CN116606335A - Synthetic method of monohydroxy acetylated hesperidin - Google Patents
Synthetic method of monohydroxy acetylated hesperidin Download PDFInfo
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- CN116606335A CN116606335A CN202310583070.3A CN202310583070A CN116606335A CN 116606335 A CN116606335 A CN 116606335A CN 202310583070 A CN202310583070 A CN 202310583070A CN 116606335 A CN116606335 A CN 116606335A
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- hesperidin
- acetylated
- monohydroxy
- drug
- hydroxyl
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- 239000001100 (2S)-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chroman-4-one Substances 0.000 title claims abstract description 66
- QUQPHWDTPGMPEX-UHFFFAOYSA-N Hesperidine Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(OC3C(C(O)C(O)C(COC4C(C(O)C(O)C(C)O4)O)O3)O)=CC(O)=C2C(=O)C1 QUQPHWDTPGMPEX-UHFFFAOYSA-N 0.000 title claims abstract description 66
- QUQPHWDTPGMPEX-UTWYECKDSA-N aurantiamarin Natural products COc1ccc(cc1O)[C@H]1CC(=O)c2c(O)cc(O[C@@H]3O[C@H](CO[C@@H]4O[C@@H](C)[C@H](O)[C@@H](O)[C@H]4O)[C@@H](O)[C@H](O)[C@H]3O)cc2O1 QUQPHWDTPGMPEX-UTWYECKDSA-N 0.000 title claims abstract description 66
- APSNPMVGBGZYAJ-GLOOOPAXSA-N clematine Natural products COc1cc(ccc1O)[C@@H]2CC(=O)c3c(O)cc(O[C@@H]4O[C@H](CO[C@H]5O[C@@H](C)[C@H](O)[C@@H](O)[C@H]5O)[C@@H](O)[C@H](O)[C@H]4O)cc3O2 APSNPMVGBGZYAJ-GLOOOPAXSA-N 0.000 title claims abstract description 66
- VUYDGVRIQRPHFX-UHFFFAOYSA-N hesperidin Natural products COc1cc(ccc1O)C2CC(=O)c3c(O)cc(OC4OC(COC5OC(O)C(O)C(O)C5O)C(O)C(O)C4O)cc3O2 VUYDGVRIQRPHFX-UHFFFAOYSA-N 0.000 title claims abstract description 66
- 229940025878 hesperidin Drugs 0.000 title claims abstract description 66
- ARGKVCXINMKCAZ-UHFFFAOYSA-N neohesperidine Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(OC3C(C(O)C(O)C(CO)O3)OC3C(C(O)C(O)C(C)O3)O)=CC(O)=C2C(=O)C1 ARGKVCXINMKCAZ-UHFFFAOYSA-N 0.000 title claims abstract description 66
- QUQPHWDTPGMPEX-QJBIFVCTSA-N hesperidin Chemical compound C1=C(O)C(OC)=CC=C1[C@H]1OC2=CC(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO[C@H]4[C@@H]([C@H](O)[C@@H](O)[C@H](C)O4)O)O3)O)=CC(O)=C2C(=O)C1 QUQPHWDTPGMPEX-QJBIFVCTSA-N 0.000 title claims abstract description 62
- 238000010189 synthetic method Methods 0.000 title description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 14
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 229910052741 iridium Inorganic materials 0.000 claims abstract description 11
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910052751 metal Inorganic materials 0.000 claims abstract description 11
- 239000002184 metal Substances 0.000 claims abstract description 11
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 230000000397 acetylating effect Effects 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 229960000583 acetic acid Drugs 0.000 claims description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 2
- 239000012346 acetyl chloride Substances 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- 239000012362 glacial acetic acid Substances 0.000 claims description 2
- 238000001308 synthesis method Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 16
- 239000003814 drug Substances 0.000 abstract description 16
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 6
- 239000000126 substance Substances 0.000 abstract description 4
- 230000002209 hydrophobic effect Effects 0.000 abstract description 3
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- 238000012986 modification Methods 0.000 abstract description 3
- 229940002612 prodrug Drugs 0.000 abstract description 2
- 239000000651 prodrug Substances 0.000 abstract description 2
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- 238000012377 drug delivery Methods 0.000 abstract 1
- 230000001151 other effect Effects 0.000 abstract 1
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- 239000007858 starting material Substances 0.000 abstract 1
- DFBIRQPKNDILPW-CIVMWXNOSA-N Triptolide Chemical compound O=C1OCC([C@@H]2C3)=C1CC[C@]2(C)[C@]12O[C@H]1[C@@H]1O[C@]1(C(C)C)[C@@H](O)[C@]21[C@H]3O1 DFBIRQPKNDILPW-CIVMWXNOSA-N 0.000 description 13
- YKUJZZHGTWVWHA-UHFFFAOYSA-N triptolide Natural products COC12CC3OC3(C(C)C)C(O)C14OC4CC5C6=C(CCC25C)C(=O)OC6 YKUJZZHGTWVWHA-UHFFFAOYSA-N 0.000 description 13
- 206010005003 Bladder cancer Diseases 0.000 description 11
