CN103588751A - 替格瑞洛中间体的制备方法 - Google Patents
替格瑞洛中间体的制备方法 Download PDFInfo
- Publication number
- CN103588751A CN103588751A CN201310549082.0A CN201310549082A CN103588751A CN 103588751 A CN103588751 A CN 103588751A CN 201310549082 A CN201310549082 A CN 201310549082A CN 103588751 A CN103588751 A CN 103588751A
- Authority
- CN
- China
- Prior art keywords
- preparation
- reaction
- rel
- ticagrelor
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 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 claims abstract description 17
- 238000000034 method Methods 0.000 title claims abstract description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 42
- 238000002360 preparation method Methods 0.000 claims abstract description 24
- 239000002994 raw material Substances 0.000 claims abstract description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims description 17
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 15
- 239000002585 base Substances 0.000 claims description 15
- 239000001301 oxygen Substances 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical group OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 12
- 238000005915 ammonolysis reaction Methods 0.000 claims description 7
- UWJJYHHHVWZFEP-UHFFFAOYSA-N pentane-1,1-diol Chemical compound CCCCC(O)O UWJJYHHHVWZFEP-UHFFFAOYSA-N 0.000 claims description 7
- 238000007142 ring opening reaction Methods 0.000 claims description 7
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 6
- 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 5
- 239000002904 solvent Substances 0.000 claims description 5
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 229960002510 mandelic acid Drugs 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 claims description 4
- 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 3
- 229910015900 BF3 Inorganic materials 0.000 claims description 3
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 3
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 3
- 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 3
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 3
- 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
- 229910021630 Antimony pentafluoride Inorganic materials 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
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- VBVBHWZYQGJZLR-UHFFFAOYSA-I antimony pentafluoride Chemical compound F[Sb](F)(F)(F)F VBVBHWZYQGJZLR-UHFFFAOYSA-I 0.000 claims description 2
- VMPVEPPRYRXYNP-UHFFFAOYSA-I antimony(5+);pentachloride Chemical compound Cl[Sb](Cl)(Cl)(Cl)Cl VMPVEPPRYRXYNP-UHFFFAOYSA-I 0.000 claims description 2
- 229960005261 aspartic acid Drugs 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
- 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 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- YHBDIEWMOMLKOO-UHFFFAOYSA-I pentachloroniobium Chemical compound Cl[Nb](Cl)(Cl)(Cl)Cl YHBDIEWMOMLKOO-UHFFFAOYSA-I 0.000 claims description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 2
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims 1
- 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 8
- 229960002528 ticagrelor Drugs 0.000 abstract description 8
- 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
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- 230000009467 reduction Effects 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 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
- 0 CC1(C)O[C@](C(CC2**)OC)[C@]2O1 Chemical compound CC1(C)O[C@](C(CC2**)OC)[C@]2O1 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000010511 deprotection reaction Methods 0.000 description 4
