CN103588750B - 替卡格雷中间体的制备方法 - Google Patents
替卡格雷中间体的制备方法 Download PDFInfo
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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
本发明揭示了一种替卡格雷中间体2-[[(3aR，4S，6R，6aS)-6-氨基四氢-2，2-二甲基-4H-环戊烯并-1，3-二氧杂-4-基]氧基]乙醇(中间体C)的制备方法。该制备方法以(1R，2R，3R.4R)-rel-1，2；3，4-二环氧环戊烷(I)为原料，依次通过叠氮开环、缩酮化、醚化、还原和拆分等步骤得到目标产物。该制备方法原料易得，工艺简洁，可以有效控制其生产成本，并使产品的品质得到提高，促进替卡格雷原料药的经济技术发展。
Description
技术领域
本发明属于有机合成路线设计及其原料药和中间体制备技术领域，特别涉及一种替卡格雷中间体2-[[(3aR,4S,6R,6aS)-6-氨基四氢-2,2-二甲基-4H-环戊烯并-1，3-二氧杂-4-基]氧基]乙醇的制备方法。
背景技术
替卡格雷(Ticagrelor，亦称替格瑞洛)是由阿斯利康公司研发的一种新型的、具有选择性的小分子抗凝血药，也是第一个可逆的结合型口服P2Y12腺苷二磷酸受体拮抗剂，对ADP引起的血小板聚集有明显的抑制作用，能有效改善急性冠心病患者的症状。该药于2010年和2011年分别通过欧盟药品管理局(EMEA)和美国食品药品管理局(FDA)的审批在欧盟及美国上市，其进口制剂替格瑞洛片已获CFDA批准在我国上市。
替卡格雷的化学名为(1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3，4-二氟苯基)环丙胺基]-5-(丙巯基)-3H-[1，2，3]***[4，5-d]嘧啶-3-基]-5-(2-羟基乙氧基)环戊烷-1，2-二醇。
替卡格雷的制备方法已有很多报道，如WO2010030224、WO2011036479、CN1680340、WO2012138981、WO2012142983、CN101143864、CN102731467、CN102659815、CN102675321、CN103130726、CN103242171、CN103304535、CN103304545、CN103288836、CN103304567、CN103288837、CN103360396等专利通过不同的合成设计研究了替卡格雷的制备方法。分析已公开的合成路线和制备方法后发现，在已知的制备方法中，大多会涉及以下三个中间体A、B及C。
本发明研究的中间体C的化学名为：2-[[(3aR,4S,6R,6aS)-6-氨基四氢-2,2-二甲基-4H-环戊烯并-1，3-二氧杂-4-基]氧基]乙醇，其合成路线主要有以下几种：
专利WO2011017108、WO9905142、CN102659815等报道了以环戊二烯为原料，通过Diels-Alder反应成环，再经过氧化、缩酮化、还原、氨基保护、酯化和还原、脱保护等步骤得到目标中间体C。
专利WO9905143、WO99828300、WO0034283、WO0136421、WO01092263、WO2010069408、WO2010022121和WO2012063126等报道了一种以手性碳环中间体(V)为原料，通过三苯基膦钯催化下的氨化反应以及氧化、酸解、缩酮化、还原、氨基保护、酯化和还原、脱保护等步骤得到目标中间体C。
