CN102675321A - Preparation method of ticagrelor - Google Patents
Preparation method of ticagrelor Download PDFInfo
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- CN102675321A CN102675321A CN2012101465007A CN201210146500A CN102675321A CN 102675321 A CN102675321 A CN 102675321A CN 2012101465007 A CN2012101465007 A CN 2012101465007A CN 201210146500 A CN201210146500 A CN 201210146500A CN 102675321 A CN102675321 A CN 102675321A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 45
- 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 title abstract description 4
- 229960002528 ticagrelor Drugs 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 72
- 238000006243 chemical reaction Methods 0.000 claims abstract description 50
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 18
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 14
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 6
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 34
- 239000002904 solvent Substances 0.000 claims description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- 239000000377 silicon dioxide Substances 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- -1 alkali-metal nitrite Chemical class 0.000 claims description 14
- 239000003513 alkali Substances 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 12
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical group [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 10
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical group OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 239000004305 biphenyl Substances 0.000 claims description 8
- 235000010290 biphenyl Nutrition 0.000 claims description 8
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 8
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 6
- 235000010288 sodium nitrite Nutrition 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 5
- 229910001385 heavy metal Inorganic materials 0.000 claims description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- AZFNGPAYDKGCRB-XCPIVNJJSA-M [(1s,2s)-2-amino-1,2-diphenylethyl]-(4-methylphenyl)sulfonylazanide;chlororuthenium(1+);1-methyl-4-propan-2-ylbenzene Chemical compound [Ru+]Cl.CC(C)C1=CC=C(C)C=C1.C1=CC(C)=CC=C1S(=O)(=O)[N-][C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 AZFNGPAYDKGCRB-XCPIVNJJSA-M 0.000 claims description 4
- 150000003973 alkyl amines Chemical class 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000004304 potassium nitrite Substances 0.000 claims description 4
- 235000010289 potassium nitrite Nutrition 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims 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 claims description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 claims description 3
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 108010037444 diisopropylglutathione ester Proteins 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- 230000036571 hydration Effects 0.000 claims description 2
- 238000006703 hydration reaction Methods 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 abstract 2
- 239000002994 raw material Substances 0.000 abstract 2
- QVUBIQNXHRPJKK-IMTBSYHQSA-N (1r,2s)-2-(3,4-difluorophenyl)cyclopropan-1-amine Chemical compound N[C@@H]1C[C@H]1C1=CC=C(F)C(F)=C1 QVUBIQNXHRPJKK-IMTBSYHQSA-N 0.000 abstract 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 abstract 1
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 abstract 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 abstract 1
- 150000001340 alkali metals Chemical class 0.000 abstract 1
- 229940008075 allyl sulfide Drugs 0.000 abstract 1
- 229960000623 carbamazepine Drugs 0.000 abstract 1
- 125000006239 protecting group Chemical group 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 34
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 22
- 238000003756 stirring Methods 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 16
- 239000007864 aqueous solution Substances 0.000 description 8
- 239000012141 concentrate Substances 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 238000010792 warming Methods 0.000 description 8
- 230000001603 reducing effect Effects 0.000 description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 238000007789 sealing Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000010025 steaming Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 2
- 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 2
- 229960003009 clopidogrel Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- SIBFNWWZWOVJJH-UHFFFAOYSA-N 2-chloro-1-methoxypropane Chemical compound COCC(C)Cl SIBFNWWZWOVJJH-UHFFFAOYSA-N 0.000 description 1
- KEZLCPVHQKRZSK-UHFFFAOYSA-O CCCSC(C)=NC([NH2+]C(C1)C2OC(C)(C)OC2C1OCC)=C Chemical compound CCCSC(C)=NC([NH2+]C(C1)C2OC(C)(C)OC2C1OCC)=C KEZLCPVHQKRZSK-UHFFFAOYSA-O 0.000 description 1
- 0 CCCSc1ncc(C)c(NC(C)*OC)n1 Chemical compound CCCSc1ncc(C)c(NC(C)*OC)n1 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- AYVGBNGTBQLJBG-UHFFFAOYSA-N [3-(hydroxymethyl)cyclopentyl]methanol Chemical compound OCC1CCC(CO)C1 AYVGBNGTBQLJBG-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 238000013176 antiplatelet therapy Methods 0.000 description 1
- 229940086777 brilinta Drugs 0.000 description 1
- HXLVDKGPVGFXTH-UHFFFAOYSA-N butyl(dimethyl)silane Chemical group CCCC[SiH](C)C HXLVDKGPVGFXTH-UHFFFAOYSA-N 0.000 description 1
- 125000006317 cyclopropyl amino group Chemical group 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- DFJDZTPFNSXNAX-UHFFFAOYSA-N ethoxy(triethyl)silane Chemical compound CCO[Si](CC)(CC)CC DFJDZTPFNSXNAX-UHFFFAOYSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000002440 industrial waste Substances 0.000 description 1
- 230000013011 mating Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 208000021090 palsy Diseases 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides a preparation method of ticagrelor, belonging to the technical field of medicine manufacturing. According to the method, a compound VII is taken as a raw material, and the method comprises the steps of: carrying out a nucleophilic substitution reaction on the raw material to obtain a compound VI; hydrogenating the VI, removing carbamazepine (Cbz) protection to obtain a compound V; carrying out a reaction on the V and 4, 6-dichloro-2-(allyl sulfide)-5-amio-pyrimidine to obtain a compound IV; carrying out a reaction on the IV and nitrite of alkali metal to obtain a compound III; carrying out a reaction on the III and (1R, 2S)-2-(3, 4-difluoro phenyl) cyclopropylamine to obtain a compound II; and finally, removing protecting group of the II to obtain a compound I.