- 230000032050 esterification Effects 0.000 description 4
- 238000005886 esterification reaction Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-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
- 229940079593 drug Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000002633 protecting effect Effects 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 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
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000005292 vacuum distillation 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
- GDDGPXKHPXLZMQ-KIAKQEDMSA-N CCCSC(N=C(C1N=N)N[C@H](C2)C2C(C/C=C/F)/C=C/F)=NC1NC(CC([C@H]1O)OCCO)[C@@H]1OC=C Chemical compound CCCSC(N=C(C1N=N)N[C@H](C2)C2C(C/C=C/F)/C=C/F)=NC1NC(CC([C@H]1O)OCCO)[C@@H]1OC=C GDDGPXKHPXLZMQ-KIAKQEDMSA-N 0.000 description 1
- 238000005698 Diels-Alder reaction Methods 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 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
- 239000012230 colorless oil Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 125000006317 cyclopropyl amino group Chemical group 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000000706 filtrate Substances 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
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 230000013011 mating Effects 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
- 239000000719 purinergic P2Y receptor antagonist Substances 0.000 description 1
- 238000011084 recovery 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
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 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
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 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格瑞洛中间体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。该方法以(1R，2R，3S.4S)-rel-1，2；3，4-二环氧环戊烷(I)为原料，通过开环、氨解、丙缩酮化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，促进替格瑞洛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，特别涉及一种替格瑞洛中间体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
替格瑞洛(Ticagrelor，亦称替卡格雷)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。
替格瑞洛的化学名为(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]三唑[4，5-d]嘧啶-3-基]-5-(2-羟基乙氧基)环戊烷-1，2-二醇。
替格瑞洛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格瑞洛的制备方法。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、丙缩酮化、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、丙缩酮化、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，更好地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-核糖通过丙缩酮化、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丙缩酮化、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，目前对替格瑞洛中间体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，提供一种新的替格瑞洛中间体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，并能促进替格瑞洛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：一种替格瑞洛中间体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，
该方法包括步骤：(1R,2R,3S.4S)-rel-1，2；3，4-二环氧环戊烷(I)通过乙二醇开环反应得到化合物(1S,2R,3S,4S)-rel-1-(2-羟基乙氧基)-2-羟基-3,4-环氧环戊烷(II)；化合物(II)通过氨解反应得到化合物(1R,2S,3R,5S)-rel-3-氨基-5-(2-羟基乙氧基)-1，2-环戊二醇(III)，化合物(III)经丙酮的缩酮化反应制得化合物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)；化合物(IV)经拆分反应得到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：
所述开环反应的溶剂为乙二醇。
所述开环反应的催化剂为氯化锌、碘化锌、三氟化硼、三氯化硼、三氯化铝、三氯化铁、四氯化钛、四氯化锡、五氟化锑、五氯化锑或五氯化铌，其投料量相对于原料(I)的摩尔比为5-15％，优选三氟化硼或四氯化锡，其投料量优选10％。
所述氨解反应的胺化剂为氨水，浓度为15-35％，优选25-30％；
所述氨解反应的温度为50-90℃，优选85℃。
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，优选二乙酰基-L-酒石酸、二苯甲酰-L-酒石酸。