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 11
- 201000005112 urinary bladder cancer Diseases 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- OTAFHZMPRISVEM-UHFFFAOYSA-N chromone Chemical group C1=CC=C2C(=O)C=COC2=C1 OTAFHZMPRISVEM-UHFFFAOYSA-N 0.000 description 4
- -1 oxazoline methyl ester Chemical class 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 206010019851 Hepatotoxicity Diseases 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 231100000334 hepatotoxic Toxicity 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 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 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 231100000304 hepatotoxicity Toxicity 0.000 description 2
- 230000007686 hepatotoxicity Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- ZECJHXWYQJXFQQ-UHFFFAOYSA-L CC1=C(C)C(C)([Ir](Cl)Cl)C(C)=C1C Chemical class CC1=C(C)C(C)([Ir](Cl)Cl)C(C)=C1C ZECJHXWYQJXFQQ-UHFFFAOYSA-L 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 description 1
- HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 229940117913 acrylamide Drugs 0.000 description 1
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- 230000033115 angiogenesis Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000025084 cell cycle arrest Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
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- 229960004679 doxorubicin Drugs 0.000 description 1
- 239000011363 dried mixture Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 229930182486 flavonoid glycoside Natural products 0.000 description 1
- 150000007955 flavonoid glycosides Chemical class 0.000 description 1
- 230000003082 hepatotoxic effect Effects 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 description 1
- 229920006008 lipopolysaccharide Polymers 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960001285 quercetin Drugs 0.000 description 1
- 235000005875 quercetin Nutrition 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- PTLRDCMBXHILCL-UHFFFAOYSA-M sodium arsenite Chemical compound [Na+].[O-][As]=O PTLRDCMBXHILCL-UHFFFAOYSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 1
- PTMFUWGXPRYYMC-UHFFFAOYSA-N triethylazanium;formate Chemical compound OC=O.CCN(CC)CC PTMFUWGXPRYYMC-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/06—Benzopyran radicals
- C07H17/065—Benzo[b]pyrans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/2208—Oxygen, e.g. acetylacetonates
- B01J31/2217—At least one oxygen and one nitrogen atom present as complexing atoms in an at least bidentate or bridging ligand
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2282—Unsaturated compounds used as ligands
- B01J31/2295—Cyclic compounds, e.g. cyclopentadienyls
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/827—Iridium
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Inorganic Chemistry (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Materials Engineering (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention discloses a method for synthesizing monohydroxy acetylated hesperidin, which takes hesperidin as a starting material, firstly uses acetic anhydride to protect all hydroxyl groups and synthesizes the acetylated hesperidin, and after the acetylated hesperidin is hydrogenated by catalytic transfer of an iridium metal catalyst, carbonyl groups on an acetylated hesperidin chromone structure are reduced with high chemo-selectivity, so that a target product monohydroxy acetylated hesperidin with only one hydroxyl group is obtained. The method has the advantages of simple operation steps, mild conditions, high catalytic activity, high chemical selectivity and high yield of the target compound. The monohydroxy acetylated hesperidin obtained by the invention can be further connected with a hydrophobic drug molecule, and can be selectively deacetylated to form an amphiphilic drug molecule to be further prepared into a nano prodrug to realize efficient drug delivery, so that the hesperidin and the hydrophobic drug molecule can exert drug effects simultaneously, or can be efficiently connected with other functional structures, so that other effects can be exerted while the drug effects of the hesperidin are realized, and the modification of physical properties of the hesperidin can also be realized.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing monohydroxy acetylated hesperidin.