Description
Technical field
The present invention relates to medical manufacturing technology field, specifically a kind of preparation method for card Gray.
Background technology
For card Gray, chemical name (1S, 2S, 3R; 5S)-3-[7-[(1R, 2S)-2-(3,4-difluoro phenyl) cyclopropylamino]-5-(propylsulfanyl)-3H-[1; 2,3] triazolo [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-1; 2-diol, U.S. chemical abstract registration number CAS NO:274693-27-5 has the structural formula of formula I:
I is a kind of novel for card Gray; Has optionally anticoagulant; It also is first reversible mating type P2Y12 adp acceptor (ADP) antagonist; Purine 2 receptor subtype P2Y12 on the ability reversibility ground vasoactive smooth muscle cell (VSMC), the platelet aggregation that ADP is caused has the obvious suppression effect, can effectively improve acute coronary patient's symptom.These article are produced by Astrazeneca AB's research and development, and commodity are called Brilinta, and tablet was in European Initial Public Offering in 2010, and tens country's sale in the whole world after this medicine listing, in process of clinical application, have shown good therapeutic action at present.Research shows; Gray compares with clopidogrel for card; Can obviously reduce primary terminal point incident such as patient's heart stalk, palsy or cardiovascular death, and the severe haemorrhage complication increases not, this medicine is similar with the clopidogrel spinoff simultaneously; Do not increase, this is undoubtedly the much progress to Antiplatelet therapy.
The existing report that is used to prepare compound I mainly contains (1) WO9905143 (2) WO0192263 etc.
In the former patent WO9905143 that grinds Astrazeneca AB of producer, related to the preparation route (Scheme 1) of a compound I
This route steps is long, and wherein relates to the osmic acid oxidation, the DIBAL-H reduction; Iron powder reducings etc. have severe toxicity or cause the reaction of a large amount of three industrial wastes easily; This route total recovery is low simultaneously, and production cost is high, therefore can not be as the first-selected route of synthetic compound I.
Astrazeneca AB has related to the preparation route (Scheme 2) of an other compound I in patent WO0192263.
This route exists route longer equally, the shortcoming that total recovery is on the low side, therefore also unsuitable optimal route as large-scale industrial production.
Summary of the invention
The invention provides a kind of can overcome above-mentioned insufficient for the card Gray the preparation method; Its preparation route is shown in Scheme 3; This method shortens on step compared with existing route to some extent, after exposed hydroxyl carries out proper protection in to existing route simultaneously, the productive rate of reaction is significantly promoted; Greatly reduced production cost, for realizing that for card Gray low-cost industrial production provides a kind of method.The compound method for card Gray shown in Scheme 3 provided by the present invention was not all carried out description in disclosed document.
Its detailed process is:
The preparation of compound VI: compound VI I is in solvent, under the alkali effect, with compound L CH
2CH
2OR prepared in reaction compound VI.Described solvent is THF or N, one or several in dinethylformamide or diethyl ether or DIPE or MTBE or benzene or toluene or the YLENE, preferred THF; Highly basic is potassium tert.-butoxide or sodium hydride or sodium tert-amyl alcohol; L is chlorine or bromine or iodine.
The preparation of compound V: compound VI adds heavy metal catalyst in solvent, and pressure hydration is taken off the Cbz protection and obtained compound V.Described solvent is one or several in methyl alcohol or ethanol or Virahol or propyl carbinol or the trimethyl carbinol or the THF, preferred alcohol; Heavy metal catalyst is palladium carbon or palladium hydroxide, preferred palladium carbon.
The preparation of compound IV: compound V adds alkali in solvent, and with 4,6-two chloro-2-(rosickyite base)-5-aminopyrimidine reaction obtains compound IV under hot conditions; Described solvent is one or several in methyl alcohol or ethanol or Virahol or propyl carbinol or the trimethyl carbinol or the THF, preferred alcohol; Alkali is sodium hydroxide or Pottasium Hydroxide or Lithium Hydroxide MonoHydrate or three (C
1-6) alkyl amine, preferred triethylamine; Hot conditions is 100 ℃-180 ℃, preferred 100 ℃-125 ℃.