相比于现有技术，本发明所涉及的替格瑞洛中间体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,3S.4S)-rel-1，2；3，4-二环氧环戊烷(I)(9.8g，0.1mol)和新蒸馏的乙二醇200mL，开动搅拌，升温至40-45℃，反应30小时，GC检测反应完成。加入10％碳酸氢钠溶液，用二氯甲烷萃取三次，合并有机相，无水硫酸镁干燥。减压浓缩，残留物经硅胶柱层析(正己烷/乙酸乙酯=4/1)得无色油状物(1S,2R,3S,4S)-rel-1-(2-羟基乙氧基)-2-羟基-3,4-环氧环戊烷(II)11.8g，收率73.8％。
实施例二：
于反应瓶中加入(1S,2R,3S,4S)-rel-1-(2-羟基乙氧基)-2-羟基-3,4-环氧环戊烷(II)(8.0g，0.05mol)、30％氨水75mL，将反应液置于微波照射下，使之达到85℃反应30分钟。冷却至室温，用二氯甲烷萃取三次。合并有机相后，用水洗涤一次，无水硫酸钠干燥。减压蒸馏回收溶剂，得粘稠油状物(1R,2S,3R,5S)-rel-3-氨基-5-(2-羟基乙氧基)-1，2-环戊二醇(III)8.4g，收率95.0％。
实施例三：
于反应瓶中加入(1R,2S,3R,5S)-rel-3-氨基-5-(2-羟基乙氧基)-1，2-环戊二醇(III)(5.3g，0.03mol)和丙酮100mL，开动搅拌，保持5-10℃下，于30分钟内滴加4mL浓硫酸。滴完后，室温反应6小时，TLC检测反应完成。用50％氢氧化钠中和至中性。静置，过滤除去盐。滤液减压浓缩，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)5.8g，收率89.1％。
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)，用乙醇/水(1∶1)100mL溶解，加入二苯甲酰-L-酒石酸(7.2g，0.02mol)，加热回流2小时，降温至25℃，静置12小时，过滤，所得固体为目标产品的二苯甲酰-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，用二氯甲烷洗涤3次，合并有机相。干燥，减压回收溶剂，得到油状物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)1.92g，收率87.3％。
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 (9)
1.一种替格瑞洛中间体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，
其特征在于该方法包括如下步骤：(1R,2R,3S.4S)-rel-1，2；3，4-二环氧环戊烷(I)通过乙二醇开环反应得到化合物(1S,2R,3S,4S)-rel-1-(2-羟基乙氧基)-2-羟基-3,4-环氧环戊烷(II)；所述化合物(II)通过氨解反应得到化合物(1R,2S,3R,5S)-rel-3-氨基-5-(2-羟基乙氧基)-1，2-环戊二醇(III)，所述化合物(III)经丙酮的缩酮化反应制得化合物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)经拆分反应得到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所述替格瑞洛中间体的制备方法，其特征在于：所述开环反应用乙二醇作溶剂。
3.根据权利要求2所述替格瑞洛中间体的制备方法，其特征在于：所述开环反应的催化剂为氯化锌、碘化锌、三氟化硼、三氯化硼、三氯化铝、三氯化铁、四氯化钛、四氯化锡、五氟化锑、五氯化锑或五氯化铌，其投料量相对于原料(I)的摩尔比为5-15％。
4.根据权利要求3所述替格瑞洛中间体的制备方法，其特征在于：所述开环反应的催化剂相对于原料(I)的摩尔比优选10％。
5.根据权利要求1所述替格瑞洛中间体的制备方法，其特征在于：所述氨解反应的胺化剂为氨水，浓度为15-35％。
6.根据权利要求5所述替格瑞洛中间体的制备方法，其特征在于：所述氨水的浓度优选25-30％。
7.根据权利要求5所述替格瑞洛中间体的制备方法，其特征在于：所述氨解反应的温度为50-90℃。
8.根据权利要求7所述替格瑞洛中间体的制备方法，其特征在于：所述氨解反应的温度优选85℃。
9.根据权利要求1所述替格瑞洛中间体的制备方法，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。
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310549082.0A CN103588751B (zh) | 2013-11-07 | 2013-11-07 | 替格瑞洛中间体的制备方法 |
| PCT/CN2014/088177 WO2015067111A1 (zh) | 2013-11-07 | 2014-10-09 | 替格瑞洛中间体的制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310549082.0A CN103588751B (zh) | 2013-11-07 | 2013-11-07 | 替格瑞洛中间体的制备方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103588751A true CN103588751A (zh) | 2014-02-19 |
| CN103588751B CN103588751B (zh) | 2014-12-17 |
Family
ID=50079103
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310549082.0A Expired - Fee Related CN103588751B (zh) | 2013-11-07 | 2013-11-07 | 替格瑞洛中间体的制备方法 |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN103588751B (zh) |
| WO (1) | WO2015067111A1 (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104610220A (zh) * | 2015-02-13 | 2015-05-13 | 江苏欧信医药化工有限公司 | 一种替格瑞洛中间体的合成方法 |
| WO2015067111A1 (zh) * | 2013-11-07 | 2015-05-14 | 苏州明锐医药科技有限公司 | 替格瑞洛中间体的制备方法 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999005143A1 (en) * | 1997-07-22 | 1999-02-04 | Astra Pharmaceuticals Ltd. | Novel compounds |
| WO2011017108A2 (en) * | 2009-07-27 | 2011-02-10 | Auspex Pharmaceuticals, Inc. | Cyclopropyl modulators of p2y12 receptor |
| CN102659815A (zh) * | 2012-05-04 | 2012-09-12 | 开原亨泰制药股份有限公司 | 一种制备选择性抗凝血药替卡格雷及其中间体的方法 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012172426A1 (en) * | 2011-06-15 | 2012-12-20 | Actavis Group Ptc Ehf | Improved process for preparing cyclopentylamine derivatives and intermediates thereof |
| CN103351372A (zh) * | 2013-07-15 | 2013-10-16 | 深圳致君制药有限公司 | 替卡格雷中间体的制备方法 |
| CN103588751B (zh) * | 2013-11-07 | 2014-12-17 | 苏州明锐医药科技有限公司 | 替格瑞洛中间体的制备方法 |
-
2013
