CN114409725B - Oleanolic acid A ring derivative with anti-tumor activity and preparation method thereof - Google Patents
Oleanolic acid A ring derivative with anti-tumor activity and preparation method thereof Download PDFInfo
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- MIJYXULNPSFWEK-GTOFXWBISA-N 3beta-hydroxyolean-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C MIJYXULNPSFWEK-GTOFXWBISA-N 0.000 title claims abstract description 63
- JKLISIRFYWXLQG-UHFFFAOYSA-N Epioleonolsaeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4CCC3C21C JKLISIRFYWXLQG-UHFFFAOYSA-N 0.000 title claims abstract description 58
- YBRJHZPWOMJYKQ-UHFFFAOYSA-N Oleanolic acid Natural products CC1(C)CC2C3=CCC4C5(C)CCC(O)C(C)(C)C5CCC4(C)C3(C)CCC2(C1)C(=O)O YBRJHZPWOMJYKQ-UHFFFAOYSA-N 0.000 title claims abstract description 58
- MIJYXULNPSFWEK-UHFFFAOYSA-N Oleanolinsaeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4=CCC3C21C MIJYXULNPSFWEK-UHFFFAOYSA-N 0.000 title claims abstract description 58
- 229940100243 oleanolic acid Drugs 0.000 title claims abstract description 58
- HZLWUYJLOIAQFC-UHFFFAOYSA-N prosapogenin PS-A Natural products C12CC(C)(C)CCC2(C(O)=O)CCC(C2(CCC3C4(C)C)C)(C)C1=CCC2C3(C)CCC4OC1OCC(O)C(O)C1O HZLWUYJLOIAQFC-UHFFFAOYSA-N 0.000 title claims abstract description 58
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 69
- 238000001035 drying Methods 0.000 claims description 18
- 238000001914 filtration Methods 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- 239000012044 organic layer Substances 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- 239000012043 crude product Substances 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 239000003208 petroleum Substances 0.000 claims description 8
- 238000010898 silica gel chromatography Methods 0.000 claims description 8
- 239000003810 Jones reagent Substances 0.000 claims description 7
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 7
- 238000011068 loading method Methods 0.000 claims description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical group C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 4
- 150000003216 pyrazines Chemical group 0.000 claims description 4
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- 238000010790 dilution Methods 0.000 claims description 2
- 239000012895 dilution Substances 0.000 claims description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 2
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 2
- 238000010791 quenching Methods 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims 5
- 238000005406 washing Methods 0.000 claims 5
- 238000007865 diluting Methods 0.000 claims 4
- 238000012544 monitoring process Methods 0.000 claims 4
- 239000011591 potassium Substances 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 230000000171 quenching effect Effects 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 27
- 230000005764 inhibitory process Effects 0.000 abstract description 16
- 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 7
- 208000005718 Stomach Neoplasms Diseases 0.000 abstract description 7
- 206010017758 gastric cancer Diseases 0.000 abstract description 7
- 201000005202 lung cancer Diseases 0.000 abstract description 7
- 208000020816 lung neoplasm Diseases 0.000 abstract description 7
- 201000011549 stomach cancer Diseases 0.000 abstract description 7
- 208000003445 Mouth Neoplasms Diseases 0.000 abstract description 5
- 201000007270 liver cancer Diseases 0.000 abstract description 5
- 208000014018 liver neoplasm Diseases 0.000 abstract description 5
- 230000009982 effect on human Effects 0.000 abstract description 4
- 206010061523 Lip and/or oral cavity cancer Diseases 0.000 abstract description 2
- 238000002474 experimental method Methods 0.000 abstract description 2
- 229930014626 natural product Natural products 0.000 abstract description 2
- 230000000144 pharmacologic effect Effects 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 14
- 125000003373 pyrazinyl group Chemical group 0.000 description 14
- 230000000694 effects Effects 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- 238000004809 thin layer chromatography Methods 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 9
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 8
- 125000000955 oleanolic acid group Chemical group 0.000 description 8
- 150000001408 amides Chemical class 0.000 description 7
- 239000013641 positive control Substances 0.000 description 7
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 6
- 150000001350 alkyl halides Chemical class 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 5
- 125000002883 imidazolyl group Chemical group 0.000 description 5
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 4
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 4
- 229960004679 doxorubicin Drugs 0.000 description 4
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 4
- 229960002584 gefitinib Drugs 0.000 description 4
- 230000005918 in vitro anti-tumor Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 3
