CN104744266B - 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
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- CN104744266B CN104744266B CN201310755220.0A CN201310755220A CN104744266B CN 104744266 B CN104744266 B CN 104744266B CN 201310755220 A CN201310755220 A CN 201310755220A CN 104744266 B CN104744266 B CN 104744266B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 74
- 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 49
- 150000001875 compounds Chemical class 0.000 claims abstract description 102
- PQCWTNQXCXUEAO-UHFFFAOYSA-N n,n-diethylaniline;hydron;chloride Chemical compound Cl.CCN(CC)C1=CC=CC=C1 PQCWTNQXCXUEAO-UHFFFAOYSA-N 0.000 claims abstract description 14
- 150000001263 acyl chlorides Chemical class 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 10
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 7
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 7
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 5
- 239000011591 potassium Substances 0.000 claims abstract description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 75
- 239000003960 organic solvent Substances 0.000 claims description 48
- 239000000243 solution Substances 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 23
- 239000003638 chemical reducing agent Substances 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 16
- 239000007864 aqueous solution Substances 0.000 claims description 15
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 150000007529 inorganic bases Chemical class 0.000 claims description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 10
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 9
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 9
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 9
- 239000000725 suspension Substances 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- 238000009413 insulation Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- JQIVECLQPHOSDY-QGZVFWFLSA-N [(2s)-1,2-diphenylpyrrolidin-2-yl]methanol Chemical compound C([C@@]1(CO)C=2C=CC=CC=2)CCN1C1=CC=CC=C1 JQIVECLQPHOSDY-QGZVFWFLSA-N 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 4
- 150000004703 alkoxides Chemical class 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical group [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- 230000009467 reduction Effects 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 229910052738 indium Inorganic materials 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 238000003032 molecular docking Methods 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- YSNXOQGDHGUKCZ-UHFFFAOYSA-N n-benzylhydroxylamine;hydron;chloride Chemical class Cl.ONCC1=CC=CC=C1 YSNXOQGDHGUKCZ-UHFFFAOYSA-N 0.000 claims 11
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims 3
- ROHUWFHOCAUEMV-UHFFFAOYSA-N 1-ethylcyclohexa-2,4-dien-1-amine Chemical compound CCC1(N)CC=CC=C1 ROHUWFHOCAUEMV-UHFFFAOYSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 229910052783 alkali metal Inorganic materials 0.000 claims 1
- 150000001340 alkali metals Chemical class 0.000 claims 1
- 150000001408 amides Chemical class 0.000 claims 1
- MMCPOSDMTGQNKG-UHFFFAOYSA-N anilinium chloride Chemical compound Cl.NC1=CC=CC=C1 MMCPOSDMTGQNKG-UHFFFAOYSA-N 0.000 claims 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims 1
- 239000010931 gold Substances 0.000 claims 1
- 229910052737 gold Inorganic materials 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
- 239000011259 mixed solution Substances 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 8
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 231100000252 nontoxic Toxicity 0.000 abstract description 2
- 230000003000 nontoxic effect Effects 0.000 abstract description 2
- 150000003140 primary amides Chemical class 0.000 abstract description 2
- 230000008707 rearrangement Effects 0.000 abstract description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- -1 Compound Compounds Chemical class 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 10