另一种较为普遍使用的方法是以D-核糖为起始原料，通过其固有的天然手性中心，控制制备过程中光学纯度。专利WO2011017108、WO2013092900和《Bioorganic & MedicinalChemistry Letters》2012年22期第3598-3602页报道了D-核糖通过叉丙酮化、1-位甲基化、5-碘代、锌／乙酸开环、羟胺化、环合、氨基保护、酯化和还原、脱保护等步骤制备中间体C的方法。
同样使用D-核糖为起始原料，专利WO9703084、《Tetrahedron：Asymmetry》1991年2卷第961-964页和1997年8卷第2249-2256页报道了另一种通过叉丙酮化、5-位碘代、内酯还原、肟醚反应、环合、构型转化、羟基酯化和还原、脱保护等步骤实现中间体C的制备。
由此可见，目前对替卡格雷中间体C的制备虽有较多的研究报道，但都存在诸多缺陷，如步骤较长、原料难得、收率偏低、分离困难、污染较重、安全制约或成本较高等，这些不利因素使得上述工艺的工业化受到一定的制约。
发明内容
本发明的目的在于克服现有技术的缺陷，按照绿色化学的合成理念，提供一种新的替卡格雷中间体2-[[(3aR,4S,6R,6aS)-6-氨基四氢-2,2-二甲基-4H-环戊烯并-1，3-二氧杂-4-基]氧基]乙醇的制备方法，该制备方法简便、经济和环保，有利于该药品的工业化生产，并能促进替卡格雷原料药的经济技术发展。
为了实现上述目的，本发明所提供的主要技术方案如下：一种替卡格雷中间体2-[[(3aR,4S,6R,6aS)-6-氨基四氢-2,2-二甲基-4H-环戊烯并-1，3-二氧杂-4-基]氧基]乙醇(中间体C)的制备方法，
该方法包括如下步骤：(1R,2R,3R.4R)-rel-1，2；3，4-二环氧环戊烷(I)在丙酮和水混合溶剂中同时发生与叠氮化钠的开环反应及缩酮化反应得到化合物(3aR,4S,6R,6aS)-rel-6-叠氮基四氢-2,2-二甲基-4H-环戊烯并-1，3-二氧杂-4-醇(II)；化合物(II)通过与2-卤代乙醇进行醚化反应生成化合物2-[[(3aR,4S,6R，6aS)-rel-6-叠氮基四氢-2,2-二甲基-4H-环戊烯并-1，3-二氧杂-4-基]氧基]乙醇(III)，化合物(III)经还原反应得到2-[[(3aR,4S,6R,6aS)-rel-6-氨基四氢-2,2-二甲基-4H-环戊烯并-1，3-二氧杂-4-基]氧基]乙醇(IV)；化合物(IV)通过拆分得到2-[[(3aR,4S,6R,6aS)-6-氨基四氢-2,2-二甲基-4H-环戊烯并-1，3-二氧杂-4-基]氧基]乙醇(中间体C)。
此外，本发明还提供如下附属技术方案：
所述开环反应中(1R,2R,3R.4R)-rel-1，2；3，4-二环氧环戊烷(I)和叠氮化钠的投料摩尔比为1：1-3，优选1：1.1-1.3。
所述丙酮和水混合溶剂为丙酮／水体系，其体积比为丙酮／水=1／0.5-1.5，优选1／1。
所述醚化反应中(3aR,4S,6R,6aS)-rel-6-叠氮基四氢-2,2-二甲基-4H-环戊烯并-1，3-二氧杂-4-醇(II)与2-卤代乙醇的投料摩尔比为1：1-3，优选1：1.5-2.0。
所述2-卤代乙醇中的卤素为氯、溴或碘，优选氯或溴。
所述醚化反应的缚酸剂为碳酸钾、氢氧化钾、叔丁醇钾、甲醇钠、氢化钠、三乙胺、吡啶或氢氧化钠，优选叔丁醇钾或氢化钠。