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 231100000283 hepatitis Toxicity 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- AOHJOMMDDJHIJH-UHFFFAOYSA-N propylenediamine Chemical compound CC(N)CN AOHJOMMDDJHIJH-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- -1 triterpene compound Chemical class 0.000 description 2
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 description 1
- ACMJJQYSPUPMPN-UHFFFAOYSA-N 4-chloro-3-fluoroaniline Chemical compound NC1=CC=C(Cl)C(F)=C1 ACMJJQYSPUPMPN-UHFFFAOYSA-N 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241000830535 Ligustrum lucidum Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- QYSXFLDJHDDOLS-UHFFFAOYSA-N methyl acetate;sulfuric acid Chemical compound COC(C)=O.OS(O)(=O)=O QYSXFLDJHDDOLS-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 150000003648 triterpenes Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0036—Nitrogen-containing hetero ring
- C07J71/0042—Nitrogen only
- C07J71/0047—Nitrogen only at position 2(3)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
An oleanolic acid A ring derivative with anti-tumor activity and a preparation method thereof relate to a structure-modified product of natural product oleanolic acid and a preparation method thereof. Pharmacological experiments prove that the synthesized oleanolic acid derivative has stronger inhibition effect on human gastric cancer cells (SGC-7901), human lung cancer cells (A549), liver cancer cells (HepG 2) and human mouth cancer cells (KB) and is superior to the parent compound oleanolic acid. The oleanolic acid derivatives include the following four classes:
Description
Technical Field
The invention relates to a natural oleanolic acid structure modifier and a preparation method thereof, in particular to an oleanolic acid A ring derivative with anti-tumor activity and a preparation method thereof.
Background
Oleanolic Acid (OA), also known as celebrating tetralin, is an oleanane-type pentacyclic triterpene compound, widely distributed in the plant kingdom, such as in the form of free form or in the form of glycoside combined with sugar in plants such as green She Danquan grass and glossy privet fruit. Studies have shown that oleanolic acid has a variety of biological activities, such as: reducing blood glucose, reducing blood lipid, resisting tumor, diminishing inflammation, inhibiting platelet aggregation, etc. The traditional Chinese medicine composition is an ideal medicine for treating hepatitis clinically, has low toxicity and small side effect, and is applied to the adjuvant therapy of hepatitis.
The chemical structural formula of oleanolic acid is:
disclosure of Invention
The invention aims to provide an oleanolic acid A ring derivative with anti-tumor activity and a preparation method thereof, wherein oleanolic acid is used as a lead compound to design and synthesize a series of oleanolic acid A ring derivatives with anti-tumor activity, and the compounds have stronger inhibition activity on human gastric cancer cells (SGC-7901), human lung cancer cells (A549), liver cancer cells (HepG 2) and oral cancer cells (KB).
The invention aims at realizing the following technical scheme:
the oleanolic acid A ring derivative with antitumor activity is structurally modified by aligning the oleanolic acid A ring and the C-28 carboxyl to obtain the C-28 carboxylic ester or amide oleanolic acid derivative of the oleanolic acid A ring, substituted pyrazine ring, imidazole ring and hydrogenated pyrazine ring respectively. The oleanolic acid derivatives include the following four classes:
1) Modification is carried out on the basis of the oleanolic acid structure, the A ring is combined with the pyrazine ring, and simultaneously the C-28 carboxyl reacts with the haloalkane or amine to generate ester or amide, so as to obtain a series of compounds. The structure is shown in the following table:
2) Modification is carried out on the basis of the oleanolic acid structure, the A ring is combined to replace the pyrazine ring, and simultaneously the C-28 carboxyl reacts with amine to generate amide, so as to obtain a series of compounds. The structure is shown in the following table:
3) Modification is carried out on the basis of the oleanolic acid structure, the A ring is combined with the imidazole ring, and simultaneously the C-28 carboxyl reacts with the haloalkane to generate ester, thus obtaining a series of compounds. The structure is shown in the following table:
4) Modification is carried out on the basis of the oleanolic acid structure, the A ring is combined with the hydrogenated pyrazine ring, and simultaneously the C-28 carboxyl reacts with amine to generate amide, so as to obtain a series of compounds. The structure is shown in the following table:
a method for preparing an oleanolic acid a-ring derivative having an antitumor activity, the method comprising the steps of:
(1) The hydroxyl group at the C-3 position of oleanolic acid is oxidized by Jones reagent to produce 3-carbonyl oleanolic acid (OA-1).
(2) OA-1 reacts with potassium t-butoxide to oxidize the methyl group at the C-2 position to a carbonyl group to produce 2, 3-dicarbonyl-oleanane-12-ene-28-carboxylic acid (OA-2).
(3) OA-2 is reacted with ethylenediamine to form a hydrogenated pyrazine ring by ring A, which yields 2, 3-and hydrogenated pyrazine ring-oleanane-12-ene-28-carboxylic acid (OA-3).
(4) The OA-3 is dehydrogenated to a pyrazine ring under the action of potassium hydroxide to produce 2, 3-naphthyridine ring-oleanane-12-alkene-28-carboxylic acid (OA-4).
(5) OA-4 reacts with corresponding haloalkane under the alkaline condition of potassium carbonate to generate 2, 3-naphthyridine ring-oleanane-12-alkene-28-carboxylic ester target compound I 1 ~Ⅰ 2 。
(6) After the OA-4 reacts with oxalyl chloride, the reaction is further carried out with corresponding amine to generate the 2, 3-naphthyridine ring-oleanane-12-alkene-28-amide target compound I 3 ~Ⅰ 7 。
(7) OA-2 is reacted with 1, 2-propanediamine to synthesize a pyrazine ring from the A ring to yield 5' -methyl-olean-2-eno [2,3-b ] pyrazin-12-ene-28-carboxylic acid (OA-5).
(8) After the OA-5 is reacted with oxalyl chloride, the reaction is further carried out with corresponding amine to generate 5' -methyl-olean-2-olefine [2,3-b ]]Pyrazine-12-ene-28-amide-type target compounds II 1 ~Ⅱ 5 。
(9) According to the method of (5), OA-1 is reacted with a corresponding haloalkane to produce 3-carbonyl-olean-12-ene-28-carboxylate compounds (OA-6-1 to OA-6-5).
(10) OA-6-1 to OA-6-5 react with hydrazine hydrate to generate 2-hydrazone-olean-12 alkene-28-carboxylic acid ester compounds (OA-7-1 to OA-7-5).
(11) Heating and refluxing OA-7-1-OA-7-5 and formic acid respectively, and cyclizing the ring A into an imidazole ring to generate olean-2-olefine [2,3-b ]]Imidazole-12-ene-28-carboxylic acid ester target compound III 1 ~Ⅲ 5 。
(12) After reacting OA-1 with oxalyl chloride, further reacting with corresponding amine to generate 3-carbonyl-12-alkene-oleanane-28-amide compounds (OA-8-1-OA-8-5).
(13) OA-8-1 to OA-8-5 react with m-chloroperoxybenzoic acid to generate 2-hydroxy-3-carbonyl-olean-12-ene-28-amide compounds (OA-9-1 to OA-9-5).
(14) OA-9-1 to OA-9-5 according to the method of (1), 2, 3-dicarbonyl-olean-12-en-28-amide compounds (OA-10-1 to OA-10-5) are produced.
(15) OA-10-1-OA-10-5 are respectively reacted with ethylenediamine to synthesize a hydrogenated pyrazine ring by the ring A, and 2, 3-and hydrogenated pyrazine ring-oleanane-12-alkene-28-amide target compound IV is generated 1 ~Ⅳ 5 。
The invention has the advantages and effects that:
the invention carries out chemical modification and reconstruction on the oleanolic acid structure of the pentacyclic triterpene natural product to obtain a series of oleanolic acid structure derivatives. Pharmacological experiments prove that the compound has stronger inhibition effect on human gastric cancer cells (SGC-7901), human lung cancer cells (A549), liver cancer cells (HepG 2) and human oral cancer cells (KB) respectively, and is superior to oleanolic acid as a parent compound.
Detailed description of the preferred embodiments
The present invention will be described in further detail with reference to examples.
