloroform forms, and thin-layer chromatography is followed the tracks of and detected, and collects the elutriant that contains the purpose composition, and the gained elutriant is concentrated, dry, obtains the target intermediate;
3) getting the target intermediate of 0.01mol, is settled solution with 20mL anhydrous methanol heating for dissolving; Get the NaBH of 0.02mol
4Be dissolved as settled solution with the 5mL anhydrous methanol, slowly be added drop-wise in the methanol solution of target intermediate, stirring at room 6h adds 200mL distilled water in reaction solution, then standing under 4 ℃ of conditions, separate out yellow solid, isolate solid, drying, obtain 9-methylol-10-miaow anthracene hydrazone, productive rate is 35%.
1) get 9 of 0.01mol, 4 of 10-anthracene dicarbaldehyde and 0.01mol, 5-dicyan imidazoles-2-hydrazine hydrogen bromide is dissolved in the dehydrated alcohol of 80mL, under 120 ℃ of conditions, back flow reaction is to (TLC follows the tracks of detection fully, about 3h), stopped reaction is cooled to 25 ℃ with reaction solution, standing 4h, separate out orange solids, filter the vacuum-drying of gained solid, obtain product A, productive rate 60%;
2) product A is advanced silica gel column chromatography, using by volume ratio is the anhydrous methanol of 1:100 and the mixed solvent wash-out that ethyl acetate forms, and thin-layer chromatography is followed the tracks of and detected, and collects the elutriant that contains the purpose composition, and the gained elutriant is concentrated, dry, obtains the target intermediate;
3) getting the target intermediate of 0.01mol, is settled solution with 30mL anhydrous methanol heating for dissolving; Get the NaBH of 0.015mol
4Be dissolved as settled solution with the 5mL anhydrous methanol, slowly be added drop-wise in the methanol solution of target intermediate, stirring at room 2h adds 80mL distilled water in reaction solution, then standing under 4 ℃ of conditions, separate out yellow solid, isolate solid, drying, obtain 9-methylol-10-miaow anthracene hydrazone, productive rate is 30%.
Embodiment 4
1) get 9 of 0.01mol, 4 of 10-anthracene dicarbaldehyde and 0.01mol, 5-dicyan imidazoles-2-hydrazine hydrogen bromide are dissolved in the mixing solutions (wherein the volume ratio of dehydrated alcohol and propyl carbinol is 4:1) that is comprised of dehydrated alcohol and propyl carbinol of 50mL, under 80 ℃ of conditions, back flow reaction is to (TLC follows the tracks of detection fully, about 4h), stopped reaction is cooled to 15 ℃ with reaction solution, standing 3h, separate out orange solids, filter the vacuum-drying of gained solid, obtain product A, productive rate 65%.
2) product A is advanced silica gel column chromatography, using by volume ratio is the anhydrous methanol of 1:50 and the mixed solvent wash-out that methylene dichloride forms, and thin-layer chromatography is followed the tracks of and detected, and collects the elutriant that contains the purpose composition, and the gained elutriant is concentrated, dry, obtains the target intermediate;
3) getting the target intermediate of 0.01mol, is settled solution with 30mL anhydrous methanol heating for dissolving; Get the NaBH of 0.1mol
4Be dissolved as settled solution with the 20mL anhydrous methanol, slowly be added drop-wise in the methanol solution of target intermediate, stirring at room 4h adds 50mL distilled water in reaction solution, then standing under 10 ℃ of conditions, separate out yellow solid, isolate solid, drying, obtain 9-methylol-10-miaow anthracene hydrazone, productive rate is 55%.
1) get 9 of 0.01mol, 4 of 10-anthracene dicarbaldehyde and 0.01mol, 5-dicyan imidazoles-2-hydrazine hydrogen bromide are dissolved in the mixing solutions (wherein the volume ratio of dehydrated alcohol and anhydrous methanol is 5:1) that is comprised of dehydrated alcohol and anhydrous methanol of 200mL, under 80 ℃ of conditions, back flow reaction is to (TLC follows the tracks of detection fully, about 6h), stopped reaction is cooled to 10 ℃ with reaction solution, standing 2h, separate out orange solids, filter the vacuum-drying of gained solid, obtain product A, productive rate 65%.
2) product A is advanced silica gel column chromatography, using by volume ratio is the anhydrous methanol of 1:20 and the mixed solvent wash-out that chloroform forms, and thin-layer chromatography is followed the tracks of and detected, and collects the elutriant that contains the purpose composition, and the gained elutriant is concentrated, dry, obtains the target intermediate;
3) getting the target intermediate of 0.01mol, is settled solution with 20mL anhydrous methanol heating for dissolving; Get the NaBH of 0.04mol
4Be dissolved as settled solution with the 10mL anhydrous methanol, slowly be added drop-wise in the methanol solution of target intermediate, stirring at room 12h adds 100mL distilled water in reaction solution, then standing under 20 ℃ of conditions, separate out yellow solid, isolate solid, drying, obtain 9-methylol-10-miaow anthracene hydrazone, productive rate is 60%.
