CN106083884A - A kind of D leucine ring substituent norcantharidin derivative and preparation method and application - Google Patents
A kind of D leucine ring substituent norcantharidin derivative and preparation method and application Download PDFInfo
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- CN106083884A CN106083884A CN201610545166.0A CN201610545166A CN106083884A CN 106083884 A CN106083884 A CN 106083884A CN 201610545166 A CN201610545166 A CN 201610545166A CN 106083884 A CN106083884 A CN 106083884A
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- ring substituent
- leucine
- substituent norcantharidin
- chromone
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- -1 leucine ring substituent norcantharidin derivative Chemical class 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- JAABVEXCGCXWRR-FBXFSONDSA-N rel-norcantharidin Chemical group C1C[C@H]2[C@@H]3C(=O)OC(=O)[C@@H]3[C@@H]1O2 JAABVEXCGCXWRR-FBXFSONDSA-N 0.000 claims abstract description 18
- 125000001424 substituent group Chemical group 0.000 claims abstract description 14
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 14
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 13
- OTAFHZMPRISVEM-UHFFFAOYSA-N chromone Chemical group C1=CC=C2C(=O)C=COC2=C1 OTAFHZMPRISVEM-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 6
- 241001597008 Nomeidae Species 0.000 claims abstract description 4
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- ROHFNLRQFUQHCH-RXMQYKEDSA-N D-leucine Chemical compound CC(C)C[C@@H](N)C(O)=O ROHFNLRQFUQHCH-RXMQYKEDSA-N 0.000 claims description 11
- 238000009835 boiling Methods 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 9
- XLVXXKZBDHWNMK-UHFFFAOYSA-N N-[(6-bromochromen-4-ylidene)amino]aniline Chemical compound C1(=CC=CC=C1)NN=C1C=COC2=CC=C(C=C12)Br XLVXXKZBDHWNMK-UHFFFAOYSA-N 0.000 claims description 8
- 239000002244 precipitate Substances 0.000 claims description 8
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 claims description 7
- 238000001556 precipitation Methods 0.000 claims description 7
- 208000035126 Facies Diseases 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 5
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 claims description 5
- 229940067157 phenylhydrazine Drugs 0.000 claims description 5
- XVNBWGGBXOJIDR-UHFFFAOYSA-N 6-bromochromen-4-one Chemical compound O1C=CC(=O)C2=CC(Br)=CC=C21 XVNBWGGBXOJIDR-UHFFFAOYSA-N 0.000 claims description 4
- 238000001514 detection method Methods 0.000 claims description 4
- 238000010790 dilution Methods 0.000 claims description 4
- 239000012895 dilution Substances 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000005698 Diels-Alder reaction Methods 0.000 claims description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 3
- 230000006837 decompression Effects 0.000 claims description 3
- 230000003292 diminished effect Effects 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 3
- 239000012153 distilled water Substances 0.000 claims description 3
- 239000002808 molecular sieve Substances 0.000 claims description 3
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 3
- 239000012265 solid product Substances 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
- 230000018044 dehydration Effects 0.000 claims description 2
- 238000006297 dehydration reaction Methods 0.000 claims description 2
- 238000011049 filling Methods 0.000 claims description 2
- 101100001669 Emericella variicolor andD gene Proteins 0.000 claims 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims 1
- 238000007259 addition reaction Methods 0.000 claims 1
- 238000001035 drying Methods 0.000 claims 1
- 238000001953 recrystallisation Methods 0.000 claims 1
- 238000005406 washing Methods 0.000 claims 1
- 230000001629 suppression Effects 0.000 abstract description 6
- 208000032839 leukemia Diseases 0.000 abstract description 5
- 210000004881 tumor cell Anatomy 0.000 abstract description 5
- 238000000034 method Methods 0.000 abstract description 4
- 150000003217 pyrazoles Chemical class 0.000 abstract description 4
- 125000003226 pyrazolyl group Chemical group 0.000 abstract description 4
- 230000003993 interaction Effects 0.000 abstract description 2
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 10
- 125000003196 D-leucino group Chemical group [H]OC(=O)[C@]([H])(N([H])[*])C([H])([H])C(C([H])([H])[H])([H])C([H])([H])[H] 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 206010028980 Neoplasm Diseases 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 229940125898 compound 5 Drugs 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 206010009944 Colon cancer Diseases 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 125000001309 chloro group Chemical class Cl* 0.000 description 2
- 150000004777 chromones Chemical class 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 230000008676 import Effects 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- HPPYHLAUVVJOLY-UHFFFAOYSA-N 2-bromochromen-4-one Chemical compound C1=CC=C2OC(Br)=CC(=O)C2=C1 HPPYHLAUVVJOLY-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
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- 238000012986 modification Methods 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
Abstract
The invention discloses oneD‑Leucine ring substituent norcantharidin derivative and preparation method and application, it is characterised in that: with 1,3 dipole-diople interaction methods existD‑C in leucine ring substituent norcantharidin structure5And C6Position introduces pyrazole ring, reacts importing chromone structure, the synthesis pyrazoles containing chromone structure with chromone derivativeD‑Leucine ring substituent norcantharidin derivative, this derivant has good inhibitory action for tumor cell line, wherein has more preferable suppression ratio and selectivity for leukaemia, preparing the aspects such as antitumor drug, has extraordinary prospects for commercial application.