1) The C-3 hydroxyl of oleanolic acid is oxidized by Jones reagent to generate 3-carbonyl-oleanane-12-alkene-28-carboxylic acid (OA-1), the 3-carbonyl-oleanane-12-alkene-28-carboxylic acid (OA-2) is oxidized to carbonyl by reaction with potassium tert-butoxide in tert-butyl alcohol to generate 2, 3-dicarbonyl-oleanane-12-alkene-28-carboxylic acid (OA-2), the intermediate (OA-2) is reacted with ethylenediamine and potassium hydroxide to synthesize a pyrazine ring by reaction of A ring, and finally the carboxyl at C-28 position is reacted with corresponding alkyl halide or amine to form ester or amide to obtain 2, 3-oleanane-12-alkene-28-carboxylic acid ester compound I 1 ~Ⅰ 2 And 5 2, 3-oleanane-12-ene-28-carboxamide compounds I 3 ~Ⅰ 7 。
Wherein: r is R 1 is-O (CH) 2 ) 3 CH 3 、-O(CH 2 ) 5 CH 3 、、/>、/>、、/>。
2) OA-2 reacts with 1, 2-propylene diamine to synthesize a ring A into substituted pyrazine ring to generate 5' -methyl-olean-2-olefine [2,3-b ]]Pyrazine-12-ene-28-carboxylic acid (OA-5), reaction of intermediate (OA-5) with oxalyl chloride and further reaction with the corresponding amine to amide the C-28-carboxyl group gives 5-5' -methyl-olean-2-eno [2,3-b ]]Pyrazine-12-ene-28-amides II 1 ~Ⅱ 5 。
Wherein: r is R 2 Is that、/>、/>、/>、/>。
3) Reacting OA-1 with corresponding haloalkane and potassium carbonate under alkaline condition to obtain 3-carbonyl-olean-12-ene-28-carboxylate compound (OA-6), further reacting with hydrazine hydrate to obtain 2-hydrazone-olean-12-ene-28-carboxylate compound (OA-7), heating and refluxing the intermediate (OA-7) with formic acid to make ring A be cyclized into imidazole ring to obtain 5 olean-2-ene [2,3-b ]]Imidazole-12-ene-28-carboxylic acid ester compound III 1 ~Ⅲ 5 。
Wherein: r is R 3 is-CH 2 CH 3 、-(CH 2 ) 2 CH 3 、-(CH 2 ) 3 CH 3 、-(CH 2 ) 3 CH 3 、-(CH 2 ) 5 CH 3 。
4) OA-1 reacts with oxalyl chloride, 3-carbonyl-12-alkene-oleanane-28-amide compound (OA-8) is generated by further reacting with corresponding amine, intermediate (OA-8) reacts with m-chloroperoxybenzoic acid to generate 2-hydroxy-3-carbonyl-oleanane-12-alkene-28-amide compound (OA-9), intermediate (OA-9) reacts with Jones reagent, C-2-hydroxy is oxidized into carbonyl to obtain 2, 3-dicarbonyl-oleanane-12-alkene-28-amide compound (OA-10), intermediate (OA-10) reacts with ethylenediamine to obtain 5 2, 3-and hydrogenated pyrazine ring-oleanane-12-alkene-28-amide target compounds IV 1 ~Ⅳ 5 。
Wherein: r is R 4 Is that、/>、/>、/>、-C 4 H 9 。
Gefitinib and etoposide are used as positive controls, and MTT method is adopted to align oleanolic acid and I compound synthesized by the oleanolic acid for preliminary in vitro anti-tumor activity test. Studies show that part of the compounds have strong inhibition effects on human gastric cancer cells (SGC-7901) and human lung cancer cells (A549) and are stronger than oleanolic acid precursors. The structure of the compound and the results of in vitro experiments are shown in the following table:
note that: a. the concentration of the compound is 10 -5 Inhibition measured at mol/L; IC (Integrated Circuit) 50 Representing half the effective inhibitory concentration.
The method takes human gastric cancer cells (SGC-7901) and human lung cancer cells (A549) as target cells, adopts an MTT method to perform preliminary in-vitro anti-tumor activity test on the synthesized oleanolic acid derivatives, and the results show that the oleanolic acid derivatives have stronger inhibition effect on SGC-7901 cells and A549 cells and are superior to the oleanolic acid as a parent compound. Wherein I is 5 And II 1 The inhibition effect on SGC-7901 and A549 cells is stronger than that of positive control medicines gefitinib and etoposide, and the positive control medicines are expressedThe inhibition effect is stronger, which shows that the anti-tumor activity of the oleanolic acid can be obviously improved by introducing the oleanolic acid A ring into the pyrazine ring and simultaneously forming the ester or the amide by the C-28 carboxyl.
Gefitinib and doxorubicin are used as positive controls, and MTT method is adopted to align oleanolic acid and synthesized class II and class III compounds for preliminary in vitro anti-tumor activity detection. Research shows that the synthesized compound has strong inhibition effect on human gastric cancer cells (SGC-7901) and human liver cancer cells (HepG 2), and the structure of the compound and the in vitro experimental results are shown in the following table:
note that: a. the concentration of the compound is 10 -5 Inhibition measured at mol/L; IC (Integrated Circuit) 50 Representing half the effective inhibitory concentration.
