CN103588750B - Method for preparing ticagrelor intermediate - Google Patents
Method for preparing ticagrelor intermediate Download PDFInfo
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- CN103588750B CN103588750B CN201310547549.8A CN201310547549A CN103588750B CN 103588750 B CN103588750 B CN 103588750B CN 201310547549 A CN201310547549 A CN 201310547549A CN 103588750 B CN103588750 B CN 103588750B
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- 238000000034 method Methods 0.000 title abstract description 8
- PYEJQVYISBUGDU-UHFFFAOYSA-N 2-(3,4-difluorophenyl)cyclopropane-1-carboxamide Chemical compound NC(=O)C1CC1C1=CC=C(F)C(F)=C1 PYEJQVYISBUGDU-UHFFFAOYSA-N 0.000 title abstract 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 50
- 238000002360 preparation method Methods 0.000 claims abstract description 26
- 238000006722 reduction reaction Methods 0.000 claims abstract description 16
- 238000006266 etherification reaction Methods 0.000 claims abstract description 7
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 claims abstract 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 18
- 239000001301 oxygen Substances 0.000 claims description 18
- 229910052760 oxygen Inorganic materials 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 150000001875 compounds Chemical class 0.000 claims description 11
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000005977 Ethylene Substances 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 5
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 claims description 5
- 229960002510 mandelic acid Drugs 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 5
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 5
- 229910052725 zinc Inorganic materials 0.000 claims description 5
- 239000011701 zinc Substances 0.000 claims description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-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
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 238000007142 ring opening reaction Methods 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 230000002829 reductive effect Effects 0.000 claims description 3
- DNISEZBAYYIQFB-PHDIDXHHSA-N (2r,3r)-2,3-diacetyloxybutanedioic acid Chemical compound CC(=O)O[C@@H](C(O)=O)[C@H](C(O)=O)OC(C)=O DNISEZBAYYIQFB-PHDIDXHHSA-N 0.000 claims description 2
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 claims description 2
- 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 claims description 2
- MIOPJNTWMNEORI-XVKPBYJWSA-N (R)-camphorsulfonic acid Chemical compound C1C[C@]2(CS(O)(=O)=O)C(=O)C[C@H]1C2(C)C MIOPJNTWMNEORI-XVKPBYJWSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-UWTATZPHSA-N (R)-malic acid Chemical compound OC(=O)[C@H](O)CC(O)=O BJEPYKJPYRNKOW-UWTATZPHSA-N 0.000 claims description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 2
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 claims description 2
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-LWMBPPNESA-L D-tartrate(2-) Chemical compound [O-]C(=O)[C@@H](O)[C@H](O)C([O-])=O FEWJPZIEWOKRBE-LWMBPPNESA-L 0.000 claims description 2
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 claims description 2
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 claims description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 2
- 229910052772 Samarium Inorganic materials 0.000 claims description 2
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- 239000004411 aluminium Substances 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- 229960005261 aspartic acid Drugs 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 238000005194 fractionation Methods 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 2
- 229910052738 indium Inorganic materials 0.000 claims description 2
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- 229940116298 l- malic acid Drugs 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- KZUNJOHGWZRPMI-UHFFFAOYSA-N samarium atom Chemical compound [Sm] KZUNJOHGWZRPMI-UHFFFAOYSA-N 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 229910052718 tin Inorganic materials 0.000 claims description 2
- 239000011135 tin Substances 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 239000011630 iodine Substances 0.000 claims 1
- 230000009467 reduction Effects 0.000 abstract description 12
- 239000002994 raw material Substances 0.000 abstract description 8