In order to prove absolutely the 9-methylol of the present invention-purposes of 10-miaow anthracene hydrazone in pharmacy, the applicant has carried out the anti tumor activity in vitro experiment to 9-methylol-10-miaow anthracene hydrazone.
1, the cultivation of cell strain
Human liver cancer cell HepG2, human A549 cell lines are selected in this experiment, leukemia K 562 cell, human breast cancer cell MDA-MB-231,5 kinds of human tumor cell lines such as human osteosarcoma cell MG-63.The all cells strain is all cultivated in the RPMI-1640 that contains the little ox blood of 10wt%, 100U/mL penicillin, 100U/mL Streptomycin sulphate or DMEM nutrient solution, contains volumetric concentration 5%CO at 37 ℃
2Cultivate in incubator.Inverted microscope observation of cell growing state.
2. primary dcreening operation
Purity 〉=the 95%(of the compound 9-methylol that the present invention uses-10-miaow anthracene hydrazone is made by the embodiment of the present invention 1).Compound is mixed with 20 μ mol/L, and solubility promoter DMSO final concentration≤1% is tested the inhibition degree of compound to growth of tumour cell under this concentration.Every growth of tumour cell is produced obvious inhibition, and meet the suppressed metamorphosis of cell under light microscopic (as cell shrinkage, fragmentation, floating etc.), be judged to be primary dcreening operation effective.
3. cell growth inhibition test
With compound with the DMSO hydrotropy after, use perfect medium to be diluted to the working fluid that final concentration is 20 μ mol/L, then use the filtering with microporous membrane degerming of diameter d=0.22 μ m, be placed under 4 ℃ and preserve.the different tumor cell lines that will be in respectively logarithmic phase are inoculated in 96 orifice plates with every hole 190 μ L, cell density to 1000 to be measured～10000 holes (marginal pore is filled with aseptic PBS) were cultivated 12 hours, after cell attachment, add the test-compound working fluid, compound is parallel establishes 4 multiple holes, DMSO final concentration≤1% wherein, establish simultaneously corresponding negative control group and (only have cell and equivalent DMSO in nutrient solution, without compound) and the blank group (compound that only has equivalent in nutrient solution, acellular), each concentration gradient is parallel is provided with 4 multiple holes, 48 hours compound effects time.Cultivation finishes front 4 hours every holes and adds 10 μ L MTT(5mg/mL PBS, be 0.5%MTT), continue to cultivate after 4 hours, the residual culture in the hole of inclining, every hole adds DMSO150 μ L/ hole, dull and stereotyped oscillator vibration 5min, the zeroing of blank group, measure to remove absorbancy (A) value after the bias light absorption value with microplate reader with the 570nm/630nm dual wavelength, record inhibiting rate.According to inhibiting rate measured under different gradient concentrations, go out compound to the half growth inhibitory concentration value of different cell strains, i.e. IC by the Bliss computed in software
50Value.The active testing result as described in Table 1.
The IC of table 1.9-methylol-10-miaow anthracene hydrazone to different tumor cell lines
50Value (μ M)
From the anti tumor activity in vitro test result, 9-methylol-10-miaow anthracene hydrazone mostly has significant in-vitro multiplication for 5 kinds of tumor cell lines surveying and suppresses active, wherein, the inhibition activity of HepG2 cell lines, human breast cancer cell MDA-MB-231, human A549 cell lines all lower than 4 μ M, is demonstrated stronger activity; Inhibition activity to leukemia cell K562 is lower, approximately 20 μ M; Only have osteosarcoma cell line MG-63 without remarkable inhibiting rate.This shows, 9-methylol-10-miaow anthracene hydrazone not only has significant anti tumor activity in vitro, also shows certain selectivity.On the other hand, compare with clinical cancer therapy drug-cis-platinum, 9-methylol-10-miaow anthracene hydrazone in 3 kinds of tumour cells of contrast test, to the activity of HepG2 and A549 all higher than cis-platinum.
In sum, the anti tumor activity in vitro of compound involved in the present invention-9-methylol-10-miaow anthracene hydrazone is remarkable, and show the selectivity to the proliferation inhibition activity of different tumour cells, have the value of furtheing investigate exploitation as potential novel organic antitumor drug, be expected to the preparation for various antitumor drugs.
Claims (10)
1.9-methylol-10-miaow anthracene hydrazone, its structural formula is shown below:
2. the synthetic method of 9-methylol claimed in claim 1-10-miaow anthracene hydrazone, is characterized in that: take 9 of Isoequivalent weight, 10-anthracene dicarbaldehyde and 4,5-dicyan imidazoles-2-hydrazine hydrogen bromide, mixing is dissolved in organic solvent, carries out the aldimine condensation reaction, obtains mix products; Mix products carries out wash-out through silica gel column chromatography with methyl alcohol and the mixed solvent that is selected from a kind of composition in methylene dichloride, chloroform and ethyl acetate, and elutriant is concentrated, dry, obtains the target intermediate; Get target intermediate and sodium borohydride and carry out reduction reaction under the alcoholic solvent existence condition, add water in reaction solution, standing, separate out, isolate solid, namely obtain 9-methylol-10-miaow anthracene hydrazone.