Description
Technical field:
The invention belongs to pharmaceutical technology field, be specifically related to a kind of pyrazoles D-Leu containing chromone structure and replace
Norcantharidin derivative and preparation method and application.
Background technology:
D-Leu ring substituent norcantharidin, chemical structural formula is as follows:
D-Leu ring substituent norcantharidin R=(R)-CH2CH(CH3)2；
1,3-Dipolar Cycloaddition becomes synthesis five member ring heterocyclic compound with its good region and main selectivity
Topmost method, is also a class reaction more active in heterocyclic drug chemical research.In recent years, due to chromone widely
Biological activity, the most anticancer, antibacterial, suppression platelet aggregation etc. and receive much attention.So, either from pharmacology still from conjunction
Angled consideration, this heterocyclic compounds has the highest synthesis to be worth.
Summary of the invention:
A first aspect of the present invention purpose is to provide a kind of D-Leu ring substituent norcantharidin derivative.
The technical scheme that the present invention takes is as follows:
A kind of D-Leu ring substituent norcantharidin derivative, its structural formula is as follows:
In formula:。
This compound relevant experimental data is as follows:
Applicant it has been investigated that: introduce at D-Leu ring substituent norcantharidin and import on the basis of five yuan of pyrazole rings
The structure of chromone can change pharmacologically active.Determined by further experiment: use chromone derivative enterprising in the structure of pyrazoles
Row replaces, and D-Leu ring substituent norcantharidin is carried out structure of modification, and the structure pyrazoles D-Leu containing chromone of preparation takes
For norcantharidin derivative, there is extraordinary pharmaceutically active.
A second aspect of the present invention purpose is to provide the preparation method of a kind of D-Leu ring substituent norcantharidin derivative,
It is characterized in that, comprise the following steps:
(1), the synthesis of dehydronorcantharidiimide element:
Maleic anhydride is finely ground, add ether, under room temperature condition, stirring is to dissolving, and instills furan, is stirred at room temperature 24
～48 hours, furan and maleic anhydride occur Diels-Alder to react, and prepare dehydronorcantharidiimide element (compound 1)；
(2), the synthesis of D-Leu ring substituent norcantharidin:
Dehydronorcantharidiimide element 4.2 grams (25mmol) and D-Leu 3.28 grams (25mmol) are added and does through molecular sieve
In dry DMF solvent 15 milliliters, it is stirred at reflux 12 hours, after being cooled to room temperature, adds ethyl acetate 60 milliliters dilution, saturated chlorine
Changing ammonium salt solution to wash 6 times, each 30 milliliters, organic facies anhydrous magnesium sulfate is dried, and the organic facies decompression distillation after filtration is spin-dried for,
White solid product (compound 3) is obtained by re-crystallizing in ethyl acetate；
(3), the synthesis of 6-bromo chromone phenylhydrazone:
Use the method that 6-bromo chromone generates Schiff's base with phenylhydrazine dehydration, concrete operations: the phenylhydrazine taking 2mmol adds
Entering to fill in the flask of 10mL oxolane, boiling water bath return stirring, to dissolving, is then slowly added dropwise into 20mL dissolved with 2mmol6-
The ethanol solution of bromo chromone, continues boiling water bath return stirring 1h, drips 10 hydrochloric acid, have pale yellow precipitate to occur.Even
Continuous boiling water bath return stirring 5h, stops water-bath, adds the stirring of people's 20mL distilled water, and pale yellow precipitate darkens, and sucking filtration obtains yellow red
Color needle-like product.Rinse repeatedly with absolute ether, be vacuum dried to obtain product 6-bromo chromone phenylhydrazone (compound 4)；
(4), chromone structure is imported:
By 1mmol D-Leu ring substituent norcantharidin and 1.1mmol6-bromo chromone phenylhydrazone in 20mL ethanol, then
Adding 1.2mL toluene-sodium-sulfonchloramide, reflux 9 hours, after TLC detection reaction completes, obtain pale yellow precipitate, filtration under diminished pressure goes out precipitation, precipitation
By recrystallizing methanol, after vacuum drying, obtain product D-Leu ring substituent norcantharidin derivative (compound 5).