- OEKWJQXRCDYSHL-FNOIDJSQSA-N ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 abstract description 4
- 229960002528 ticagrelor Drugs 0.000 abstract description 4
- 230000008901 benefit Effects 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 abstract 1
- 239000008186 active pharmaceutical agent Substances 0.000 abstract 1
- 238000007098 aminolysis reaction Methods 0.000 abstract 1
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 150000002576 ketones Chemical class 0.000 abstract 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 abstract 1
- 0 CC(C)(O[C@@]1*(CO)O2)O[C@@]1C2=O Chemical compound CC(C)(O[C@@]1*(CO)O2)O[C@@]1C2=O 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- PYMYPHUHKUWMLA-LMVFSUKVSA-N aldehydo-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- 230000032050 esterification Effects 0.000 description 4
- 238000005886 esterification reaction Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000003368 amide group Chemical group 0.000 description 3
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 3
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000002633 protecting effect Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 1
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 1
- JUFVTLATTDPLJO-NQPNHJOESA-N CC(C)(O[C@@H]1C(C2)O)OC1=C2N Chemical compound CC(C)(O[C@@H]1C(C2)O)OC1=C2N JUFVTLATTDPLJO-NQPNHJOESA-N 0.000 description 1
- PYQVLBGTFIFUGH-YSLANXFLSA-N CC(C)(O[C@@H]1C(CI)O2)O[C@H]1C2=O Chemical compound CC(C)(O[C@@H]1C(CI)O2)O[C@H]1C2=O PYQVLBGTFIFUGH-YSLANXFLSA-N 0.000 description 1
- UPFLIGKDIHZWMZ-RKXXOXFUSA-N CC1(C)O[C@H]2C(O)OC(CI)[C@H]2O1 Chemical compound CC1(C)O[C@H]2C(O)OC(CI)[C@H]2O1 UPFLIGKDIHZWMZ-RKXXOXFUSA-N 0.000 description 1
- KYPBTFBELUVCHH-XBDOLRODSA-N CC[C@@H](C)[C@H]1OC(C)(C)O[C@H]1/C=N/OCc1ccccc1 Chemical compound CC[C@@H](C)[C@H]1OC(C)(C)O[C@H]1/C=N/OCc1ccccc1 KYPBTFBELUVCHH-XBDOLRODSA-N 0.000 description 1
- 238000005698 Diels-Alder reaction Methods 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 208000022120 Jeavons syndrome Diseases 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- DCKVGYMEVQQASB-UHFFFAOYSA-N OCC(OCC1O)=C1O Chemical compound OCC(OCC1O)=C1O DCKVGYMEVQQASB-UHFFFAOYSA-N 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 125000006317 cyclopropyl amino group Chemical group 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 230000013011 mating Effects 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- 238000005502 peroxidation Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 239000000719 purinergic P2Y receptor antagonist Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing a ticagrelor intermediate 2-[[(3aR, 4S, 6R, 6aS)-6-aminotetralin-2, 2-dimethyl-4H-cyclopenteno-1,3-dioxin-4-group]oxygroup] ethanol (intermediate C). The method comprises the following steps: using (1R, 2R, 3R.4R)-rel-1,2 and 3, 4 bicyclo oxacyclopentane (I) as raw materials and obtaining a target product sequentially through nitrine opening ring, aminolysis, ketone condensation, etherification, reduction, resolution and the like. The preparation method has the advantages of being easy to obtain raw materials and simple in process, can effectively control the production cost, increases the quality of products, and promotes economic and technological development of ticagrelor active pharmaceutical ingredients.
Description
Technical field
The invention belongs to organic synthetic route design and bulk drug thereof and intermediate preparing technical field, particularly a kind of ADZ6140 intermediate 2-[[(3aR, 4S, 6R, amino tetrahydrochysene-2 of 6aS)-6-, 2-dimethyl-4H-cyclopenta-1,3-dioxa-4-yl] oxygen base] preparation method of ethanol.
Background technology
ADZ6140 (Ticagrelor, also claim ticagrelor) Shi You Astrazeneca AB research and development a kind of novel, there is optionally small molecules anticoagulant, also be the oral P2Y12 adenosine diphosphate receptor antagonists of first reversible mating type, the platelet aggregation that ADP is caused has obvious restraining effect, can effectively improve acute coronary patient's symptom.This medicine went on the market by examining in European Union and the U.S. of drug administration of European Union (EMEA) and FDA (Food and Drug Adminstration) (FDA) respectively in 2010 and 2011, and its import preparation ticagrelor sheet has obtained CFDA approval and gone on the market in China.