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 8
- 238000000605 extraction Methods 0.000 description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 0 *c(ccc([C@@](CCl)O)c1)c1F Chemical compound *c(ccc([C@@](CCl)O)c1)c1F 0.000 description 5
- 229910000085 borane Inorganic materials 0.000 description 5
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 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 description 5
- 229960002528 ticagrelor Drugs 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000003146 anticoagulant agent Substances 0.000 description 4
- 229940127219 anticoagulant drug Drugs 0.000 description 4
- 235000010290 biphenyl Nutrition 0.000 description 4
- 239000004305 biphenyl Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 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 3
- 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 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 239000002360 explosive Substances 0.000 description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 3
- SUUDTPGCUKBECW-UHFFFAOYSA-N n-propylformamide Chemical compound CCCNC=O SUUDTPGCUKBECW-UHFFFAOYSA-N 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- RYOLLNVCYSUXCP-MRVPVSSYSA-N (1s)-2-chloro-1-(3,4-difluorophenyl)ethanol Chemical compound ClC[C@@H](O)C1=CC=C(F)C(F)=C1 RYOLLNVCYSUXCP-MRVPVSSYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000000370 acceptor Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 230000007096 poisonous effect Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 2
- GOYDNIKZWGIXJT-UHFFFAOYSA-N 1,2-difluorobenzene Chemical class FC1=CC=CC=C1F GOYDNIKZWGIXJT-UHFFFAOYSA-N 0.000 description 1
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 1
- 239000005465 B01AC22 - Prasugrel Substances 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- WLOOMXNTKDUTHL-UHFFFAOYSA-N O=C(CCl)c1cc(F)c(C2CC2)cc1 Chemical compound O=C(CCl)c1cc(F)c(C2CC2)cc1 WLOOMXNTKDUTHL-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- HVVNJUAVDAZWCB-YFKPBYRVSA-N [(2s)-pyrrolidin-2-yl]methanol Chemical class OC[C@@H]1CCCN1 HVVNJUAVDAZWCB-YFKPBYRVSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 229960003009 clopidogrel Drugs 0.000 description 1
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004807 desolvation Methods 0.000 description 1
- 235000015177 dried meat Nutrition 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000006197 hydroboration reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- DTGLZDAWLRGWQN-UHFFFAOYSA-N prasugrel Chemical compound C1CC=2SC(OC(=O)C)=CC=2CN1C(C=1C(=CC=CC=1)F)C(=O)C1CC1 DTGLZDAWLRGWQN-UHFFFAOYSA-N 0.000 description 1
- 229960004197 prasugrel Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
Abstract
Description
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CN105969757A (zh) * | 2016-06-03 | 2016-09-28 | 中国科学院成都生物研究所 | 一种酶的固定化方法及应用 |
CN107382735A (zh) * | 2017-07-24 | 2017-11-24 | 苏州信恩医药科技有限公司 | 一种替格瑞洛中间体的合成方法 |
CN107686447A (zh) * | 2017-08-25 | 2018-02-13 | 许昌恒生制药有限公司 | 一种替格瑞洛中间体的制备方法 |
CN112851485B (zh) * | 2021-01-15 | 2021-11-23 | 常州制药厂有限公司 | 一种替格瑞洛关键中间体的制备方法 |
Citations (3)
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CN1867571A (zh) * | 2003-10-09 | 2006-11-22 | Ppg-Sipsy公司 | 用于不对称还原反应的由氧氮硼杂环烷-硼烷络合物所衍生手性化合物的原位制备方法 |
CN102532097A (zh) * | 2011-10-19 | 2012-07-04 | 华东理工大学 | 一种度洛西汀中间体-(s)-n,n-二甲基-3-羟基-3-(2-噻吩基)-1-丙胺的不对称合成方法 |
CN102924457A (zh) * | 2011-08-12 | 2013-02-13 | 上海恒瑞医药有限公司 | 三唑并嘧啶类衍生物、其制备方法及其用途 |
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CN1867571A (zh) * | 2003-10-09 | 2006-11-22 | Ppg-Sipsy公司 | 用于不对称还原反应的由氧氮硼杂环烷-硼烷络合物所衍生手性化合物的原位制备方法 |
CN102924457A (zh) * | 2011-08-12 | 2013-02-13 | 上海恒瑞医药有限公司 | 三唑并嘧啶类衍生物、其制备方法及其用途 |
CN102532097A (zh) * | 2011-10-19 | 2012-07-04 | 华东理工大学 | 一种度洛西汀中间体-(s)-n,n-二甲基-3-羟基-3-(2-噻吩基)-1-丙胺的不对称合成方法 |
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