The method takes human gastric cancer cells (SGC-7901) and human liver cancer cells (HepG 2) as target cells, adopts an MTT method to perform preliminary biological activity test on the synthesized oleanolic acid derivatives, and results show that the oleanolic acid derivatives have stronger inhibition effect on SGC-7901 cells and HepG2 cells and are superior to the oleanolic acid of parent compounds. Wherein II 5 And III 4 The inhibition effect on SGC-7901 and HepG2 cells is stronger than that of positive control medicines gefitinib and doxorubicin, and the effect is stronger, which shows that the oleanolic acid A ring is introduced into substituted pyrazine ring and imidazole ring, and simultaneously, the C-28 carboxyl is formed into ester or amide, so that the anti-tumor activity of oleanolic acid can be obviously improved.
Taking 5-fluorouracil and doxorubicin as positive control, adopting MTT method to align oleanolic acid and IV compound synthesized by the oleanolic acid to perform preliminary in vitro anti-tumor activity detection. The research shows that the synthesized compound has stronger inhibition effect on human lung cancer cells (A549) and human mouth cancer cells (KB), and the structure of the compound and the in vitro experimental results are shown in the following table:
note that: a. the concentration of the compound is 10 -5 Inhibition measured at mol/L; IC (Integrated Circuit) 50 Representing half the effective inhibitory concentration.
The method takes human lung cancer cells (A549) and human oral cancer cells (KB) as target cells, adopts an MTT method to carry out preliminary biological activity test on the synthesized oleanolic acid derivatives, and results show that the oleanolic acid derivatives have stronger inhibition effect on the A549 cells and the KB cells and are superior to the oleanolic acid as parent compound. Wherein IV 3 The inhibition effect on A549 cells and KB cells is stronger than that of the positive control medicaments 5-fluorouracil and doxorubicin, and the effect is stronger, which shows that the anti-tumor activity of oleanolic acid can be obviously improved by introducing the oleanolic acid A ring into the hydrogenated pyrazine ring and amide-forming the C-28 carboxyl.
The invention is further illustrated by the following examples:
example 1
2, 3-Pyrazino-oleanane-12-ene-28-carboxylic acid ethyl ester (I) 1 ) Is prepared from
OA (0.50 g,0.001 mol) was dissolved in 10mL of acetone, jones reagent (25 drops) was slowly added dropwise under ice bath, the temperature was raised to room temperature for further reaction for 1.5 h, TLC monitored the end of the reaction, and the reaction was quenched by addition of 15mL isopropanol. Ethyl acetate was added to dilute the mixture, and the organic layers (100 mL. Times.3) were washed with saturated brine and combined. Anhydrous Na 2 SO 4 Drying, filtering, recovering solvent under reduced pressure, and recrystallizing and purifying crude product with methanol to obtain white powdery solid OA-1.
Intermediate OA-1 (0.500 g,0.001 mmol) was dissolved in 15mL t-butanol, potassium t-butoxide 0.25g was added and ethyl formate 2.5mL,50 was slowly added dropwise o C heating in water bath for 5hTLC monitored the end point of the reaction. Ethyl acetate was added to dilute the mixture, and the organic layers (100 mL. Times.3) were washed with saturated brine and combined. Anhydrous MgSO 4 Drying, filtering and decompressing to recycle the solvent to obtain the light yellow solid OA-2.
Intermediate OA-2 (0.5 g,0.001 mol) was dissolved in ethanol 5mL, magnesium sulfate 0.7g was added, ethylenediamine-ethanol solution (1 drop ethylenediamine) was slowly added dropwise, the reaction was carried out at room temperature for 6h, TLC monitored the end of the reaction, ethyl acetate was added for dilution, and the organic layers were washed with saturated brine (100 mL. Times.3) and the organic phases were combined. Anhydrous MgSO 4 Drying, filtering and decompressing to recover the solvent to obtain the light yellow oily matter OA-3.
Intermediate OA-3 (0.50 g,0.001 mol) was dissolved in 20mL of absolute ethanol, potassium hydroxide (0.07 g,0.001 mol) and manganese dioxide (0.26 g, 0.003mol) 80 were added o C water bath reflux for 8 h, tlc monitored the end point of the reaction. Ethyl acetate was added to dilute the mixture, and the organic layers (100 mL. Times.3) were washed with saturated brine and combined. Anhydrous MgSO 4 Drying, filtering and decompressing to recover the solvent to obtain yellow oily OA-4.