Chemistry (1S, 2S, 3R, 5S)-3-[7-[(1R by name of ADZ6140,2S)-2-(3,4-difluorophenyl) cyclopropyl amino]-5-(the third sulfydryl)-3H-[1,2,3] triazole [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyl-oxethyl) pentamethylene-1,2-glycol.
The existing a lot of reports of the preparation method of ADZ6140, as the patents such as WO2010030224, WO2011036479, CN1680340, WO2012138981, WO2012142983, CN101143864, CN102731467, CN102659815, CN102675321, CN103130726, CN103242171, CN103304535, CN103304545, CN103288836, CN103304567, CN103288837, CN103360396 by different synthetic design studies the preparation method of ADZ6140.After analyzing published synthetic route and preparation method, find, in known preparation method, mostly can relate to following three intermediate A, B and C.
The chemistry of the intermediate C of the present invention's research is by name: 2-[[(3aR, 4S, 6R, 6aS) amino tetrahydrochysene-2 of-6-, 2-dimethyl-4H-cyclopenta-1,3-dioxa-4-yl] oxygen base] ethanol, its synthetic route mainly contains following several:
Patent WO2011017108, WO9905142, CN102659815 etc. have reported take cyclopentadiene as raw material; by Diels-Alder, be reacted into ring, then obtain target intermediate C through steps such as peroxidation, ketal, reduction, amido protecting, esterification and reduction, deprotections.
Patent WO9905143, WO99828300, WO0034283, WO0136421, WO01092263, WO2010069408, WO2010022121 and WO2012063126 etc. have reported that a kind of to take chiral carbocyclic ring intermediate (V) be raw material, by steps such as the aminating reaction under triphenylphosphine palladium catalysis and oxidation, acidolysis, ketal, reduction, amido protecting, esterification and reduction, deprotections, obtain target intermediate C.
The another kind of method of comparatively generally using is to take D-ribose as starting raw material, by its intrinsic natural chiral center, controls optical purity in preparation process.Patent WO2011017108, WO2013092900 and < < Bioorganic & Medicinal Chemistry Letters > > 22 phases in 2012 3598-3602 page have reported that D-ribose is by the method that fork acetonization, 1-position methylate, the step such as 5-iodo, the open loop of zinc/acetic acid, hydroxylamination, cyclization, amido protecting, esterification and reduction, deprotection is prepared intermediate C.
Same use D-ribose is starting raw material, and patent WO9703084, < < Tetrahedron:Asymmetry > > 2 volumes 961-964 page in 1991 and 8 volumes 2249-2256 page in 1997 have been reported the another kind of preparation that realizes intermediate C by steps such as fork acetonization, 5-position iodo, lactone reduction, the reaction of oxime ether, cyclization, configuration conversion, hydroxy esterification and reduction, deprotections.
As can be seen here, though at present the preparation of ADZ6140 intermediate C is had to more research report, but all there is many defects, as step is long, raw material is rare, yield is on the low side, separation difficulty, heavy contamination, safety restriction or cost more high, these unfavorable factors make the industrialization of above-mentioned technique be subject to certain restriction.
Summary of the invention
The object of the invention is to overcome the defect of prior art, according to the synthetic theory of Green Chemistry, provide a kind of new ADZ6140 intermediate 2-[[(3aR, 4S, 6R, amino tetrahydrochysene-2 of 6aS)-6-, 2-dimethyl-4H-cyclopenta-1,3-dioxa-4-yl] oxygen base] preparation method of ethanol, this preparation method is easy, economy and environmental protection, the suitability for industrialized production that is conducive to this medicine, and can promote the economic technology of ADZ6140 bulk drug to develop.