The preparation of compound III: compound IV adds acid in water, obtains compound III with alkali-metal nitrite reaction.Described acid is one or several in formic acid or acetic acid or Hydrogen chloride or the dilute sulphuric acid, preferred acetic acid; Alkali-metal nitrite is Sodium Nitrite or potassium nitrite, preferred Sodium Nitrite.
The preparation of compound I I: compound III adds alkali in solvent, with (1R, 2S)-reaction of 2-(3, the 4-difluorophenyl) cyclopropylamine obtains compound I I.Described solvent is one or several in methyl alcohol or ethanol or Virahol or propyl carbinol or the trimethyl carbinol or the acetonitrile, preferred alcohol; Alkali is three (C
1-6) alkyl amine, preferred triethylamine.
The preparation of compound I: compound I I adds deprotecting regent in solvent, the deprotection base obtains compound I.Described solvent is one or several in methyl alcohol or ethanol or Virahol or propyl carbinol or the trimethyl carbinol or the THF, preferred alcohol; Deprotecting regent is trifluoroacetic acid or hydrochloric acid, preferred hydrochloric acid.
Wherein, R is that triethyl is silica-based or tertiary butyl dimethyl-is silica-based or tert-butyl diphenyl is silica-based or methoxyl methyl or THP trtrahydropyranyl or tetrahydrofuran base.
Embodiment
Specific embodiment of the present invention below is provided, showing possible implementation process, but does not limit the present invention.
Embodiment 1
The preparation of compound VI a
With compound VI Ia (615g 2mol) joins in the 3.5L THF, add in batches the potassium tert.-butoxide solid (269.5g, 2.4mol).Mixture stirred 10 minutes, and zero degree drips 2-bromine oxethyl tertiary butyl dimethylsilane (573.5g, 1L tetrahydrofuran solution 2.4mol) down; Reaction solution stirred 1.5 hours, and the TLC demonstration reacts completely, and reaction solution adds entry 2L; ETHYLE ACETATE 2L tells organic phase, drying; Concentrate compound VI a857.3g, yield is 92%.
The preparation of compound Va
(838.2g 1.8mol) joins in the 5L ethanol, adds 10% palladium carbon (40g), and the reaction solution hydrogen exchange is removed air with compound VI a; 1.5 handkerchiefs that pressurize, 50 ℃ of reactions 10 hours, TLC shows and reacts completely; Reacting liquid filtering is removed palladium carbon, filtrating concentrate compound Va572.9g, yield is 96%.
The preparation of compound IV a
(563.6g 1.7mol) joins in the 5L ethanol, adds 4,6-two chloro-2-(rosickyite alkyl)-5-PYRIMITHAMINE (445g with Va; 1.87mol) and triethylamine (189g, 1.87mol), the reaction sealing is warming up between 100-125 ℃; Stirring reaction 20 hours, cooling, the pressure reducing and steaming solvent adds ETHYLE ACETATE 3L and water 3L; Regulate mixed solution PH to 5 with Hydrogen chloride, tell organic phase, dry concentrating obtains compound IV a806.8g, and yield is 89%.
The preparation of compound III a
(761.9g 1.4mol) is dissolved among acetate 5L and the water 1L, and reaction solution is cooled to below 0 ℃, drips Sodium Nitrite (96.6g with Va; 1.4mol) aqueous solution 500ml, finish, TLC shows and to react completely; Reaction solution is warming up to room temperature, adds ETHYLE ACETATE 5L, and the unsaturated carbonate aqueous solutions of potassium is washed; Tell organic phase, dry concentrating obtains compound IV a 668.7g, and yield is 86%.
The preparation of compound I Ia
Will (1R, 2S)-2-(3, the 4-difluorophenyl) cyclopropylamine (223.3g, (653g is in 3L ethanolic soln 1.2mol) 1.32mol) to add compound III a; (133.6g 1.32mol), finishes, and stirring reaction is 15 hours under the room temperature to add triethylamine in the room temperature downhill reaction liquid; The TLC demonstration reacts completely, and concentrating under reduced pressure boils off most of ethanol, adds ETHYLE ACETATE 5L, water 3L; Regulate PH to 4.5 with Hydrogen chloride, tell organic layer, dry concentrating obtains compound I Ia 714.8g, and yield is 88%.
The preparation of compound I
With IIa (676.9g 1mol) is dissolved among the ethanol 5L, add under the stirring at room aqueous hydrochloric acid (3M, 3.34L); Finish, stirring at room 24 hours, the TLC demonstration reacts completely, and reaction solution is regulated PH to 7.2 with diluted sodium hydroxide solution; Ethanol is removed in decompression, adds ETHYLE ACETATE 5L, tells organic phase, the saturated common salt washing; Drying, concentrating under reduced pressure obtain compound I 486g, and yield is 93%.