The reaction that the present invention relates to is as follows:
It is anti-swollen in preparation that a third aspect of the present invention purpose is to provide a kind of D-Leu ring substituent norcantharidin derivative
Application in terms of tumor medicine.Pass through experimental verification: above-claimed cpd, for different tumor strain such as human liver cancer cells, cancer cell of oral cavity,
Stomach cancer cell, ovarian cancer cell, leukaemia, colon-cancer cell etc., inhibited, wherein for HL60, (leukemia is thin
Born of the same parents) there is more preferably suppression ratio and selectivity, antitumor drug can be manufactured separately, can also resist swollen with other as active component
Tumor medicine prepares anti-tumor compositions, has extraordinary prospects for commercial application.
Beneficial effects of the present invention is as follows:
Applicant is found by research: import on the basis of D-Leu ring substituent norcantharidin introduces five yuan of pyrazole rings
The structure of chromone, the derivant of generation, there is good pharmaceutically active, through further experiment and analysis, the different heterocycle of research
Same a part is assembled and on affecting produced by pharmacologically active, goes in D-Leu replacement by 1,3-dipole-diople interaction method
C in norcantharidin structure5And C6Position introduces pyrazole ring, reacts importing chromone structure with chromone derivative, and synthesis is containing chromone structure
Pyrazoles D-Leu ring substituent norcantharidin derivative, this derivant is in terms of preparing antitumor drug, and it is the best to have
Prospects for commercial application.
Detailed description of the invention:
Below in conjunction with embodiment, the present invention is described further, but embodiment should not be construed as the model limiting the present invention
Enclose.
Embodiment 1:
(1), the synthesis of dehydronorcantharidiimide element:
Maleic anhydride is finely ground, add ether, under room temperature condition, stirring is to dissolving, and instills furan, is stirred at room temperature 24
～48 hours, furan and maleic anhydride occur Diels-Alder to react, and prepare dehydronorcantharidiimide element (compound 1)；
(2), the synthesis of D-Leu ring substituent norcantharidin:
Dehydronorcantharidiimide element 4.2 grams (25mmol) and D-Leu 3.28 grams (25mmol) are added and does through molecular sieve
In dry DMF solvent 15 milliliters, it is stirred at reflux 12 hours, after being cooled to room temperature, adds ethyl acetate 60 milliliters dilution, saturated chlorine
Changing ammonium salt solution to wash 6 times, each 30 milliliters, organic facies anhydrous magnesium sulfate is dried, and the organic facies decompression distillation after filtration is spin-dried for,
White solid product (compound 3) is obtained by re-crystallizing in ethyl acetate；
(3), the synthesis of 6-bromo chromone phenylhydrazone:
The phenylhydrazine taking 2mmol adds in the flask filling 10mL oxolane, and boiling water bath return stirring, to dissolving, then delays
Slowly it is added dropwise to the 20mL ethanol solution dissolved with 2mmol 6-bromo chromone, continues boiling water bath return stirring 1h, drip 10
Hydrochloric acid, has pale yellow precipitate to occur.Boiling water bath return stirring 5h continuously, stops water-bath, adds the stirring of people's 20mL distilled water, faint yellow
Precipitation darkens, and sucking filtration obtains yellowish red color needle-like product.Rinse repeatedly with absolute ether, be vacuum dried to obtain product 6-bromo chromone
Phenylhydrazone (compound 4).