所述还原反应可采用金属铁、锌、锡、铝、铟或钐的还原，也可采用水合肼／三氯化铁、硼氢化钠、硼氢化锌或四氢铝锂还原，还可采用钯炭催化作用下的汉斯酯1，4-二氢吡啶(HEH)还原，优选钯炭催化作用下的汉斯酯1，4-二氢吡啶(HEH)还原。
所述拆分反应的拆分剂为L-酒石酸、D-酒石酸、L-扁桃酸、D-扁桃酸、二乙酰基-L-酒石酸、二苯甲酰-L-酒石酸、D-樟脑磺酸、L-樟脑磺酸、L-苯甘氨酸、D-苯甘氨酸、L-苹果酸、D-苹果酸、L-天冬氨酸或L-谷氨酸，优选L-酒石酸或D-扁桃酸。
相比于现有技术，本发明所涉及的替卡格雷中间体2-[[(3aR,4S,6R,6aS)-6-氨基四氢-2,2-二甲基-4H-环戊烯并-1，3-二氧杂-4-基]氧基]乙醇的制备方法，其优点主要是合成步骤简洁，反应条件温和易控，原料廉价易得，产品收率及产品纯度高，适于大规模工业化生产。
具体实施方式
实施例一：
于反应瓶中加入(1R,2R,3R.4R)-rel-1，2；3，4-二环氧环戊烷(I)(9.8g，0.1mol)、叠氮化钠(8.13g，0.125mol)及丙酮／水(1／1)混合溶剂200mL，开动搅拌，升温至45-50℃，反应72小时，GC检测反应完成。加入***至溶液分层，分出有机相。水相用***和丙酮(4：1)100mL萃取5次。合并有机相，无水硫酸镁干燥。减压浓缩，残留物经柱层析(***／正戊烷=5／1)得白色固体(3aR,4S,6R,6aS)-rel-6-叠氮基四氢-2,2-二甲基-4H-环戊烯并-1，3-二氧杂-4-醇(II)9.0g，收率45.2％。
实施例二：
氮气保护下，于反应瓶中加入(3aR,4S,6R,6aS)-rel-6-叠氮基四氢-2,2-二甲基-4H-环戊烯并-1，3-二氧杂-4-醇(II)(8.0g，0.04mol)、四丁基溴化铵(相转移催化剂)0.25g和干燥甲苯100mL，搅拌下分批加入氢化钠(1.92g，0.08mol)，滴加2-溴乙醇(9.92g，0.08mol)，并缓慢升温至回流。保持回流反应约24小时，TLC检测反应完成。冷却至室温，加水搅拌15分钟，分层。有机相用盐水洗涤，无水硫酸钠干燥。减压蒸馏回收溶剂，残余油状物用正己烷重结晶，得白色固体2-[[(3aR,4S，6R,6aS)-rel-6-叠氮基四氢-2,2-二甲基-4H-环戊烯并-1，3-二氧杂-4-基]氧基]乙醇(III)8.1g，收率83.3％。
实施例三：
氮气保护下，于反应瓶中加入2-[[(3aR,4S,6R,6aS)-rel-6-叠氮基四氢-2,2-二甲基-4H-环戊烯并-1，3-二氧杂-4-基]氧基]-乙醇(III)(7.3g，0.03mol)、汉斯酯1，4-二氢吡啶(9.1g，0.036mol)、10％钯炭1.8g和乙醇50mL，开动搅拌，加热至回流并保持回流反应5小时，TLC检测反应完成。冷却至室温，过滤，回收催化剂。减压浓缩，残留物溶于二氯甲烷，依次用5％的盐酸、饱和食盐水和水洗涤。无水硫酸钠干燥，减压蒸馏回收溶剂，得到浅黄色油状物2-[[(3aR,4S,6R,6aS)-rel-6-氨基四氢-2,2-二甲基-4H-环戊烯并-1，3-二氧杂-4-基]氧基]乙醇(IV)5.9g，收率90.6％。
实施例四：
于反应瓶中加入2-[[(3aR,4S,6R,6aS)-rel-6-氨基四氢-2,2-二甲基-4H-环戊烯并-1，3-二氧杂-4-基]氧基]-乙醇(IV)(4.4g，0.02mol)，用乙酸乙酯溶解，加入L-酒石酸(3.0g，0.02mol)，室温搅拌6-8小时，降温至0℃，过滤，所得固体为目标产品的L-酒石酸盐。将该固体置于50mL水中，用30％氢氧化钠调节pH至12-13，用乙酸乙酯萃取3次，合并有机相。干燥，减压回收溶剂，得到的油状物2-[[(3aR，4S,6R,6aS)-6-氨基四氢-2,2-二甲基-4H-环戊烯并-1，3-二氧杂-4-基]氧基]乙醇(中间体C)1.85g，收率84.1％。