Embodiment 2
The preparation of compound VI b
With compound VI Ib (615g 2mol) joins 3L N, in the dinethylformamide, add in batches 40% sodium hydride solid (144g, 2.4mol).Mixture stirred 10 minutes, and zero degree drips 2-iodine ethoxy triethyl silane (687g, 1L N 2.4mol) down; Dinethylformamide solution, reaction solution stirred 1 hour, and the TLC demonstration reacts completely; Reaction solution adds entry 2L, and ETHYLE ACETATE 2L tells organic phase; Drying, concentrate compound VI b847.5g, yield is 91%.
The preparation of compound Vb
(838.2g 1.8mol) joins in the 5L methyl alcohol, adds 15% palladium hydroxide (40g) with compound VI b; The reaction solution hydrogen exchange is removed air, 2 handkerchiefs that pressurize, and 50 ℃ were reacted 12 hours; The TLC demonstration reacts completely; Reacting liquid filtering is removed palladium hydroxide, filtrating concentrate compound Vb578.8g, yield is 97%.
The preparation of compound IV b
(563.6g 1.7mol) joins in the 5L methyl alcohol, adds 4,6-two chloro-2-(rosickyite alkyl)-5-PYRIMITHAMINE (445g with Vb; 1.87mol) and sodium hydroxide (74.8g, 1.87mol), the reaction sealing is warming up between 100-125 ℃; Stirring reaction 24 hours, cooling, the pressure reducing and steaming solvent adds ETHYLE ACETATE 3L and water 3L; Regulate mixed solution PH to 5 with Hydrogen chloride, tell organic phase, dry concentrating obtains compound IV b770.5g, and yield is 85%.
The preparation of compound III b
(761.9g 1.4mol) is dissolved among formic acid 5L and the water 1L, and reaction solution is cooled to below 0 ℃, drips potassium nitrite (119.1g with V b; 1.4mol) aqueous solution 500ml, finish, TLC shows and to react completely; Reaction solution is warming up to room temperature, adds ETHYLE ACETATE 5L, and the unsaturated carbonate aqueous solutions of potassium is washed; Tell organic phase, dry concentrating obtains compound IV b 632.3g, and yield is 83%.
The preparation of compound I Ib
Will (1R, 2S)-2-(3, the 4-difluorophenyl) cyclopropylamine (204.7g, (598.6g is in 3L methanol solution 1.1mol) 1.21mol) to add compound III b; (173.3g 1.21mol), finishes, and stirring reaction is 15 hours under the room temperature to add tripropyl amine in the room temperature downhill reaction liquid; The TLC demonstration reacts completely, and concentrating under reduced pressure boils off most of methyl alcohol, adds ETHYLE ACETATE 5L, water 3L; Regulate PH to 4.5 with Hydrogen chloride, tell organic layer, dry concentrating obtains compound I Ib 670.1g, and yield is 90%.
The preparation of compound I
With IIb (643g 0.95mol) is dissolved among the methyl alcohol 5L, add under the stirring at room trifluoroacetic acid (1140g, 10mol); Finish, stirring at room 24 hours, the TLC demonstration reacts completely, and reaction solution is regulated PH to 7.2 with diluted sodium hydroxide solution; Methyl alcohol is removed in decompression, adds ETHYLE ACETATE 5L, tells organic phase, the saturated common salt washing; Drying, concentrating under reduced pressure obtain compound I 476.6g, and yield is 96%.
Embodiment 3
The preparation of compound VI c
With compound VI Ic (615g 2mol) joins the 5L MTBE, add the sodium tert-amyl alcohol solid (264g, 2.4mol).Mixture stirred 10 minutes, and zero degree drips 1-chloro-2-methoxyl methyl ethane (299g, 1L methyl tertbutyl ethereal solution 2.4mol) down; Reaction solution stirred 1 hour, and the TLC demonstration reacts completely, and reaction solution adds entry 2L; ETHYLE ACETATE 2L tells organic phase, drying; Concentrate compound VI c704.9g, yield is 89%.
The preparation of compound Vc
(672.3g 1.7mol) joins in the 4L Virahol, adds 10% palladium carbon (30g) with compound VI c; The reaction solution hydrogen exchange is removed air, 1.5 handkerchiefs that pressurize, and 50 ℃ were reacted 12 hours; The TLC demonstration reacts completely; Reacting liquid filtering is removed palladium carbon, filtrating concentrate compound Vc421.8g, yield is 95%.
The preparation of compound IV c
(418.1g 1.6mol) joins in the 4L Virahol, adds 4,6-two chloro-2-(rosickyite alkyl)-5-PYRIMITHAMINE (419.1g with Vc; 1.76mol) and Pottasium Hydroxide (98.6g, 1.76mol), the reaction sealing is warming up between 100-125 ℃; Stirring reaction 15 hours, cooling, the pressure reducing and steaming solvent adds ETHYLE ACETATE 3L and water 3L; Regulate mixed solution PH to 5 with Hydrogen chloride, tell organic phase, dry concentrating obtains compound IV c644.5g, and yield is 87%.