(4), chromone structure is imported:
By 1mmol D-Leu ring substituent norcantharidin and 1.1mmol6-bromo chromone phenylhydrazone in 20mL ethanol, then
Adding 1.2mL toluene-sodium-sulfonchloramide, reflux 9 hours, after TLC detection reaction completes, obtain pale yellow precipitate, filtration under diminished pressure goes out precipitation, precipitation
By recrystallizing methanol, after vacuum drying, obtain product (compound 5).
Compound 5 title: D-Leu ring substituent norcantharidin derivative；
Chemical formula: C30H25BrN3O7；
Physico-chemical parameter: yellow crystal, productivity 57.6%, m.p.128-130 DEG C；
Structural confirmation:
1H NMR(CD3OD) δ: 7.34-7.18 (m, 8H, Ar-H), 6.47 (s, 1H, C=C-H), 5.16 (d, J=
9.60Hz, 1H, H5), 4.74 (d, J=17.60Hz, 1H, H4), 4.56 (d, J=17.60Hz, 1H, H1), 4.02 (d, J=
9.60Hz, 1H, H6), 3.43 (d, J=7.20Hz, 1H, H3), 3.30 (d, J=7.20Hz, 1H, H2), 2.00-2.07 (m, 1H,
CH),1.30-1.35(m,1H,H1of CH2),1.58-1.70(m,1H,H2of CH2), 0.75-0.79 (dd, 6H, J=
2.4Hz,6.8Hz,2CH3)；
IR 3415 (N-C=O), 3085 (ArH), 1700 (C=O), 1541 (C=N), 1309 (C-O-C) cm-1；
M/e:618 (100.0%), 620 (97.5%)；
Anal.calcd.for C30H25BrN3O7: C, 58.19；H,4.07；N,6.75.
Application Example: use mtt assay detection test-compound to different tumor strains anti-tumor activity.
Compound (5) prepared by above-described embodiment, respectively with different tumor strains (tumor cell Bel-7402, KB,
SGC7901, HO8901, HL-60, ECA109) it is experimental subject, test compound (5) is made for the vitro inhibition of different tumor strains
With: experiment uses tetramethyl azo azoles salt trace enzyme reaction colorimetry (mtt assay), and activity half-inhibition concentration represents (IC50)。
Specific experiment step is as follows:
By compound 5 with DMSO dissolve, dilution, tumor cell Bel-7402 (human liver cancer cell), KB (cancer cell of oral cavity),
SGC7901 (stomach cancer cell), HO8901 (ovarian cancer cell), HL-60 (leukaemia), ECA109 (colon-cancer cell) are in 96 holes
Planting into 4000/200 μ L/ holes on plate, every hole adds compound 2 μ L, final concentration of 12.0 μMs, 6.0 μMs, 3.0 μMs, 1.5 μMs, is total to
It is same as 37 DEG C, 5%CO2Cell culture incubator is hatched 72 hours, with DMSO (1%) as blank.After 72 hours, add the denseest
Degree is the MTT of 0.25mg/mL, is placed in 37 DEG C, 5%CO2In cell culture incubator 4 hours, blotting solvent afterwards, every hole adds 100 μ
L DMSO, measures absorbance (OD value) with enzyme linked immunological instrument at 570nm, and the data obtained is used for calculating IC50Value.Variable concentrations
Test-compound carries out scalping with 96 orifice plates, according to the suppression ratio of gained, calculates IC50Value, result see table.
Table 1, the D-Leu ring substituent norcantharidin derivative IC to six kinds of tumor cell lines50Value.
By upper table data it can be seen that the compound prepared of the present invention, for various tumor cell strains, there is suppression and make
With, wherein for HL60 (leukaemia), there is more preferable suppression ratio and selectivity, antitumor drug, also can be manufactured separately
Anti-tumor compositions can be prepared as active component and other antitumor drug, there is extraordinary prospects for commercial application.