3. the synthetic method of 9-methylol according to claim 2-10-miaow anthracene hydrazone is characterized in that: specifically comprise the following steps:
1) take 9 of Isoequivalent weight, 10-anthracene dicarbaldehyde and 4,5-dicyan imidazoles-2-hydrazine hydrogen bromide mixes and to be dissolved in organic solvent, and back flow reaction is to fully under 70～150 ℃ of conditions, and reaction solution is standing, separate out, and obtains mix products;
2) mix products is through silica gel column chromatography, carry out wash-out with anhydrous methanol and the mixed solvent that is selected from a kind of composition in methylene dichloride, chloroform and ethyl acetate, thin-layer chromatography is followed the tracks of and is detected, and collects the elutriant that contains the purpose composition, concentrated, dry, obtain the target intermediate;
3) getting target intermediate and sodium borohydride is dissolved in respectively in alcoholic solvent, under 0～30 ℃ of condition, the alcoholic solution of sodium borohydride is dripped in the alcoholic solution of target intermediate, stirring reaction is to complete, add water in reaction solution, standing, separate out, isolate solid, namely obtain 9-methylol-10-miaow anthracene hydrazone.
4. the synthetic method of 9-methylol according to claim 3-10-miaow anthracene hydrazone, it is characterized in that: in step 1), described organic solvent is dehydrated alcohol or anhydrous methanol, or the combination of dehydrated alcohol and anhydrous methanol or propyl carbinol.
5. the synthetic method of 9-methylol according to claim 3-10-miaow anthracene hydrazone, it is characterized in that: in step 1), the temperature of back flow reaction is 70～100 ℃.
6. the synthetic method of 9-methylol according to claim 3-10-miaow anthracene hydrazone, is characterized in that: step 2) in, for the mixed solvent of wash-out, the volume ratio of methyl alcohol and methylene dichloride or chloroform or ethyl acetate is 1:20～100.
7. the synthetic method of 9-methylol according to claim 3-10-miaow anthracene hydrazone, it is characterized in that: in step 3), the mol ratio of product B and sodium borohydride is 1:1.5～10.
8. the synthetic method of 9-methylol according to claim 3-10-miaow anthracene hydrazone, it is characterized in that: in step 3), described alcoholic solvent is dehydrated alcohol and/or anhydrous methanol.
9. the application of 9-methylol claimed in claim 1-10-miaow anthracene hydrazone in the preparation antitumor drug.
10. the antitumor drug for preparing take 9-methylol claimed in claim 1-10-miaow anthracene hydrazone as effective constituent.
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| CN107936044A (en) * | 2017-11-22 | 2018-04-20 | 广西师范大学 | It is a kind of using pyridyl ketone contracting thiocarbohydrazone as the copper complex and its synthetic method of ligand and application |
| CN110903307A (en) * | 2019-10-28 | 2020-03-24 | 广西师范大学 | Dinuclear metal complex with 9-aldehyde-10-mianthracene hydrazone as ligand and synthetic method and application thereof |
| CN110938035A (en) * | 2019-10-28 | 2020-03-31 | 广西师范大学 | 9-benzenesulfonic acid-10-mianthracene hydrazone and synthesis method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107936044A (en) * | 2017-11-22 | 2018-04-20 | 广西师范大学 | It is a kind of using pyridyl ketone contracting thiocarbohydrazone as the copper complex and its synthetic method of ligand and application |
| CN110903307A (en) * | 2019-10-28 | 2020-03-24 | 广西师范大学 | Dinuclear metal complex with 9-aldehyde-10-mianthracene hydrazone as ligand and synthetic method and application thereof |
| CN110938035A (en) * | 2019-10-28 | 2020-03-31 | 广西师范大学 | 9-benzenesulfonic acid-10-mianthracene hydrazone and synthesis method and application thereof |
| CN110950896A (en) * | 2019-10-28 | 2020-04-03 | 广西师范大学 | Copper (II) complex with 9-aldehyde-10-pyrimidinehydrazone as ligand and synthetic method and application thereof |
| EP3816157A1 (en) | 2019-10-28 | 2021-05-05 | Guangxi Normal University | 9-benzenesulfonic acid-10-imidazolylanthrahydrazone and synthesis method and application thereof |
| CN110950896B (en) * | 2019-10-28 | 2021-05-14 | 广西师范大学 | Copper (II) complex with 9-aldehyde-10-pyrimidinehydrazone as ligand and synthetic method and application thereof |
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