The preparation of compound III c
With Vc (625g, 1.35mol) be dissolved in hydrochloric acid (3mol/L, 5L) in, reaction solution is cooled to below 0 ℃; The dropping potassium nitrite (114.9g, aqueous solution 500ml 1.35mol) finishes, and the TLC demonstration reacts completely; Reaction solution is warming up to room temperature, adds ETHYLE ACETATE 5L, and the unsaturated carbonate aqueous solutions of potassium is washed; Tell organic phase, dry concentrating obtains compound IV c 557.7g, and yield is 87%.
The preparation of compound I Ic
Will (1R, 2S)-2-(3, the 4-difluorophenyl) cyclopropylamine (204.7g, (521.4g is in 3L aqueous isopropanol 1.1mol) 1.21mol) to add compound III c; (224.3g 1.21mol), finishes, and stirring reaction is 15 hours under the room temperature to add Tributylamine in the room temperature downhill reaction liquid; The TLC demonstration reacts completely, and concentrating under reduced pressure boils off most of Virahol, adds ETHYLE ACETATE 5L, water 3L; Regulate PH to 4.5 with Hydrogen chloride, tell organic layer, dry concentrating obtains compound I Ic 631.3g, and yield is 86%.
The preparation of compound I
With IIc (606.7g 1mol) is dissolved among the Virahol 5L, add under the stirring at room trifluoroacetic acid (1140g, 10mol); Finish, stirring at room 24 hours, the TLC demonstration reacts completely, and reaction solution is regulated PH to 7.2 with diluted sodium hydroxide solution; Methyl alcohol is removed in decompression, adds ETHYLE ACETATE 5L, tells organic phase, the saturated common salt washing; Drying, concentrating under reduced pressure obtain compound I 491.2g, and yield is 94%.
Embodiment 4
The preparation of compound VI d
With compound VI Id (615g 2mol) joins in the 4L toluene, add the potassium tert.-butoxide solid (269.5g, 2.4mol).Mixture stirred 10 minutes, and zero degree drips 2-(2-bromine oxethyl) tetrahydrochysene-2H-pyrans (501.8g, 1L toluene solution 2.4mol) down; Reaction solution stirred 2 hours, and the TLC demonstration reacts completely, and reaction solution adds entry 2L; ETHYLE ACETATE 2L tells organic phase, drying; Concentrate compound VI a775.2g, yield is 89%.
The preparation of compound Vd
(740.4g 1.7mol) joins in the 5L trimethyl carbinol, adds 15% palladium hydroxide (40g) with compound VI d; The reaction solution hydrogen exchange is removed air, 2 handkerchiefs that pressurize, and 50 ℃ were reacted 10 hours; The TLC demonstration reacts completely; Reacting liquid filtering is removed palladium hydroxide, filtrating concentrate compound V d476.5g, yield is 93%.
The preparation of compound IV d
(476.5g 1.5mol) joins in the 5L trimethyl carbinol, adds 4,6-two chloro-2-(rosickyite alkyl)-5-PYRIMITHAMINE (392.9g with V d; 1.65mol) and Lithium Hydroxide MonoHydrate (39.5g, 1.65mol), the reaction sealing is warming up between 100-125 ℃; Stirring reaction 20 hours, cooling, the pressure reducing and steaming solvent adds ETHYLE ACETATE 3L and water 3L; Regulate mixed solution PH to 5 with Hydrogen chloride, tell organic phase, dry concentrating obtains compound IV d 656.8g, and yield is 87%.
The preparation of compound III d
With Vd (654g, 1.3mol) be dissolved in sulfuric acid (3mol/L, 5L) in, reaction solution is cooled to below 0 ℃; The dropping Sodium Nitrite (89.7g, aqueous solution 500ml 1.3mol) finishes, and the TLC demonstration reacts completely; Reaction solution is warming up to room temperature, adds ETHYLE ACETATE 5L, and the unsaturated carbonate aqueous solutions of potassium is washed; Tell organic phase, dry concentrating obtains compound IV d 588.0g, and yield is 88%.
The preparation of compound I Id
Will (1R, 2S)-2-(3, the 4-difluorophenyl) cyclopropylamine (204.7g, (598.6g is in 3L t-butanol solution 1.1mol) 1.21mol) to add compound III a; (122.2g 1.21mol), finishes, and stirring reaction is 20 hours under the room temperature to add triethylamine in the room temperature downhill reaction liquid; The TLC demonstration reacts completely, and concentrating under reduced pressure boils off most of trimethyl carbinol, adds ETHYLE ACETATE 5L, water 3L; Regulate PH to 4.5 with Hydrogen chloride, tell organic layer, dry concentrating obtains compound I Id 647.4g, and yield is 91%.
The preparation of compound I
With IId (646.8g 1mol) is dissolved among the trimethyl carbinol 5L, add under the stirring at room aqueous hydrochloric acid (3M, 3.34L); Finish, stirring at room 24 hours, the TLC demonstration reacts completely, and reaction solution is regulated PH to 7.2 with diluted sodium hydroxide solution; The trimethyl carbinol is removed in decompression, adds ETHYLE ACETATE 5L, tells organic phase, the saturated common salt washing; Drying, concentrating under reduced pressure obtain compound I 475.5g, and yield is 91%.
The recrystallization of compound I
The 100g compound I is joined in the 500ml ETHYLE ACETATE, be heated to 50 ℃ and stirred 30 minutes, remove by filter insolubles.Be added dropwise to normal hexane 500ml within ten minutes, the nature that finishes is cooled to 20 ℃, stirs 1 hour under this temperature, filters, and filter cake is washed with normal hexane.With 40 ℃ of following vacuum-dryings of product of gained 10 hours to pure product I 73g, HPLC detects purity greater than 98%.
Claims (7)
1. one kind is replaced the preparation method who blocks Gray, it is characterized in that experiencing reaction process as follows:
(1) compound VI I is in solvent, under the alkali effect, with compound L CH
2CH
2Nucleophilic substitution reaction takes place and prepares compound VI in OR;
Described solvent is THF or N, one or several in dinethylformamide or diethyl ether or DIPE or MTBE or benzene or toluene or the YLENE; Highly basic is potassium tert.-butoxide or sodium hydride or sodium tert-amyl alcohol; L is chlorine or bromine or iodine;
(2) compound VI adds heavy metal catalyst in solvent, and pressure hydration is taken off the Cbz protection and obtained compound V:
Described solvent is one or several in methyl alcohol or ethanol or Virahol or propyl carbinol or the trimethyl carbinol or the THF; Heavy metal catalyst is palladium carbon or palladium hydroxide;
(3) compound V adds suitable alkali in solvent, and with 4,6-two chloro-2-(rosickyite base)-5-aminopyrimidine reaction obtains compound IV under hot conditions:
Described solvent is one or several in methyl alcohol or ethanol or Virahol or propyl carbinol or the trimethyl carbinol or the THF; Alkali is sodium hydroxide or Pottasium Hydroxide or Lithium Hydroxide MonoHydrate or three (C
1-6) alkyl amine; Hot conditions is 100 ℃-180 ℃;
(4) compound IV adds acid in water, obtains compound III with alkali-metal nitrite reaction:
Described acid is one or several in formic acid or acetic acid or Hydrogen chloride or the dilute sulphuric acid; Alkali-metal nitrite is Sodium Nitrite or potassium nitrite;
(5) compound III is in solvent, adds alkali, with (1R, 2S)-reaction of 2-(3, the 4-difluorophenyl) cyclopropylamine obtains compound I I:
Described solvent is one or several in methyl alcohol or ethanol or Virahol or propyl carbinol or the trimethyl carbinol or the acetonitrile; Alkali is three (C
1-6) alkyl amine;
(6) compound I I adds deprotecting regent in solvent, and the deprotection base obtains compound I:
Described solvent is one or several in methyl alcohol or ethanol or Virahol or propyl carbinol or the trimethyl carbinol or the THF; Deprotecting regent is trifluoroacetic acid or hydrochloric acid;
Wherein, R is that triethyl is silica-based or tertiary butyl dimethyl-is silica-based or tert-butyl diphenyl is silica-based or methoxyl methyl or THP trtrahydropyranyl or tetrahydrofuran base.
2. a kind of preparation method for card Gray as claimed in claim 1 is characterized in that, in described step (1), and the preferred THF of said solvent; The preferred potassium tert.-butoxide of said alkali;
Wherein, R is that triethyl is silica-based or tertiary butyl dimethyl-is silica-based or tert-butyl diphenyl is silica-based or methoxyl methyl or THP trtrahydropyranyl or tetrahydrofuran base.
3. a kind of preparation method for card Gray as claimed in claim 1 is characterized in that, in described step (2), and described solvent preferred alcohol; The preferred palladium carbon of described heavy metal catalyst;
Wherein, R is that triethyl is silica-based or tertiary butyl dimethyl-is silica-based or tert-butyl diphenyl is silica-based or methoxyl methyl or THP trtrahydropyranyl or tetrahydrofuran base.
4. a kind of preparation method for card Gray as claimed in claim 1 is characterized in that, in described step (3), and described solvent preferred alcohol; The preferred triethylamine of said alkali; Preferred 100 ℃-125 ℃ of described hot conditions;
Wherein, R is that triethyl is silica-based or tertiary butyl dimethyl-is silica-based or tert-butyl diphenyl is silica-based or methoxyl methyl or THP trtrahydropyranyl or tetrahydrofuran base.
5. a kind of preparation method for card Gray as claimed in claim 1 is characterized in that, in described step (4), and the preferred acetic acid of described acid; The preferred Sodium Nitrite of described alkali-metal nitrite;
Wherein, R is that triethyl is silica-based or tertiary butyl dimethyl-is silica-based or tert-butyl diphenyl is silica-based or methoxyl methyl or THP trtrahydropyranyl or tetrahydrofuran base.
6. a kind of preparation method for card Gray as claimed in claim 1 is characterized in that, in described step (5), and described solvent preferred alcohol; The preferred triethylamine of described alkali;
Wherein, R is that triethyl is silica-based or tertiary butyl dimethyl-is silica-based or tert-butyl diphenyl is silica-based or methoxyl methyl or THP trtrahydropyranyl or tetrahydrofuran base.
7. a kind of preparation method for card Gray as claimed in claim 1 is characterized in that, in described step (6), and described solvent preferred alcohol; The preferred hydrochloric acid of described deprotecting regent;
Wherein, R is that triethyl is silica-based or tertiary butyl dimethyl-is silica-based or tert-butyl diphenyl is silica-based or methoxyl methyl or THP trtrahydropyranyl or tetrahydrofuran base.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999005143A1 (en) * | 1997-07-22 | 1999-02-04 | Astra Pharmaceuticals Ltd. | Novel compounds |
| CN1432017A (en) * | 2000-06-02 | 2003-07-23 | 阿斯特拉曾尼卡有限公司 | Triazolo pyrimidine compounds |
| CN102311437A (en) * | 2010-07-01 | 2012-01-11 | 北京迈劲医药科技有限公司 | Preparation method of platelet-aggregation-resisting medicament Ticagrelor |
-
2012
- 2012-05-11 CN CN201210146500.7A patent/CN102675321B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999005143A1 (en) * | 1997-07-22 | 1999-02-04 | Astra Pharmaceuticals Ltd. | Novel compounds |
| CN1432017A (en) * | 2000-06-02 | 2003-07-23 | 阿斯特拉曾尼卡有限公司 | Triazolo pyrimidine compounds |
| CN102311437A (en) * | 2010-07-01 | 2012-01-11 | 北京迈劲医药科技有限公司 | Preparation method of platelet-aggregation-resisting medicament Ticagrelor |
Non-Patent Citations (1)
| Title |
|---|
| HAO ZHANG，等: "Synthesis and biological evaluation of ticagrelor derivatives as novel antiplatelet agents", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, vol. 22, no. 11, 16 April 2012 (2012-04-16), pages 3598 - 3602, XP028423327, DOI: doi:10.1016/j.bmcl.2012.04.050 * |
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| CN104284897A (en) * | 2013-04-07 | 2015-01-14 | 杭州领业医药科技有限公司 | Crystalline form of ticagrelor and manufacturing method and usage thereof |
| WO2014166337A1 (en) * | 2013-04-07 | 2014-10-16 | 杭州领业医药科技有限公司 | Crystalline form of ticagrelor and manufacturing method and usage thereof |
| CN104284897B (en) * | 2013-04-07 | 2016-06-01 | 杭州领业医药科技有限公司 | Brilliant type of ADZ6140 and its production and use |
| TWI634116B (en) * | 2013-04-10 | 2018-09-01 | 江蘇恆瑞醫藥股份有限公司 | An intermediate of ticagrelor and a preparation method thereof and a preparation method of ticagrelor |
| CN104098553A (en) * | 2013-04-10 | 2014-10-15 | 江苏恒瑞医药股份有限公司 | Ticagrelor intermediate and preparation method thereof and ticagrelor preparation method |
| WO2014166324A1 (en) | 2013-04-10 | 2014-10-16 | 江苏恒瑞医药股份有限公司 | Midbody of ticagrelor and preparation method therefor, and preparation method for ticagrelor |
| CN104098553B (en) * | 2013-04-10 | 2017-11-28 | 江苏恒瑞医药股份有限公司 | The preparation method of intermediate of ticagrelor and preparation method thereof and ticagrelor |
| US9359366B2 (en) | 2013-04-10 | 2016-06-07 | Jiangsu Hengrui Medicine Co., Ltd. | Intermediate of Ticagrelor and preparation method therefor, and preparation method for Ticagrelor |