To achieve these goals, main technical schemes provided by the present invention is as follows: a kind of ADZ6140 intermediate 2-[[(3aR, 4S, 6R, 6aS) amino tetrahydrochysene-2 of-6-, 2-dimethyl-4H-cyclopenta-1,3-dioxa-4-yl] oxygen base] preparation method of ethanol (intermediate C)
The method comprises the steps: (1R, 2R, 3R.4R)-rel-1,2; 3,4-diepoxy pentamethylene (I) occurs to obtain compound (3aR with ring-opening reaction and the ketal reaction of sodiumazide in acetone and water mixed solvent simultaneously, 4S, 6R, 6aS)-rel-6-azido-tetrahydrochysene-2,2-dimethyl-4H-cyclopenta-1,3-dioxa-4-alcohol (II); Compound (II) generates compound 2-[[(3aR by carrying out etherification reaction with 2-ethylene halohydrin, 4S, 6R, 6aS)-rel-6-azido-tetrahydrochysene-2,2-dimethyl-4H-cyclopenta-1,3-dioxa-4-yl] oxygen base] ethanol (III), compound (III) obtains 2-[[(3aR through reduction reaction, 4S, 6R, amino tetrahydrochysene-2 of 6aS)-rel-6-, 2-dimethyl-4H-cyclopenta-1,3-dioxa-4-yl] oxygen base] ethanol (IV); Compound (IV) obtains 2-[[(3aR by fractionation, 4S, 6R, 6aS) amino tetrahydrochysene-2 of-6-, 2-dimethyl-4H-cyclopenta-1,3-dioxa-4-yl] oxygen base] ethanol (intermediate C).
In addition, the present invention also provides following attached technical scheme:
(1R, 2R, 3R.4R)-rel-1 in described ring-opening reaction, 2; The molar ratio of 3,4-diepoxy pentamethylene (I) and sodiumazide is 1:1-3, preferably 1:1.1-1.3.
Described acetone and water mixed solvent are acetone/water system, and its volume ratio is acetone/water=1/0.5-1.5, preferably 1/1.
(3aR, 4S, 6R, 6aS)-rel-6-azido-tetrahydrochysene-2 in described etherification reaction, 2-dimethyl-4H-cyclopenta-1,3-dioxa-4-alcohol (II) is 1:1-3 with the molar ratio of 2-ethylene halohydrin, preferably 1:1.5-2.0.
Halogen in described 2-ethylene halohydrin is chlorine, bromine or iodine, preferably chlorine or bromine.
The acid binding agent of described etherification reaction is salt of wormwood, potassium hydroxide, potassium tert.-butoxide, sodium methylate, sodium hydride, triethylamine, pyridine or sodium hydroxide, preferably potassium tert.-butoxide or sodium hydride.
Described reduction reaction can adopt the reduction of metallic iron, zinc, tin, aluminium, indium or samarium, also can adopt hydrazine hydrate/iron trichloride, sodium borohydride, zinc borohydride or Lithium Aluminium Hydride reduction, also can adopt this ester 1 of the Chinese under the katalysis of palladium charcoal, 4-dihydropyridine (HEH) reduction, preferably this ester Isosorbide-5-Nitrae-dihydropyridine (HEH) reduction of the Chinese under the katalysis of palladium charcoal.
The resolving agent of described resolution reaction is L-TARTARIC ACID, D-tartrate, L-amygdalic acid, D-amygdalic acid, diacetyl-L-TARTARIC ACID, dibenzoyl-L-tartaric acid, D-camphorsulfonic acid, L-camphorsulfonic acid, L-phenylglycine, D-PG, L MALIC ACID, D-malic acid, L-Aspartic acid or Pidolidone, preferably L-TARTARIC ACID or D-amygdalic acid.
Than prior art, ADZ6140 intermediate 2-[[(3aR involved in the present invention, 4S, 6R, amino tetrahydrochysene-2 of 6aS)-6-, 2-dimethyl-4H-cyclopenta-1,3-dioxa-4-yl] oxygen base] preparation method of ethanol, its advantage is mainly that synthesis step is succinct, the gentle easily control of reaction conditions, raw material is cheap and easy to get, and product yield and product purity are high, are suitable for large-scale industrial production.
Embodiment
Embodiment mono-:
In reaction flask, add (1R, 2R, 3R.4R)-rel-1,2; 3,4-diepoxy pentamethylene (I) (9.8g, 0.1mol), sodiumazide (8.13g, 0.125mol) and acetone/water (1/1) mixed solvent 200mL, start stirring, is warming up to 45-50 ℃, reacts 72 hours, and GC detection reaction completes.Add ether to solution layering, separate organic phase.Water extracts 5 times with ether and acetone (4:1) 100mL.Merge organic phase, anhydrous magnesium sulfate drying.Concentrating under reduced pressure, residue obtains white solid (3aR, 4S, 6R, 6aS)-rel-6-azido-tetrahydrochysene-2,2-dimethyl-4H-cyclopenta-1,3-dioxa-4-alcohol (II) 9.0g, yield 45.2% through column chromatography (ether/Skellysolve A=5/1).