Background
Hesperidin is a flavonoid glycoside rich in citrus fruits and has antioxidant and antiinflammatory activities. There is growing evidence that hesperidin can inhibit tumor proliferation by inducing apoptosis and cell cycle arrest, inhibiting tumor cell migration and angiogenesis. In addition, hesperidin can enhance antitumor effect of doxorubicin, cytarabine, tamoxifen or quercetin, and reduce hepatorenal toxicity induced by cisplatin, lipopolysaccharide, sodium arsenite, cyclophosphamide, methotrexate and acrylamide. However, the clinical application of hesperidin is greatly limited due to poor water solubility and poor bioavailability. At present, the hesperidin can be delivered only by means of nanoparticle encapsulation and the like, however, the method has the advantages of extremely high cost, low drug loading rate and low efficiency. Therefore, by linking the molecule with good water solubility and high bioavailability with hesperidin or by making into high drug-carrying nano-preparation, the preparation becomes an important solution for high-efficiency delivery and achieving the functions.
However, hesperidin molecules are chemically inert and poorly reactive, which presents great difficulties for the attachment to other molecules. The hydroxyl can be used as a better active modification site, but the characteristics of different activity degrees of each hydroxyl in the hesperidin molecule, numerous hydroxyl groups and distribution at a plurality of positions of the molecule bring difficulty to site-directed modification of the structure. Only one hydroxyl active site is designed and synthesized, and the hesperidin molecule which protects other hydroxyl has important value. Acetylation protection of hydroxyl groups is the most common mode of hydroxyl protection, and is used in large amounts in organic synthesis due to the ease of selective removal of acetyl groups, etc. The method for synthesizing the monohydroxy acetylated hesperidin by protecting all hydroxyl groups in molecules and reducing carbonyl groups at the chromone position into hydroxyl groups is the simplest method, but no report on success is made at present, wherein one important reason is that the activity of a reducing agent is insufficient or the chemical selectivity is lacking when a traditional reduction method is used for the chromone region of the hesperidin molecules, so that the ketocarbonyl groups on the acetylated hesperidin cannot be reduced or acetyl (partial acetyl groups) can be reduced, and therefore, the searching of a proper reduction method or reducing agent is the key for successfully synthesizing the monohydroxy acetylated hesperidin, and has important research value.
Disclosure of Invention
The invention aims to overcome the difficulty that only a single carbonyl group of an acetylated hesperidin with 9 carbonyl groups is selectively reduced in a chromone region, and provides a method for synthesizing monohydroxy acetylated hesperidin with high activity and high chemical selectivity.
Aiming at the purposes, the technical scheme adopted by the invention comprises the following steps:
(1) Protecting all hydroxyl groups on the hesperidin 1 by using an acetylating reagent to obtain acetylated hesperidin 2;
(2) And (3) reducing the ketocarbonyl into hydroxyl by the acetylated hesperidin 2 under the action of an iridium metal catalyst 3 to obtain monohydroxy acetylated hesperidin.
In the step (1), the acetylating reagent is any one of acetic anhydride, acetyl chloride and glacial acetic acid.
In the step (2), the iridium metal catalyst 3 is preferably used in an amount of 1 to 2% by mol based on the amount of the acetylated hesperidin 2. The iridium metal catalyst 3 is synthesized by the method in the literature of "Gang Zhou, ahmed H.Aboo, craig M.Robertson, ruixia Liu, zhenhua Li, konstantin Luzyanin, neil G.Berry, weiping Chen, and Jianliang Xiao, ACS Catalysis 2018 (9), 8020-8026".
In the step (2), the reaction temperature for reducing the ketocarbonyl group to the hydroxyl group is 20-40 ℃.