| CN104211704B (en) * | 2013-06-03 | 2017-08-25 | 杭州领业医药科技有限公司 | Triazole [4,5 d] pyrimidine compound of crystal habit and its production and use |
| CN104211704A (en) * | 2013-06-03 | 2014-12-17 | 杭州领业医药科技有限公司 | Crystallized triazolo[4,5-d]pyrimidine compounds, and preparation method and use thereof |
| CN106496234B (en) * | 2013-06-03 | 2019-08-30 | 杭州领业医药科技有限公司 | Triazole [4,5-d] pyrimidine compound of crystal habit and its preparation method and application |
| CN106496234A (en) * | 2013-06-03 | 2017-03-15 | 杭州领业医药科技有限公司 | Triazole [4,5 d] pyrimidine compound of crystal habit and its production and use |
| CN106496235A (en) * | 2013-06-03 | 2017-03-15 | 杭州领业医药科技有限公司 | Triazole [4,5 d] pyrimidine compound of crystal habit and its production and use |
| CN104230818A (en) * | 2013-06-06 | 2014-12-24 | 郝聪梅 | Improved preparation method for ticagrelor intermediate |
| CN104230818B (en) * | 2013-06-06 | 2018-01-12 | 郝聪梅 | The improvement preparation method of ticagrelor midbody |
| US9604991B2 (en) | 2013-06-24 | 2017-03-28 | Suzhou Miracpharma Technology Co., Ltd. | Preparation method of ticagrelor and intermediates thereof |
| WO2014206187A1 (en) * | 2013-06-24 | 2014-12-31 | 苏州明锐医药科技有限公司 | Preparation method of ticagrelor and intermediates thereof |
| CN103304545B (en) * | 2013-06-26 | 2015-05-20 | 苏州明锐医药科技有限公司 | 5-amino-1,4-disubstituent-1,2,3-triazole and preparation method thereof |
| CN103304545A (en) * | 2013-06-26 | 2013-09-18 | 苏州明锐医药科技有限公司 | 5-amino-1,4-disubstituent-1,2,3-triazole and preparation method thereof |
| CN103288836A (en) * | 2013-06-27 | 2013-09-11 | 苏州明锐医药科技有限公司 | Preparation method of ticagrelor |
| CN104341402A (en) * | 2013-07-23 | 2015-02-11 | 博瑞生物医药技术(苏州)有限公司 | Preparation method of intermediate ticagrelor |
| CN104341402B (en) * | 2013-07-23 | 2018-04-27 | 博瑞生物医药（苏州）股份有限公司 | A kind of method for preparing ticagrelor midbody |
| CN104059069A (en) * | 2013-08-22 | 2014-09-24 | 程刚 | Preparation method of ticagrelor |
| CN104059069B (en) * | 2013-08-22 | 2016-08-10 | 北京康立生医药技术开发有限公司 | A kind of preparation method of Ticagrelor |
| CN104650085A (en) * | 2013-11-22 | 2015-05-27 | 天津市汉康医药生物技术有限公司 | Ticagrelor sesquihydrate compound |
| CN103626745A (en) * | 2013-12-04 | 2014-03-12 | 青岛黄海制药有限责任公司 | Preparation method for ticagrelor intermediate |
| CN103626745B (en) * | 2013-12-04 | 2016-02-24 | 青岛黄海制药有限责任公司 | A kind of preparation method of ticagrelor midbody |
| CN104710425A (en) * | 2013-12-16 | 2015-06-17 | 石药集团中奇制药技术（石家庄）有限公司 | Ticagrelor new crystal and preparation method thereof |
| CN104710425B (en) * | 2013-12-16 | 2019-06-14 | 石药集团中奇制药技术（石家庄）有限公司 | A kind of ticagrelor newly crystallizes and preparation method thereof |
| CN103992323B (en) * | 2014-04-18 | 2017-03-29 | 南通常佑药业科技有限公司 | A kind of preparation method of ticagrelor |
| CN103992323A (en) * | 2014-04-18 | 2014-08-20 | 南通常佑药业科技有限公司 | Ticagrelor preparation method |
| US10011605B2 (en) | 2014-06-18 | 2018-07-03 | Flamma Spa | Process for the preparation of triazolo[4,5-D] pyrimidine cyclopentane compounds |
| CN104140428A (en) * | 2014-07-14 | 2014-11-12 | 福建广生堂药业股份有限公司 | Ticagrelor hydrates and preparation method thereof |
| CN104193748A (en) * | 2014-08-14 | 2014-12-10 | 严白双 | Method for synthesizing ticagrelor |
| WO2016141889A1 (en) * | 2015-03-12 | 2016-09-15 | 四川海思科制药有限公司 | Novel triazolopyrimidine derivative and use thereof |
| CN107266488A (en) * | 2016-04-06 | 2017-10-20 | 湖南华腾制药有限公司 | A kind of ticagrelor midbody and preparation method thereof |
| CN108690026A (en) * | 2017-04-11 | 2018-10-23 | 天方药业有限公司 | A kind of preparation method of ticagrelor |
| CN111848632A (en) * | 2020-09-07 | 2020-10-30 | 河南师范大学 | Preparation method of platelet aggregation inhibitor ticagrelor |
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