Embodiment bis-:
Under nitrogen protection, in reaction flask, add (3aR, 4S; 6R; 6aS)-rel-6-azido-tetrahydrochysene-2,2-dimethyl-4H-cyclopenta-1,3-dioxa-4-alcohol (II) (8.0g; 0.04mol), Tetrabutyl amonium bromide (phase-transfer catalyst) 0.25g and dry toluene 100mL; under stirring, add sodium hydride (1.92g, 0.08mol) in batches, drip ethylene bromohyrin (9.92g; 0.08mol), and be slowly warming up to backflow.Keep back flow reaction approximately 24 hours, TLC detection reaction completes.Be cooled to room temperature, add water and stir 15 minutes, layering.Organic phase salt water washing, anhydrous sodium sulfate drying.Vacuum distillation recovered solvent, remaining oily matter normal hexane recrystallization, obtains white solid 2-[[(3aR, 4S, 6R, 6aS)-rel-6-azido-tetrahydrochysene-2,2-dimethyl-4H-cyclopenta-1,3-dioxa-4-yl] oxygen base] ethanol (III) 8.1g, yield 83.3%.
Embodiment tri-:
Under nitrogen protection, in reaction flask, add 2-[[(3aR, 4S; 6R; 6aS)-rel-6-azido-tetrahydrochysene-2,2-dimethyl-4H-cyclopenta-1,3-dioxa-4-yl] oxygen base]-ethanol (III) (7.3g; 0.03mol), this ester 1 of the Chinese; 4-dihydropyridine (9.1g, 0.036mol), 10% palladium charcoal 1.8g and ethanol 50mL, start stirring; be heated to reflux and keep back flow reaction 5 hours, TLC detection reaction completes.Be cooled to room temperature, filter, reclaim catalyzer.Concentrating under reduced pressure, residue is dissolved in methylene dichloride, uses successively 5% hydrochloric acid, saturated aqueous common salt and water washing.Anhydrous sodium sulfate drying, vacuum distillation recovered solvent, obtains light yellow oil 2-[[(3aR, 4S, 6R, 6aS) amino tetrahydrochysene-2 of-rel-6-, 2-dimethyl-4H-cyclopenta-1,3-dioxa-4-yl] oxygen base] ethanol (IV) 5.9g, yield 90.6%.
Embodiment tetra-:
In reaction flask, add 2-[[(3aR, 4S, 6R, amino tetrahydrochysene-2 of 6aS)-rel-6-, 2-dimethyl-4H-cyclopenta-1,3-dioxa-4-yl] oxygen base]-ethanol (IV) (4.4g, 0.02mol), with acetic acid ethyl dissolution, add L-TARTARIC ACID (3.0g, 0.02mol), stirring at room 6-8 hour, be cooled to 0 ℃, filter the L-TARTARIC ACID salt that gained solid is target product.This solid is placed in to 50mL water, with 30% sodium hydroxide, regulates pH to 12-13, be extracted with ethyl acetate 3 times, merge organic phase.Dry, decompression and solvent recovery, the oily matter 2-[[(3aR obtaining, 4S, 6R, 6aS) amino tetrahydrochysene-2 of-6-, 2-dimethyl-4H-cyclopenta-1,3-dioxa-4-yl] oxygen base] ethanol (intermediate C) 1.85g, yield 84.1%.
It is pointed out that above-mentioned preferred embodiment is only explanation technical conceive of the present invention and feature, its object is to allow person skilled in the art can understand content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalences that spirit is done according to the present invention change or modify, within all should being encompassed in protection scope of the present invention.