- 2013-11-07 CN CN201310549082.0A patent/CN103588751B/zh not_active Expired - Fee Related
-
2014
- 2014-10-09 WO PCT/CN2014/088177 patent/WO2015067111A1/zh active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999005143A1 (en) * | 1997-07-22 | 1999-02-04 | Astra Pharmaceuticals Ltd. | Novel compounds |
| WO2011017108A2 (en) * | 2009-07-27 | 2011-02-10 | Auspex Pharmaceuticals, Inc. | Cyclopropyl modulators of p2y12 receptor |
| CN102659815A (zh) * | 2012-05-04 | 2012-09-12 | 开原亨泰制药股份有限公司 | 一种制备选择性抗凝血药替卡格雷及其中间体的方法 |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015067111A1 (zh) * | 2013-11-07 | 2015-05-14 | 苏州明锐医药科技有限公司 | 替格瑞洛中间体的制备方法 |
| CN104610220A (zh) * | 2015-02-13 | 2015-05-13 | 江苏欧信医药化工有限公司 | 一种替格瑞洛中间体的合成方法 |
| CN104610220B (zh) * | 2015-02-13 | 2015-10-21 | 江苏欧信医药化工有限公司 | 一种替格瑞洛中间体的合成方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2015067111A1 (zh) | 2015-05-14 |
| CN103588751B (zh) | 2014-12-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101613341B (zh) | 一种瑞舒伐他汀钙侧链关键中间体的合成方法 | |
| CN102718773B (zh) | 一种由青蒿酸制备青蒿素的方法 | |
| CN103588750B (zh) | 替卡格雷中间体的制备方法 | |
| CN103588751B (zh) | 替格瑞洛中间体的制备方法 | |
| CN105085362B (zh) | 高纯度结晶型阿托伐他汀钙的制备方法 | |
| CN1067652A (zh) | 高纯1-(3-氯苯基)-4-甲基-7，8-二甲氧基-5h-2，3-苯并二氮杂的制备方法 | |
| CN103159776B (zh) | 一种天然活性产物炭球菌素及其类似物的全合成方法 | |
| CN1473832A (zh) | (3aS,6aR)－1，3－二苄基－四氢－4H呋喃并[3，4－d]－咪唑－2，4〔1H〕－二酮〔I〕的合成方法 | |
| CN103172645B (zh) | 一种青蒿素的高效合成方法 | |
| CN104326922A (zh) | 替格瑞洛中间体(1r,2s)-2-(2,3-二氟苯基)环丙胺的制备方法 | |
| CN105418564B (zh) | 一种丁苯酞新的预处理方法 | |
| CN105481867A (zh) | 三步接力催化构建手性螺环氧化吲哚及其合成方法和应用 | |
| CN103319356A (zh) | 抗疟疾原料本芴醇一步法绿色合成工艺 | |
| Rong et al. | Synthesis of steroidal 1, 2, 4-trioxane as potential antimalarial agent | |
| CN105481823A (zh) | 一种替格瑞洛中间体的合成方法 | |
| CN107043385B (zh) | 一种制备地瑞那韦中间体的方法 | |
| CN104230790B (zh) | 一种西他沙星侧链中间体制备方法 | |
| CN110862382B (zh) | 一种替格瑞洛中间体的制备方法 | |
| CN103193790B (zh) | 抗疟疾类药物青蒿素的高效制备方法 | |
| KR101462850B1 (ko) | 고순도 엔테카비르 일수화물의 제조방법 | |
| CN103214496A (zh) | 一种双氢青蒿素的简单快速制备工艺 | |
| CN1305876C (zh) | 制备高纯度头孢泊肟酯的方法 | |
| CN103408423A (zh) | 一种天然活性产物l-菊苣酸的合成工艺 | |
| CN111978328A (zh) | 一种替格瑞洛的合成方法 | |
| CN104151322B (zh) | 一种用于制备石杉碱甲的中间体的合成方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20200108 Address after: No. 2-3-2-1, Fuyuan apartment, Suizhou North Road, Suining economic and Technological Development Zone, Sichuan Province Patentee after: Sichuan Tiandi Renhe Technology Co.,Ltd. Address before: 215000 Jiangsu Province, Suzhou City Industrial Park Commercial Plaza Building 1 room 1305 Lianfeng Co-patentee before: Xu Xuenong Patentee before: SUZHOU MIRACPHARMA TECHNOLOGY Co.,Ltd. |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20200417 Address after: No. 403, Zone G, No. 8, Beida South Road, xixiantang District, Nanning City, Guangxi Zhuang Autonomous Region, 530000 Patentee after: Guangxi Dingrui Technology Service Co.,Ltd. Address before: No. 2-3-2-1, Fuyuan apartment, Suizhou North Road, Suining economic and Technological Development Zone, Sichuan Province Patentee before: Sichuan Tiandi Renhe Technology Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20200519 Address after: 223001 room 2303, building 1, new century Haoyuan, Qinghe District, Huai'an City, Jiangsu Province Patentee after: Jiangsu Qianyuan Construction Co.,Ltd. Address before: No. 403, Zone G, No. 8, Beida South Road, xixiantang District, Nanning City, Guangxi Zhuang Autonomous Region, 530000 Patentee before: Guangxi Dingrui Technology Service Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20141217 Termination date: 20211107 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |