CN110590840A - Preparation method of zoledronic acid flavone compound - Google Patents
Preparation method of zoledronic acid flavone compound Download PDFInfo
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- CN110590840A CN110590840A CN201910979463.XA CN201910979463A CN110590840A CN 110590840 A CN110590840 A CN 110590840A CN 201910979463 A CN201910979463 A CN 201910979463A CN 110590840 A CN110590840 A CN 110590840A
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- CN
- China
- Prior art keywords
- zoledronic acid
- reaction
- minutes
- molar concentration
- flavone compound
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Links
- 229960004276 zoledronic acid Drugs 0.000 title claims abstract description 53
- -1 zoledronic acid flavone compound Chemical class 0.000 title claims abstract description 51
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 title claims abstract description 33
- 229930003944 flavone Natural products 0.000 title claims abstract description 33
- 235000011949 flavones Nutrition 0.000 title claims abstract description 33
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract 5
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 36
- 230000035484 reaction time Effects 0.000 claims description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 230000003301 hydrolyzing effect Effects 0.000 claims description 11
- 238000010992 reflux Methods 0.000 claims description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- DEPDDPLQZYCHOH-UHFFFAOYSA-N 1h-imidazol-2-amine Chemical compound NC1=NC=CN1 DEPDDPLQZYCHOH-UHFFFAOYSA-N 0.000 claims description 8
- 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 claims description 8
- 229940045109 genistein Drugs 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- QRZMXADUXZADTF-UHFFFAOYSA-N 4-aminoimidazole Chemical compound NC1=CNC=N1 QRZMXADUXZADTF-UHFFFAOYSA-N 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 239000002202 Polyethylene glycol Substances 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 238000005804 alkylation reaction Methods 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 claims description 6
- 235000006539 genistein Nutrition 0.000 claims description 6
- TZBJGXHYKVUXJN-UHFFFAOYSA-N genistein Natural products C1=CC(O)=CC=C1C1=COC2=CC(O)=CC(O)=C2C1=O TZBJGXHYKVUXJN-UHFFFAOYSA-N 0.000 claims description 6
- ZCOLJUOHXJRHDI-CMWLGVBASA-N genistein 7-O-beta-D-glucoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=C2C(=O)C(C=3C=CC(O)=CC=3)=COC2=C1 ZCOLJUOHXJRHDI-CMWLGVBASA-N 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 239000003444 phase transfer catalyst Substances 0.000 claims description 6
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- 229960004555 rutoside Drugs 0.000 claims description 6
- JMGZEFIQIZZSBH-UHFFFAOYSA-N Bioquercetin Natural products CC1OC(OCC(O)C2OC(OC3=C(Oc4cc(O)cc(O)c4C3=O)c5ccc(O)c(O)c5)C(O)C2O)C(O)C(O)C1O JMGZEFIQIZZSBH-UHFFFAOYSA-N 0.000 claims description 5
- IVTMALDHFAHOGL-UHFFFAOYSA-N eriodictyol 7-O-rutinoside Natural products OC1C(O)C(O)C(C)OC1OCC1C(O)C(O)C(O)C(OC=2C=C3C(C(C(O)=C(O3)C=3C=C(O)C(O)=CC=3)=O)=C(O)C=2)O1 IVTMALDHFAHOGL-UHFFFAOYSA-N 0.000 claims description 5
- 229930003935 flavonoid Natural products 0.000 claims description 5
- 235000017173 flavonoids Nutrition 0.000 claims description 5
- 229960001285 quercetin Drugs 0.000 claims description 5
- FDRQPMVGJOQVTL-UHFFFAOYSA-N quercetin rutinoside Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 FDRQPMVGJOQVTL-UHFFFAOYSA-N 0.000 claims description 5
- 235000005493 rutin Nutrition 0.000 claims description 5
- IKGXIBQEEMLURG-BKUODXTLSA-N rutin Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@@H]1OC[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 IKGXIBQEEMLURG-BKUODXTLSA-N 0.000 claims description 5
- ALABRVAAKCSLSC-UHFFFAOYSA-N rutin Natural products CC1OC(OCC2OC(O)C(O)C(O)C2O)C(O)C(O)C1OC3=C(Oc4cc(O)cc(O)c4C3=O)c5ccc(O)c(O)c5 ALABRVAAKCSLSC-UHFFFAOYSA-N 0.000 claims description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- 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 claims description 4
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 4
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 claims description 4
- ZCCUUQDIBDJBTK-UHFFFAOYSA-N psoralen Chemical compound C1=C2OC(=O)C=CC2=CC2=C1OC=C2 ZCCUUQDIBDJBTK-UHFFFAOYSA-N 0.000 claims description 4
- 235000005875 quercetin Nutrition 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- KDHWOCLBMVSZPG-UHFFFAOYSA-N 3-imidazol-1-ylpropan-1-amine Chemical compound NCCCN1C=CN=C1 KDHWOCLBMVSZPG-UHFFFAOYSA-N 0.000 claims description 3
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 3
- VXGRJERITKFWPL-UHFFFAOYSA-N 4',5'-Dihydropsoralen Natural products C1=C2OC(=O)C=CC2=CC2=C1OCC2 VXGRJERITKFWPL-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 150000002215 flavonoids Chemical class 0.000 claims description 2
- JBQATDIMBVLPRB-UHFFFAOYSA-N isoliquiritigenin Natural products OC1=CC(O)=CC=C1C1OC2=CC(O)=CC=C2C(=O)C1 JBQATDIMBVLPRB-UHFFFAOYSA-N 0.000 claims description 2
- DXDRHHKMWQZJHT-FPYGCLRLSA-N isoliquiritigenin Chemical compound C1=CC(O)=CC=C1\C=C\C(=O)C1=CC=C(O)C=C1O DXDRHHKMWQZJHT-FPYGCLRLSA-N 0.000 claims description 2
- 235000008718 isoliquiritigenin Nutrition 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 2
- 239000012670 alkaline solution Substances 0.000 claims 1
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 8
- 230000000694 effects Effects 0.000 description 6
- 208000001132 Osteoporosis Diseases 0.000 description 5
- 150000002212 flavone derivatives Chemical class 0.000 description 5
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 4
- 229940122361 Bisphosphonate Drugs 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 150000004663 bisphosphonates Chemical class 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 210000002997 osteoclast Anatomy 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000001100 (2S)-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chroman-4-one Substances 0.000 description 1
- HOSAORYWYJOQNO-UHFFFAOYSA-N 2-phenylchromen-4-one;2-phenyl-2,3-dihydrochromen-4-one Chemical group O1C2=CC=CC=C2C(=O)CC1C1=CC=CC=C1.O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 HOSAORYWYJOQNO-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- 206010065687 Bone loss Diseases 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 241000628997 Flos Species 0.000 description 1
- 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 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000003262 anti-osteoporosis Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 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 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 201000007983 brain glioma Diseases 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 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 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 229940025878 hesperidin Drugs 0.000 description 1
- 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 description 1
- 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 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 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 description 1
- 238000010883 osseointegration Methods 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000004526 pharmaceutical effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical compound [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- 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
- C07H17/07—Benzo[b]pyran-4-ones
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Physical Education & Sports Medicine (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of zoledronic acid flavone compounds, which connects zoledronic acid with flavone compounds by a chemical method to form zoledronic acid chemical compounds. The obtained product can fully play the roles of the zoledronic acid and the flavone compound, and the aim of combined treatment is fulfilled. The invention has simple preparation process, easy control of reaction, good stability, industrialization and wide popularization prospect in the field of drug synthesis.
Description
Technical Field
The invention relates to the technical field of drug synthesis, relates to a preparation method of a bisphosphonate drug, and particularly relates to a preparation method of a zoledronic acid flavone compound.
Background
Zoledronic acid is an imidazole heterocyclic bisphosphonate developed by Novartis corporation, Switzerland, belongs to the third generation of bisphosphonate class of drugs, first marketed in Canada in 10 months of 2000, and subsequently approved in more than 80 countries or regions, such as the European Union, the United states, etc., under the trade name Zomet. Zoledronic acid, which has a main pharmacological action against bone loss-induced bone mass reduction by decreasing osteoclast activity and accelerating osteoclast apoptosis, is the diphosphate having the best effect of inhibiting bone resorption. The medicine has direct antiproliferative and apoptosis promoting activity on brain glioma, hepatocarcinoma, prostatic cancer, breast cancer, etc., can be used for treating cancer, and can be widely used for treating breast cancer, neuroblastoma, osteosarcoma, prostatic cancer, hepatocarcinoma, gastric cancer, colon cancer, etc. In addition, the medicine is also a clinical common medicine for osteoporosis patients, is a known effective anti-osteoporosis medicine, and is a good foundation for researching the osseointegration of the titanium implant of the osteoporosis rat after the bilateral ovaries are removed. Meanwhile, in order to increase the pharmaceutical effect of zoledronic acid, it is often co-administered with other drugs, such as a pharmaceutical composition containing zoledronic acid and its formulation (CN 104095863B), a pharmaceutical composition for treating osteoporosis (CN 101229177B), etc.
The flavonoid compounds are compounds which exist in the nature and have a 2-phenyl chromone (flavanone) structure. Many of the flavonoids have medicinal value, such as rutin in fructus fici and flos Sophorae and hesperidin in pericarpium Citri Tangerinae, and can reduce fragility of blood vessel, improve permeability of blood vessel, and reduce blood lipid and cholesterol, and can be used for preventing and treating senile hypertension and cerebral hemorrhage, preventing osteoporosis, and delaying aging.
Therefore, the zoledronic acid and the flavonoid compounds have the effects of preventing and treating osteoporosis, and therefore, if the zoledronic acid and the flavonoid compounds act together, a more obvious effect is achieved. Although the combined application is reported at present, the new compound formed by the chemical reaction of the zoledronic acid and other compounds is not reported yet.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method of zoledronic acid flavone compounds.
The purpose of the invention is realized by the following scheme: a preparation method of zoledronic acid flavone compounds is characterized in that zoledronic acid is chemically connected with the flavone compounds to form zoledronic acid chemical compounds, and the preparation method comprises the following steps:
(1) dissolving a flavone compound with a hydroxyl group in an alkaline organic solvent, adding tosyl chloride, wherein the molar concentration of the flavone compound and the tosyl chloride is (0.5-5): 1, the reaction temperature is 80-200 ℃, the reaction time is 30-120 minutes, and introducing nitrogen for protection in the reaction process to react to obtain an intermediate;
(2) taking amino imidazole as a raw material, taking polyethylene glycol as a phase transfer catalyst in the presence of potassium carbonate, and carrying out alkylation reaction with ethyl chloroacetate at the molar concentration of 1:1 and the reaction temperature of 120 ℃ for 120 minutes; hydrolyzing and salifying to prepare amino imidazole-1-yl acetic acid hydrochloride, reacting with phosphoric acid/phosphorus trichloride, and hydrolyzing to prepare amino zoledronic acid, wherein the molar concentration is 1:1, the reaction temperature is 120 ℃, and the reaction time is 120 minutes;
(3) dissolving zoledronic acid in 0.1 mol/L alkaline aqueous solution, and refluxing for 0.5-2 hours; adding the obtained intermediate into a reaction system for reflux, wherein the molar concentration of the zoledronic acid and the intermediate is (0.5-5): 1, the reaction temperature is 80-120 ℃, and the reaction time is 30-150 minutes, so that the zoledronic acid flavone compound is obtained through reaction.
The flavone compound is one of genistein, quercetin, rutin, isoliquiritigenin, and psoralen B.
The alkaline organic solvent is one or more of ethylenediamine, triethylamine, triethanolamine, ethanolamine, dimethylformamide and pyridine.
The aminoimidazole is one of 2-aminoimidazole, 4-aminoimidazole and 1- (3-aminopropyl) imidazole.
The alkaline aqueous solution is one of sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate and ammonia water.
The obtained product can fully play the roles of the zoledronic acid and the flavone compound, and the aim of combined treatment is fulfilled.
The invention has the advantages that:
(1) the zoledronic acid and flavone compound prepared by the invention has double effects of zoledronic acid and flavone compound, and more obvious effect can be obtained;
(2) the invention has simple preparation process, easy control of reaction, good stability, industrialization and wide popularization prospect in the field of drug synthesis.
Detailed Description
The technical solution of the present invention is further described below by specific examples. The following examples are further illustrative of the present invention and do not limit the scope of the present invention.
Example 1
The zoledronic acid flavone compound is prepared by chemically connecting zoledronic acid with the flavone compound to form a zoledronic acid chemical compound according to the following steps:
(1) dissolving a flavone compound genistein with a hydroxyl group in an alkaline organic solvent ethylenediamine, adding tosyl chloride, wherein the molar concentration of the genistein to the tosyl chloride is 1:1, the reaction temperature is 200 ℃, the reaction time is 60 minutes, introducing nitrogen for protection in the reaction process, and reacting to obtain a genistein-tosyl chloride intermediate;
(2) taking 2-aminoimidazole as a raw material, taking polyethylene glycol as a phase transfer catalyst in the presence of potassium carbonate, and carrying out alkylation reaction with ethyl chloroacetate at the molar concentration of 1:1 and the reaction temperature of 120 ℃ for 120 minutes; hydrolyzing and salifying to prepare amino imidazole-1-yl acetic acid hydrochloride, reacting with phosphoric acid/phosphorus trichloride, and hydrolyzing at the molar concentration of 1:1 and the reaction temperature of 120 ℃ for 120 minutes to obtain 2-amino zoledronic acid;
(3) dissolving 2-amino zoledronic acid in 0.1 mol/L aqueous solution of sodium hydroxide, and refluxing for 1 hour; adding the obtained genistein-tosyl chloride intermediate into a reaction system for reflux, wherein the molar concentration of zoledronic acid and the genistein-tosyl chloride intermediate is 1:1, the reaction temperature is 120 ℃, and the reaction time is 30 minutes, so as to obtain the zoledronic acid-genistein.
Example 2
A zoledronic acid flavone compound, similar to the example, is prepared by the following steps:
(1) dissolving a flavone compound quercetin with hydroxyl groups in an alkaline organic solvent triethylamine, adding tosyl chloride, wherein the molar concentration of the quercetin and the tosyl chloride is 3:1, the reaction temperature is 150 ℃, the reaction time is 120 minutes, and introducing nitrogen for protection in the reaction process to react to obtain a quercetin-tosyl chloride intermediate;
(2) taking 2-aminoimidazole as a raw material, taking polyethylene glycol as a phase transfer catalyst in the presence of potassium carbonate, and carrying out alkylation reaction with ethyl chloroacetate at the molar concentration of 1:1 and the reaction temperature of 120 ℃ for 120 minutes; hydrolyzing and salifying to prepare amino imidazole-1-yl acetic acid hydrochloride, reacting with phosphoric acid/phosphorus trichloride, and hydrolyzing at the molar concentration of 1:1 and the reaction temperature of 120 ℃ for 120 minutes to obtain 2-amino zoledronic acid;
(3) dissolving 2-amino zoledronic acid in 0.1 mol/L alkaline aqueous solution, and refluxing for 1 hour; adding the obtained quercetin-tosyl chloride intermediate into a reaction system for reflux, wherein the molar concentration of the 2-amino zoledronic acid and the quercetin-tosyl chloride intermediate is 3:1, the reaction temperature is 100 ℃, the reaction time is 60 minutes, and the 2-amino zoledronic acid-quercetin is obtained by reaction.
Example 3
A zoledronic acid flavone compound, similar to the example, is prepared by the following steps:
(1) dissolving a flavone compound rutin with a hydroxyl group in an alkaline organic solvent triethanolamine, adding tosyl chloride, wherein the molar concentration of the flavone compound rutin and the tosyl chloride is 5:1, the reaction temperature is 100 ℃, the reaction time is 100 minutes, and introducing nitrogen for protection in the reaction process to obtain a rutin-tosyl chloride intermediate;
(2) 4-amino imidazole is used as a raw material, and polyethylene glycol is used as a phase transfer catalyst in the presence of potassium carbonate to carry out alkylation reaction with ethyl chloroacetate, wherein the molar concentration is 1:1, the reaction temperature is 120 ℃, and the reaction time is 120 minutes; hydrolyzing and salifying to prepare amino imidazole-1-yl acetic acid hydrochloride, reacting with phosphoric acid/phosphorus trichloride, and hydrolyzing to prepare 4-amino zoledronic acid, wherein the molar concentration is 1:1, the reaction temperature is 120 ℃, and the reaction time is 120 minutes;
(3) 4-amino zoledronic acid is dissolved in 0.1 mol/L sodium bicarbonate water solution and refluxed for 0.5 hour; adding the obtained rutin-tosyl chloride intermediate into a reaction system for reflux, wherein the molar concentration of 4-amino zoledronic acid and the rutin-tosyl chloride intermediate is 5:1, the reaction temperature is 80 ℃, the reaction time is 150 minutes, and the 4-amino zoledronic acid-rutin is obtained through reaction.
Example 4
A preparation method of zoledronic acid flavone compounds is characterized in that zoledronic acid is chemically connected with the flavone compounds to form zoledronic acid chemical compounds, and the preparation method comprises the following steps:
(1) dissolving a flavone compound genistein with a hydroxyl group in alkaline organic solvent triethanolamine, adding tosyl chloride, wherein the molar concentration of the genistein to the tosyl chloride is 1:1, the reaction temperature is 80 ℃, the reaction time is 120 minutes, introducing nitrogen for protection in the reaction process, and reacting to obtain a genistein-tosyl chloride intermediate;
(2) 1- (3-aminopropyl) imidazole is used as a raw material, and is subjected to alkylation reaction with ethyl chloroacetate in the presence of potassium carbonate by using polyethylene glycol as a phase transfer catalyst, wherein the molar concentration is 1:1, the reaction temperature is 120 ℃, and the reaction time is 120 minutes; then, preparing amino imidazole-1-yl acetic acid hydrochloride through hydrolysis and salification, reacting with phosphoric acid/phosphorus trichloride, and hydrolyzing, wherein the molar concentration is 1:1, the reaction temperature is 120 ℃, and the reaction time is 120 minutes, so as to prepare 1- (3-aminopropyl) zoledronic acid;
(3) dissolving 1- (3-aminopropyl) zoledronic acid in 0.1 mol/L alkaline aqueous solution, and refluxing for 0.5 hour; adding the obtained genistein-tosyl chloride intermediate into a reaction system for reflux, wherein the molar concentration of 1- (3-aminopropyl) zoledronic acid and the genistein-tosyl chloride intermediate is 1:1, the reaction temperature is 80 ℃, the reaction time is 150 minutes, and the 1- (3-aminopropyl) zoledronic acid-genistein is obtained through reaction.
Claims (5)
1. A preparation method of zoledronic acid flavone compounds is characterized in that zoledronic acid is chemically connected with the flavone compounds to form zoledronic acid chemical compounds, and the preparation method comprises the following steps:
(1) dissolving a flavone compound with a hydroxyl group in an alkaline organic solvent, adding tosyl chloride, wherein the molar concentration of the flavone compound and the tosyl chloride is (0.5-5): 1, the reaction temperature is 80-200 ℃, the reaction time is 30-120 minutes, and introducing nitrogen for protection in the reaction process to react to obtain an intermediate;
(2) taking amino imidazole as a raw material, taking polyethylene glycol as a phase transfer catalyst in the presence of potassium carbonate, and carrying out alkylation reaction with ethyl chloroacetate at the molar concentration of 1:1 and the reaction temperature of 120 ℃ for 120 minutes; hydrolyzing and salifying to prepare amino imidazole-1-yl acetic acid hydrochloride, reacting with phosphoric acid/phosphorus trichloride, and hydrolyzing to prepare amino zoledronic acid, wherein the molar concentration is 1:1, the reaction temperature is 120 ℃, and the reaction time is 120 minutes;
(3) dissolving zoledronic acid in 0.1 mol/L alkaline aqueous solution, and refluxing for 0.5-2 hours; adding the obtained intermediate into a reaction system for reflux, wherein the molar concentration of the zoledronic acid and the intermediate is (0.5-5): 1, the reaction temperature is 80-120 ℃, and the reaction time is 30-150 minutes, so that the zoledronic acid flavone compound is obtained through reaction.
2. The method of claim 1, wherein the flavonoid is one of genistein, quercetin, rutin, isoliquiritigenin, and psoralen.
3. The method for preparing zoledronic acid flavone compound according to claim 1, wherein said basic organic solvent is one or more of ethylenediamine, triethylamine, triethanolamine, ethanolamine, dimethylformamide, and pyridine.
4. The method of claim 1, wherein the aminoimidazole is one of 2-aminoimidazole, 4-aminoimidazole and 1- (3-aminopropyl) imidazole.
5. The method of claim 1, wherein the aqueous alkaline solution is one of sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, and ammonia.
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| WO2017132263A1 (en) * | 2016-01-25 | 2017-08-03 | SEWELL, William | Phosphonate-drug conjugates |
| CN110240582A (en) * | 2019-06-21 | 2019-09-17 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | A kind of chromocor derivative and the preparation method and application thereof with inhibition tumour cell |
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