Claims (10)
1. an ADZ6140 intermediate 2-[[(3aR, 4S, 6R, 6aS) amino tetrahydrochysene-2 of-6-, 2-dimethyl-4H-cyclopenta-1,3-dioxa-4-yl] oxygen base] preparation method of ethanol (intermediate C),
It is characterized in that this preparation method comprises the steps: (1R, 2R, 3R.4R)-rel-1,2; 3,4-diepoxy pentamethylene (I) obtains compound (3aR, 4S with sodiumazide generation ring-opening reaction and ketal reaction in acetone and water mixed solvent simultaneously, 6R, 6aS)-rel-6-azido-tetrahydrochysene-2,2-dimethyl-4H-cyclopenta-1,3-dioxa-4-alcohol (II); Described compound (II) generates compound 2-[[(3aR by carrying out etherification reaction with 2-ethylene halohydrin, 4S, 6R, 6aS)-rel-6-azido-tetrahydrochysene-2,2-dimethyl-4H-cyclopenta-1,3-dioxa-4-yl] oxygen base] ethanol (III), described compound (III) obtains compound 2-[[(3aR, 4S through reduction reaction, 6R, amino tetrahydrochysene-2 of 6aS)-rel-6-, 2-dimethyl-4H-cyclopenta-1,3-dioxa-4-yl] oxygen base] ethanol (IV); Described compound (IV) obtains 2-[[(3aR by fractionation, 4S, 6R, 6aS) amino tetrahydrochysene-2 of-6-, 2-dimethyl-4H-cyclopenta-1,3-dioxa-4-yl] oxygen base] ethanol (intermediate C).
2. the preparation method of ADZ6140 intermediate according to claim 1, is characterized in that: (1R, 2R, 3R.4R)-rel-1 in described nitrine ring-opening reaction, 2; The molar ratio of 3,4-diepoxy pentamethylene (I) and sodiumazide is 1:1-3.
3. the preparation method of ADZ6140 intermediate according to claim 2, is characterized in that: the preferred 1:1.1-1.3 of described molar ratio.
4. the preparation method of ADZ6140 intermediate according to claim 2, is characterized in that: the volume ratio of described acetone and water mixed solvent is acetone/water=1/0.5-1.5.
5. the preparation method of ADZ6140 intermediate according to claim 4, is characterized in that: described volume ratio preferably 1/1.
6. the preparation method of ADZ6140 intermediate according to claim 1, it is characterized in that: (3aR in described etherification reaction, 4S, 6R, 6aS)-rel-6-azido-tetrahydrochysene-2,2-dimethyl-4H-cyclopenta-1,3-dioxa-4-alcohol (II) is 1:1-3 with the molar ratio of 2-ethylene halohydrin.
7. the preparation method of ADZ6140 intermediate according to claim 6, is characterized in that: the halogen in described 2-ethylene halohydrin is chlorine, bromine or iodine.
8. the preparation method of ADZ6140 intermediate according to claim 6, is characterized in that: the acid binding agent of described etherification reaction is salt of wormwood, potassium hydroxide, potassium tert.-butoxide, sodium methylate, sodium hydride, triethylamine, pyridine or sodium hydroxide.
9. the preparation method of ADZ6140 intermediate according to claim 1, it is characterized in that: described reduction reaction reductive agent is this ester Isosorbide-5-Nitrae-dihydropyridine/palladium charcoal of iron, zinc, tin, aluminium, indium, samarium, hydrazine hydrate/iron trichloride, sodium borohydride, zinc borohydride or the Chinese.
10. the preparation method of ADZ6140 intermediate according to claim 1; it is characterized in that: described 2-[[(3aR; 4S; 6R; amino tetrahydrochysene-2 of 6aS)-rel-6-; 2-dimethyl-4H-cyclopenta-1,3-dioxa-4-yl] oxygen base] resolving agent of ethanol (IV) is L-TARTARIC ACID, D-tartrate, L-amygdalic acid, D-amygdalic acid, diacetyl-L-TARTARIC ACID, dibenzoyl-L-tartaric acid, D-camphorsulfonic acid, L-camphorsulfonic acid, L-phenylglycine, D-PG, L MALIC ACID, D-malic acid, L-Aspartic acid or Pidolidone.
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