In the step (2), the solvent used for reducing the ketone carbonyl into hydroxyl is selected from any one of pyridine, ethyl acetate, tetrahydrofuran, N-dimethylformamide, dimethyl sulfoxide, dichloromethane and chloroform.
The beneficial effects of the invention are as follows:
the invention adopts a simple and easily obtained iridium metal catalyst to complete high chemical selectivity transfer hydrogenation of acetylated hesperidin with 9 carbonyl groups, and obtains monohydroxy acetylated hesperidin with carbonyl groups reduced to hydroxyl groups in a chromone region, and the product can be formed by connecting other molecules with good water solubility and high bioavailability together through a simple chemical reaction by a one-step reaction, or can be further prepared into a high-drug-loading nano preparation.
Drawings
Fig. 1 is a graph showing THE effect of THE THE nanomedicine prepared by monohydroxy acetylated hesperidin on inhibiting proliferation of bladder cancer cells.
Figure 2 is a graph of THE effect of THE THE nanomedicine prepared by monohydroxy acetylated hesperidin in inhibiting bladder cancer in mice.
Fig. 3 is a graph showing THE hepatotoxic effects of THE THE nanomedicine prepared by monohydroxy acetylated hesperidin in reducing triptolide alone.
Detailed Description
The present invention will be described in further detail with reference to the drawings and examples, but the scope of the present invention is not limited to these examples.
In the following examples, the specific synthesis method of the iridium metal catalyst 3 used is: oxazoline methyl ester (100 mg, racemization), pentamethyl cyclopentadienyl iridium dichloride dimer (170 mg) and sodium acetate (402 mg) are placed in a 25 mL reaction tube, the operation of vacuumizing and argon filling is carried out for three times by double-row tubes, water (1 mL) and methylene dichloride (10 mL) are added, and the reaction is carried out for 24 hours at room temperature. The reaction solution was filtered through celite, washed with water and saturated brine, dried over anhydrous sodium sulfate, and recrystallized from a 1:1 volume ratio of diethyl ether to n-hexane to give yellow solid iridium metal catalyst 3 (165 mg, 62%). The synthetic route is as follows:
the structural characterization data of the obtained iridium metal catalyst 3 are as follows: 1 H NMR(400MHz,CDCl 3 )δ8.38(d,J＝7.6Hz,2H),7.62–7.56(m,1H),7.49–7.42(m,2H),4.88(dd,J＝11.0,8.2Hz,1H),4.84–4.75(m,1H),4.51(dd,J＝11.9,8.1Hz,1H),1.64(s,15H). 13 C NMR(101MHz,CDCl 3 )δ175.01,167.38,133.32,129.99,128.27,124.14,85.15,72.05,71.28,9.21.HRMS for C 20 H 23 ClIrNO 3 [M+Na] + m/z theory 576.0894; found 576.0889.
Example 1
(1) Hesperidin 1 (6.1 g) was dissolved in pyridine (50 mL), and acetic anhydride (50 mL) was added to the solution and reacted at 90 ℃ for 24 hours. After the reaction solution is cooled to room temperature, the solvent is dried by spin, 200mL of water is added, after the mixture is fully stirred, the water is filtered, the obtained solid filter residue is dissolved by chloroform, then dried by anhydrous sodium sulfate, the dried mixture is dried by spin to obtain a crude product, and the crude product is subjected to column chromatography by taking a mixed solution with the volume ratio of normal hexane to ethyl acetate being 3:1 as a developing agent to obtain pure white solid acetylated hesperidin 2 (7.1 g, 75%), wherein the structural characterization data are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.36(d,J＝8.8Hz,1H),7.16(d,J＝2.3Hz,1H),7.00(d,J＝8.5Hz,1H),6.47(d,J＝2.5Hz,1H),6.31(d,J＝2.4Hz,1H),5.48–5.37(m,1H),5.25(d,J＝16.1Hz,6H),5.02(t,J＝10.2Hz,1H),4.69(s,1H),3.92–3.90(m,1H),3.86(s,3H),3.81(dt,J＝11.7,3.3Hz,2H),3.64(td,J＝11.6,10.4,4.9Hz,1H),2.99(dd,J＝16.6,12.9Hz,1H),2.76(dd,J＝16.6,3.0Hz,1H),2.38(s,3H),2.33(s,3H),2.09(s,3H),2.08(s,3H),2.04(s,9H),1.96(s,3H),1.15(d,J＝6.3Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ188.73,170.19,170.03,169.85,169.34,169.15,168.87,163.80,161.89,151.89,151.59,139.93,130.74,124.95,121.18,112.45,109.60,105.91,102.16,98.09,97.59,78.68,77.22,73.26,72.45,70.87,70.80,69.36,68.97,68.61,66.66,66.15,56.04,21.05,20.80,20.66,20.63,20.60,17.28.HRMS C 44 H 50 O 23 [M+H] + m/z theory 946.2723; found 946.2743.