需要指出的是，上述较佳实施例仅为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。
Claims (10)
1.一种替卡格雷中间体2-[[(3aR,4S,6R,6aS)-6-氨基四氢-2,2-二甲基-4H-环戊烯并-1,3-二氧杂-4-基]氧基]乙醇(中间体C)的制备方法，
其特征在于该制备方法包括如下步骤：(1R,2R,3R.4R)-rel-1,2；3,4-二环氧环戊烷(I)在丙酮和水混合溶剂中同时与叠氮化钠发生开环反应及缩酮化反应得到化合物(3aR,4S,6R,6aS)-rel-6-叠氮基四氢-2,2-二甲基-4H-环戊烯并-1,3-二氧杂-4-醇(II)；所述化合物(II)通过与2-卤代乙醇进行醚化反应生成化合物2-[[(3aR,4S,6R,6aS)-rel-6-叠氮基四氢-2,2-二甲基-4H-环戊烯并-1,3-二氧杂-4-基]氧基]乙醇(III)，所述化合物(III)经还原反应得到化合物2-[[(3aR,4S,6R,6aS)-rel-6-氨基四氢-2,2-二甲基-4H-环戊烯并-1,3-二氧杂-4-基]氧基]乙醇(IV)；所述化合物(IV)通过拆分得到2-[[(3aR,4S,6R,6aS)-6-氨基四氢-2,2-二甲基-4H-环戊烯并-1,3-二氧杂-4-基]氧基]乙醇(中间体C)。
2.根据权利要求1所述替卡格雷中间体的制备方法，其特征在于：所述叠氮开环反应中(1R,2R,3R.4R)-rel-1,2；3,4-二环氧环戊烷(I)和叠氮化钠的投料摩尔比为1:1-3。
3.根据权利要求2所述替卡格雷中间体的制备方法，其特征在于：所述投料摩尔比优选1:1.1-1.3。
4.根据权利要求2所述替卡格雷中间体的制备方法，其特征在于：所述丙酮和水混合溶剂的体积比为丙酮/水＝1/0.5-1.5。
5.根据权利要求4所述替卡格雷中间体的制备方法，其特征在于：所述体积比优选1/1。
6.根据权利要求1所述替卡格雷中间体的制备方法，其特征在于：所述醚化反应中(3aR,4S,6R,6aS)-rel-6-叠氮基四氢-2,2-二甲基-4H-环戊烯并-1,3-二氧杂-4-醇(II)与2-卤代乙醇的投料摩尔比为1:1-3。
7.根据权利要求6所述替卡格雷中间体的制备方法，其特征在于：所述2-卤代乙醇中的卤素为氯、溴或碘。
8.根据权利要求6所述替卡格雷中间体的制备方法，其特征在于：所述醚化反应的缚酸剂为碳酸钾、氢氧化钾、叔丁醇钾、甲醇钠、氢化钠、三乙胺、吡啶或氢氧化钠。
9.根据权利要求1所述替卡格雷中间体的制备方法，其特征在于：所述还原反应还原剂为铁、锌、锡、铝、铟、钐、水合肼/三氯化铁、硼氢化钠、硼氢化锌或汉斯酯1,4-二氢吡啶/钯炭。
10.根据权利要求1所述替卡格雷中间体的制备方法，其特征在于：所述2-[[(3aR,4S,6R,6aS)-rel-6-氨基四氢-2,2-二甲基-4H-环戊烯并-1,3-二氧杂-4-基]氧基]乙醇(IV)的拆分剂为L-酒石酸、D-酒石酸、L-扁桃酸、D-扁桃酸、二乙酰基-L-酒石酸、二苯甲酰-L-酒石酸、D-樟脑磺酸、L-樟脑磺酸、L-苯甘氨酸、D-苯甘氨酸、L-苹果酸、D-苹果酸、L-天冬氨酸或L-谷氨酸。
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