Intermediate OA-4 (0.50 g,0.001 mmol) was dissolved in 12mL of N, N-dimethylformamide, 12 drops (0.005 mol) of bromoethane, anhydrous potassium carbonate (0.30 g, 0.002mol) were slowly added dropwise, the reaction was continued for 5h at room temperature, and TLC monitored the end of the reaction. Ethyl acetate was added to dilute the mixture, and the organic layers (100 mL. Times.3) were washed with saturated brine and combined. Anhydrous Na 2 SO 4 Drying, filtering, recovering solvent under reduced pressure, loading the crude product on a dry column, purifying by silica gel column chromatography, eluting with petroleum ether/ethyl acetate=15/1 (V/V), to obtain white powdery solid with yield 43.20%. mp 134.3-138.1 ℃. ESI-MS 518.3 (M+H) +;1H-NMR (CDCl 3,300 MHz) delta 8.27,8.41 (m, 2H, NCHCHN), 2.87 (m, 1H, H-3), 5.29-5.38 (m, 1H, H-12), 2.50 (t, J=7.0 Hz, 1H, H-18), 4.12 (m, 2H, COOCH2CH 3), 1.93 (t, J=11.7 Hz, 3H, COOCH2CH 3), 1.76, 1.68, 1.47 (s, 9H, CH 3X 3), 1.20, 1.12 (s, 6H, CH 3X 2), 1.07 (t, J=7.5 Hz, 1H, H-9), 0.95 (s, 3H, CH 3), 0.92 (t, J=6.5 Hz, 1H, H-5), 0.81 (s, 3H, CH 3).
Example 2
Olean-2-eno [2,3-b ]]Imidazole-12-ene-28-carboxylic acid ethyl ester (III) 1 ) Is prepared from
Oleanolic acid OA (0.500 g) was dissolved in 50mL of acetone, jones reagent 1mL was slowly added dropwise under ice bath, the temperature was raised to room temperature for further reaction for 1.5 h, TLC monitored the end of the reaction, and 15mL isopropanol was added to quench the reaction. Ethyl acetate was added to dilute the mixture, and the organic layers (100 mL. Times.3) were washed with saturated brine and combined. Anhydrous Na 2 SO 4 Drying, filtering, recovering solvent under reduced pressure, and recrystallizing and purifying the crude product by methanol to obtain 0.490g of white powdery solid OA-1.
Intermediate OA-1 (0.500 g) was dissolved in 12mL of N, N-Dimethylformamide (DMF), and 0.30g of anhydrous potassium carbonate was added thereto, 12 drops (0.24 mL,5.02 mmol) of bromoethane was slowly added dropwise thereto, and the reaction was carried out at room temperature for 5 hours, and the TLC detected the end of the reaction. Ethyl acetate was added to dilute the mixture, and the organic layers (100 mL. Times.3) were washed with saturated brine and combined. Anhydrous Na 2 SO 4 Drying, filtering, and purifying the crude product by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=15/1 (V/V)) to obtain 0.324g of white flaky solid OA-6.
Intermediate OA-6 (0.300 g) was dissolved in 30mL of methanol, 1mL of hydrazine hydrate was added, the temperature was raised to 70℃and the reaction was refluxed for 2 hours, and the TLC detected the end of the reaction. The solvent was recovered under reduced pressure, diluted with ethyl acetate, and the organic layers were washed with saturated brine (100 mL. Times.3) and combined. Anhydrous Na 2 SO 4 Drying, filtering, and purifying the crude product by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=20/1 (V/V)) to obtain 0.226g of yellow oily OA-7.
Intermediate OA-7 (0.001 mol) was dissolved in 20mL of absolute ethanol, formic acid (0.001 mol) was added and the reaction was refluxed at 70℃for 3 hours, and the TLC detected the end of the reaction. Adding 50mL of ice water into the reaction solution, standing for crystallization, filtering to obtain a filter cake, and drying. The crude product is subjected to column loading by a dry method and is purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=20/1 (V/V)) to obtain white crystal III 1 The yield is 63.29 percent, mp 196.2-199.7 o C. 1 H-NMR(CDCl 3 ,300MHz) δ:7.52（s,1H,NCHN）,5.24(t,J=3.2Hz,1H, H-12),2.63(t, J=6.5Hz,1H,H-18),4.22~4.06(m,2H,COOCH 2 CH 3 ),1.21(t,J=11.3Hz ,3H,COOCH 2 CH 3 ),1.18(s,3H),0.99(s,3H),0.99(s,3H),1.01(s,3H),0.99(s,3H),0.89(s,3H),0.89(s,3H) ; 13 C-NMR(CDCl 3, 150MHz)δ:178.9,165.5,155.3,143.2,123.1,62.3,53.7,51.6,47.6,47.0,46.9,42.5,42.1,40.5,39.5,37.9,34.8,33.7,33.1,32.8,30.9,29.4,27.5,27.5,26.6,25.0,23.8,23.6,23.6,21.0,17.3,15.9,14.1; ESI-MS(m/z):506.4[M+H] + . Elemental anal.(%) calcd. For C 33 H 50 N 2 O 2 : C 78.21,H 9.95,N 5.53,O 6.31;found: C 78.24,H 9.97,N 5.49,O 6.29。
Example 3
5',6' -dihydro-olean-2-eno [2,3-b]Pyrazin-12-ene-28-acyl-3 '-fluoro-4' -chloroaniline (IV) 1 ) Is prepared from
OA (0.100 g,0.22 mmol) was dissolved in 10mL acetone, jones reagent 3 drops (0.08 mL) were slowly added dropwise in an ice bath, reacted for 1h at room temperature, TLC monitored the end of the reaction, and quenched by addition of 3mL isopropanol. Ethyl acetate was added to dilute the mixture, and the organic layers (100 mL. Times.3) were washed with saturated brine and combined. Anhydrous Na 2 SO 4 Drying, filtering, recovering solvent under reduced pressure, loading the crude product onto a column by dry method, and purifying by silica gel column chromatography (eluent: V (petroleum ether)/V (ethyl acetate) =6/1)]0.095g of white powdery solid OA-1 was obtained.
Intermediate OA-1 (0.100 g,0.22 mmol) was dissolved in 5mL of Dichloromethane (DCM), oxalyl chloride (0.24 mmol) was added and stirred at room temperature for 20h to yield 3-oxo-12-en-oleanane-28-yl chloride, which was removed by rotary evaporation of the reaction solvent and unreacted oxalyl chloride. 3mL of dichloromethane and triethylamine are added to the acyl chloride to adjust the pH to 9-10, after stirring for 5min, 3-fluoro-4-chloro-aniline (0.44 mmol) is added to the mixture, the mixture is reacted for 6h at room temperature, and TLC (thin layer chromatography) detects the end point of the reaction. After completion of the reaction, 50mL of methylene chloride was added to the reaction mixture to dilute the mixture, and the mixture was washed with dilute hydrochloric acid (100 mL. Times.3) to combine the organic phases. Anhydrous Na 2 SO 4 Drying, filtering, and recovering the solvent under reduced pressure. The crude product is subjected to column loading by a dry method, and is purified by silica gel column chromatography [ eluent: V (petroleum ether)/V (ethyl acetate) =8/1 ]]0.123g of white crystal OA-8 was obtained.
Intermediate OA-8 (0.164 g,0.3 mmol) was dissolved in 5mL of dichloromethane and 10mL of 1.5% sulfuric acid-methyl acetate was addedAn alcoholic solution, m-chloroperoxybenzoic acid (m-CPBA) (0.06 g,0.3 mmol), was reacted in an ice bath for 24h, and TLC was used to detect the end point of the reaction. Adding Na 2 SO 3 The saturated solution was quenched for 0.5h, diluted with dichloromethane, washed with dilute hydrochloric acid (100 mL. Times.3) and the organic phases combined. Anhydrous Na 2 SO 4 Drying, filtration and recovery of the solvent under reduced pressure gave 0.139g of OA-9 as a yellow oily liquid.
Intermediate OA-9, prepared according to the synthetic method of OA-1, was obtained as a pale yellow solid OA-10, 0.121. 0.121 g.