(2) Acetylated hesperidin 2 (2.0 g,2.11 mmol) and iridium metal catalyst 3 (13 mg,0.021 mmol) were placed in a reaction tube, the reaction tube was evacuated and argon-filled three times, methylene chloride (5 mL) was added for dissolution, and then formic acid-triethylamine azeotrope (5 mL) was added for reaction at room temperature for 10 hours. After the reaction liquid is washed by water, the reaction liquid is dried by anhydrous sodium sulfate, the solvent is dried by spin to obtain a crude product, and pure product which is yellow solid monohydroxy acetylated hesperidin (1.6 g, 79%) is obtained after column chromatography (eluent is mixed liquid of ethyl acetate and n-hexane in a volume ratio of 3:1), and the structural characterization data are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.33–7.28(m,1H),7.16(t,J＝2.3Hz,1H),7.05–6.97(m,1H),6.48(d,J＝2.5Hz,1H),6.32(d,J＝2.4Hz,1H),5.49–5.35(m,1H),5.30–5.10(m,7H),5.02(t,J＝10.0Hz,1H),4.70(s,1H),3.95–3.87(m,1H),3.86(s,3H),3.85–3.75(m,1H),3.64(td,J＝11.6,10.4,4.9Hz,1H),3.69–3.58(m,1H),3.11–2.92(m,1H),2.79–2.66(m,1H),2.38(s,3H),2.35(s,3H),2.09(s,3H),2.08(s,3H),2.04(s,9H),1.96(s,3H),1.15(d,J＝6.2Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ170.17,170.01,169.77,169.44,169.33,169.14,168.85,163.98,163.80,161.88,151.88,151.58,139.93,130.74,124.94,121.18,112.45,109.60,105.90,102.16,98.08,97.58,78.67,73.26,72.44,70.87,70.80,69.35,68.97,68.63,66.66,66.14,56.03,53.81,21.04,20.79,20.75,20.64,20.61,20.59,17.27.HRMS C 44 H 52 O 23 [M+H] + m/z theory 948.2919; found 948.2932.
Application example of monohydroxy acetylated hesperidin
Triptolide is a class of highly antitumor active molecules extracted from natural products (J.T.Wen, J.Liu, L.Wan, L.Xin, J.C.Guo, Y.Q.Sun, X.Wang, J.Wang, int Immunopharmacol 2022,106,108616;P.Noel,D.D.Von Hoff,A.K.Saluja,M.Velagapudi,E.Borazanci,H.Han,Trends in pharmacological sciences 2019,40,327.) but is highly hydrophobic, low in bioavailability and highly toxic (M.Yanchun, W.Yi, W.Lu, Q.Yu, Y.Jian, K.Pengzhou, Y.Ting, L.Hongyi, W.Fang, C.Xiaolong, C.Yongping, eur J Pharmacol 2019,851,43;L.Zhao,Z.Lan,L.Peng,L.Wan,D.Liu,X.Tan,C.Tang,G.Chen,H.Liu,Cell Prolif 2022,55,e13278;J.Wen,J.Liu,X.Wang,J.Wang,Phytother Res 2021,35,4334.). THE monohydroxy acetylated hesperidin (I) is connected with triptolide which is simply modified by succinic anhydride, and after acetyl selective deprotection, THE amphiphilic THE molecule can be obtained, and THE molecule is further self-assembled into THE THE nano prodrug.