Claims (4)
1. one kindD -Leucine ring substituent norcantharidin derivative, its structural formula is as follows:
In formula:。
2. one kindD -The preparation method of leucine ring substituent norcantharidin derivative, it is characterised in that comprise the following steps: will
Maleic anhydride and ether be synthesized dehydronorcantharidiimide element, dehydronorcantharidiimide element andD -Leucine is synthesizedD -
Leucine ring substituent norcantharidin, then uses 6-bromo chromone and phenylhydrazine dehydration to synthesize 6-bromo chromone phenylhydrazone, finally
WillD -Leucine ring substituent norcantharidin and 6-bromo chromone phenylhydrazone carry out dipolar addition reaction, synthesisD -Leucine replacement is gone
Norcantharidin derivant.
One the most according to claim 2D -The preparation method of leucine ring substituent norcantharidin derivative, its feature exists
In, comprise the following steps:
(1), the synthesis of dehydronorcantharidiimide element:
Maleic anhydride is finely ground, add ether, under room temperature condition, stirring is to dissolving, and instills furan, is stirred at room temperature 24 ~ 48 little
Time, furan and maleic anhydride occur Diels-Alder to react, prepare dehydronorcantharidiimide element；
(2),D -The synthesis of leucine ring substituent norcantharidin:
By dehydronorcantharidiimide element 4.2 grams andD -Leucine 3.28 grams adds the DMF solvent 15 milliliters through molecular sieve drying
In, it is stirred at reflux 12 hours, is cooled to after room temperature add ethyl acetate 60 milliliters dilution, saturated ammonium chloride solution washing 6 times, often
Secondary 30 milliliters, organic facies anhydrous magnesium sulfate is dried, and the organic facies decompression distillation after filtration is spin-dried for, and obtains by re-crystallizing in ethyl acetate
White solid product；
(3), the synthesis of 6-bromo chromone phenylhydrazone:
The phenylhydrazine taking 2mmol adds in the flask filling 10mL oxolane, and boiling water bath return stirring, to dissolving, the most slowly drips
Add the 20mL ethanol solution dissolved with 2mmol 6-bromo chromone, continue boiling water bath return stirring 1h, drip 10 hydrochloric acid,
Pale yellow precipitate is had to occur；Boiling water bath return stirring 5h continuously, stops water-bath, adds the stirring of people's 20mL distilled water, pale yellow precipitate
Darkening, sucking filtration obtains yellowish red color needle-like product；Rinse repeatedly with absolute ether, be vacuum dried to obtain product 6-bromo chromone benzene
Hydrazone；
(4), chromone structure is imported:
By 1mmolD -Leucine ring substituent norcantharidin and 1.1mmol6-bromo chromone phenylhydrazone, in 20mL ethanol, add
1.2mL toluene-sodium-sulfonchloramide, refluxes 9 hours, after TLC detection reaction completes, obtains pale yellow precipitate, and filtration under diminished pressure goes out precipitation, precipitation first
Alcohol recrystallization, obtains product after vacuum dryingD -Leucine ring substituent norcantharidin derivative.
4. one kindD -The application in terms of preparing antitumor drug of the leucine ring substituent norcantharidin derivative.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610545166.0A CN106083884B (en) | 2016-07-06 | 2016-07-06 | A kind of D-Leu ring substituent norcantharidin derivative and the preparation method and application thereof |
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| CN201610545166.0A CN106083884B (en) | 2016-07-06 | 2016-07-06 | A kind of D-Leu ring substituent norcantharidin derivative and the preparation method and application thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107602578A (en) * | 2017-11-07 | 2018-01-19 | 绍兴文理学院 | A kind of preparation method and applications of the D valine ring substituent norcantharidin derivatives of the structure containing pyridazinone |
| CN107722029A (en) * | 2017-11-07 | 2018-02-23 | 绍兴文理学院 | A kind of preparation method and applications of the D leucine ring substituent norcantharidin derivatives of the structure containing pyridazinone |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107602578A (en) * | 2017-11-07 | 2018-01-19 | 绍兴文理学院 | A kind of preparation method and applications of the D valine ring substituent norcantharidin derivatives of the structure containing pyridazinone |
| CN107722029A (en) * | 2017-11-07 | 2018-02-23 | 绍兴文理学院 | A kind of preparation method and applications of the D leucine ring substituent norcantharidin derivatives of the structure containing pyridazinone |
| CN107602578B (en) * | 2017-11-07 | 2019-07-16 | 绍兴文理学院 | A kind of preparation method and applications of the D-Val ring substituent norcantharidin derivative of the structure containing pyridazinone |
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| CN106083884B (en) | 2018-07-17 |
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