Intermediate OA-10 (0.168 g,0.3 mmol) was dissolved in 10mL of anhydrous ethanol, 0.150g of anhydrous magnesium sulfate was added, a saturated ethylenediamine-ethanol solution (2 drops, ethylenediamine, 0.6 mmol) was slowly added dropwise, heat refluxing was performed for 5h, and TLC detected the end of the reaction. Ethyl acetate was added to dilute the mixture, and the organic layers (100 mL. Times.3) were washed with saturated brine and combined. Anhydrous Na 2 SO 4 Drying, filtering, recovering solvent under reduced pressure, loading the crude product onto a column by dry method, and purifying by silica gel column chromatography (eluent: V (petroleum ether)/V (ethyl acetate) =15/1)]0.096g of white powdery solid IV is obtained 1 The yield is 35.78 percent, m.p.163.1-165.2 ℃; 1 H-NMR(CDCl 3 ,500MHz)δ:7.99(s,1H,NH),7.34(t,J＝9.1Hz,1H),7.32(s,1H),7.26(s,1H),5.28(s,1H),2.36(t,J＝7.5Hz,1H),1.56～1.51,1.49～1.42(m,4H,NCH 2 CH 2 N),1.57～1.40(m,6H),1.47(t,J＝7.0Hz,1H),1.39～1.37,1.36～1.34(m,4H,NCH 2 CH 2 N),1.35～1.33(m,4H),1.31～1.24(m,4H),1.23(s,3H),1.18(s,3H),1.14(s,3H),1.12(s,3H),1.02(s,3H),0.96(s,3H),0.95(s,3H);13CNMR(150MHz,CDCl3)δ:180.4,165.9,165.5,163.2,150.6,141.3,131.9,123.4,118.8,117.2,109.2,51.9,51.2,50.2,48.6,45.3,43.7,40.1,36.8,35.7,34.5,34.3,31.2,30.5,30.1,29.8,28.4,28.1,25.3,24.6,24.5,24.2,22.2,20.1,20.1,18.9,18.3,18.1;ESI-MS m/z:619.3[M＋H] ＋ .Anal.calcd for C 38 H 51 ClFN 3 O:C 73.58,H 8.29,N 6.77;found C 73.50,H 8.18,N 6.65。
Claims (1)
1. an oleanolic acid a-ring derivative having antitumor activity, characterized by comprising the following preparation steps:
dissolving 0.50g,0.001mol of oleanolic acid OA in 10mL of acetone, slowly dropwise adding 25 drops of Jones reagent under ice bath, heating to room temperature for continuous reaction for 1.5 h, monitoring the reaction end point by TLC, adding 15mL isopropanol, and quenching reaction; diluting with ethyl acetate, and washing the organic layer with saturated saline to obtain an organic phase; anhydrous Na 2 SO 4 Drying, filtering, recovering solvent under reduced pressure, recrystallizing and purifying crude product with methanol to obtain white powdery solid 3-carbonyl oleanolic acid OA-1;
dissolving 0.500g of intermediate, 0.001mmol of 3-carbonyl oleanolic acid OA-1 in 15mL of tertiary butanol, adding 0.25g of tertiary butanol potassium, slowly dropwise adding 2.5mL of ethyl formate, heating in a 50 ℃ water bath for 5h, and monitoring the reaction end point by TLC; diluting with ethyl acetate, and washing the organic layer with saturated saline to obtain an organic phase; anhydrous MgSO 4 Drying, filtering and decompressing to recover the solvent to obtain light yellow solid 2, 3-dicarbonyl-oleanane-12-alkene-28-carboxylic acid OA-2;
dissolving 0.5g,0.001mol of intermediate 2, 3-dicarbonyl-oleanane-12-alkene-28-carboxylic acid OA-2 in 5mL of ethanol, adding 0.7g of magnesium sulfate, slowly dropwise adding 1 drop of ethylenediamine-ethanol solution, reacting for 6h at room temperature, monitoring the reaction end point by TLC, adding ethyl acetate for dilution, washing the organic layer by saturated saline water, and merging organic phases; anhydrous MgSO 4 Drying, filtering and decompressing to recover the solvent to obtain light yellow oily substance 2, 3-and hydrogenated pyrazine ring-oleanane-12-alkene-28-carboxylic acid OA-3;
dissolving 0.50g,0.001mol of intermediate 2, 3-pentazopyrazine ring-oleanane-12-ene-28-carboxylic acid OA-3 in 20mL of absolute ethanol, adding 0.07g,0.001mol of potassium hydroxide, 0.26g,0.003mol of manganese dioxide, refluxing in a water bath at 80 ℃ for 8 hours, and monitoring the reaction end point by TLC; diluting with ethyl acetate, and washing the organic layer with saturated saline to obtain an organic phase; anhydrous MgSO 4 Drying, filtering and decompressing to recover the solvent to obtain yellow oily matter 2, 3-naphthyridine ring-oleanane-12-alkene-28-carboxylic acid OA-4;
dissolving 0.50g,0.001mmol of intermediate 2, 3-naphthyridine ring-oleanane-12-alkene-28-carboxylic acid OA-4 in 12mL of N, N-dimethylformamide, slowly dropwise adding 12 drops of 0.005mol of bromoethane, 0.30g,0.002mol of anhydrous potassium carbonate, and reversing at room temperatureMonitoring the reaction end point by TLC for 5 h; diluting with ethyl acetate, washing the organic phase with saturated saline, and concentrating the organic phase with anhydrous Na 2 SO 4 Drying, filtering, recovering solvent under reduced pressure, loading the crude product on a dry method column, purifying by silica gel column chromatography, eluting with petroleum ether/ethyl acetate=15/1V/V to obtain white powdery solid.
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