Fig. 1 is an experimental result that THE THE nano-drug prepared by monohydroxy acetylated hesperidin can effectively inhibit proliferation of bladder cancer cells. 5637 cells were treated with THE indicated doses of THE THE nanomedicine for 14 hours and stained with crystal violet. Comparison with a control group without nano-drug shows that THE THE nano-drug prepared by monohydroxy acetylated hesperidin can obviously observe THE proliferation of bladder cancer cells at 2 mu M, and THE inhibition is more obvious at 4 mu M.
Figure 2 is an experimental model and results of THE significant inhibition of bladder cancer in mice by THE THE nanomedicine prepared by monohydroxyacetylated hesperidin. Wherein, A is a schematic diagram of the establishment and treatment of a bladder cancer model, showing that the bladder cancer model is established in 7 days, and the bladder cancer model is killed after 20 days in a treatment period of 1 to 15 days after the model is determined; THE THE nano-drug prepared by THE monohydroxy acetylated hesperidin can efficiently enter THE inside of a tumor through tail vein injection, and a small animal imaging result shows that THE THE nano-drug can be efficiently delivered to THE tumor part of a mouse; c is that THE mice are sacrificed after 20 days of treatment, and THE obtained size comparison of THE bladder cancer tissues can show that THE THE nano-drug can effectively inhibit bladder cancer in THE mice.
Fig. 3 is an experimental result that THE THE nano-drug prepared by monohydroxy acetyl hesperidin can effectively reduce hepatotoxicity caused by single administration of triptolide. Performing blood index and biochemical index analysis on a C57 mouse by injecting PBS, 8.5mg/kg hesperidin, 5mg/kg triptolide and 15mg/kg THE nano-drug through tail vein for 24 hours respectively, wherein n=3; scale dimensions 50 μm, p <0.05; * P <0.01; * P <0.001; a-E: THE results of mice treated with triptolide alone are obviously abnormal in blood and biochemical indexes, THE results of THE triptolide are obviously toxic to THE livers of THE mice, but THE results of THE hesperidin and THE nano-drug are compared with THE results of a control group, THE results of THE hesperidin and THE nano-drug are not obviously toxic to THE livers of THE mice, and THE results of THE triptolide and THE nano-drug prepared by monohydroxy acetyl hesperidin are reflected to obviously reduce THE hepatotoxicity compared with THE triptolide.
THE results of fig. 1 to 3 are combined to show that THE THE nano-drug prepared by THE monohydroxy acetyl hesperidin can play THE role of THE synergistic inhibition of bladder cancer by THE hesperidin and THE triptolide, not only improves THE bioavailability of THE triptolide, but also utilizes THE high anti-tumor activity of THE triptolide, and simultaneously reduces THE problem of high toxicity of THE triptolide by THE hesperidin.
Claims (5)
1. The synthesis method of the monohydroxy acetylated hesperidin is characterized by comprising the following steps of:
(1) Protecting all hydroxyl groups on the hesperidin 1 by using an acetylating reagent to obtain acetylated hesperidin 2;
(2) And (3) reducing the ketocarbonyl into hydroxyl by the acetylated hesperidin 2 under the action of an iridium metal catalyst 3 to obtain monohydroxy acetylated hesperidin.
2. The method for synthesizing monohydroxyacetylated hesperidin according to claim 1, characterized in that: in the step (1), the acetylating reagent is any one of acetic anhydride, acetyl chloride and glacial acetic acid.
3. The method for synthesizing monohydroxyacetylated hesperidin according to claim 1, characterized in that: in the step (2), the amount of the iridium metal catalyst 3 is 1-2% of the molar amount of the acetylated hesperidin 2.
4. The method for synthesizing monohydroxyacetylated hesperidin according to claim 1, characterized in that: in the step (2), the reaction temperature for reducing the ketone carbonyl group into the hydroxyl group is 20-40 ℃.
5. The method for synthesizing monohydroxyacetylated hesperidin according to claim 1, characterized in that: in the step (2), the solvent used for reducing the ketone carbonyl into hydroxyl is selected from any one of pyridine, ethyl acetate, tetrahydrofuran, N-dimethylformamide, dimethyl sulfoxide, dichloromethane and chloroform.
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