CN106243108A - A kind of highly purified ticagrelor and preparation method thereof - Google Patents
A kind of highly purified ticagrelor and preparation method thereof Download PDFInfo
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- CN106243108A CN106243108A CN201610325632.4A CN201610325632A CN106243108A CN 106243108 A CN106243108 A CN 106243108A CN 201610325632 A CN201610325632 A CN 201610325632A CN 106243108 A CN106243108 A CN 106243108A
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- ticagrelor
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- 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 claims abstract description 316
- 229960002528 ticagrelor Drugs 0.000 title claims abstract description 313
- 238000002360 preparation method Methods 0.000 title claims abstract description 45
- 239000002904 solvent Substances 0.000 claims abstract description 59
- 150000001408 amides Chemical class 0.000 claims abstract description 19
- 150000002148 esters Chemical class 0.000 claims abstract description 13
- 239000003146 anticoagulant agent Substances 0.000 claims abstract description 7
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 7
- 230000010100 anticoagulation Effects 0.000 claims abstract description 6
- 230000002785 anti-thrombosis Effects 0.000 claims abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 4
- 239000012535 impurity Substances 0.000 claims description 123
- 239000000203 mixture Substances 0.000 claims description 80
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 59
- 238000000034 method Methods 0.000 claims description 52
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 51
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
- 239000007787 solid Substances 0.000 claims description 32
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 29
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 claims description 14
- 239000012296 anti-solvent Substances 0.000 claims description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 9
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 9
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical class COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 9
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 239000012046 mixed solvent Substances 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 6
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 6
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- UWJJYHHHVWZFEP-UHFFFAOYSA-N pentane-1,1-diol Chemical compound CCCCC(O)O UWJJYHHHVWZFEP-UHFFFAOYSA-N 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 5
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 5
- 229940011051 isopropyl acetate Drugs 0.000 claims description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 3
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 3
- 229940113088 dimethylacetamide Drugs 0.000 claims description 3
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 claims description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 3
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 3
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 3
- 238000001556 precipitation Methods 0.000 claims description 3
- 238000011287 therapeutic dose Methods 0.000 claims description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims 2
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- 238000003756 stirring Methods 0.000 description 31
- 238000006243 chemical reaction Methods 0.000 description 22
- 239000002585 base Substances 0.000 description 20
- 238000004128 high performance liquid chromatography Methods 0.000 description 20
- 239000012043 crude product Substances 0.000 description 19
- 238000010606 normalization Methods 0.000 description 15
- 238000000746 purification Methods 0.000 description 15
- 238000001035 drying Methods 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 208000035126 Facies Diseases 0.000 description 13
- 239000012065 filter cake Substances 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 150000002118 epoxides Chemical class 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- -1 VI compound Chemical class 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 238000002156 mixing Methods 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 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 5
- 229920002472 Starch Polymers 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
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- 239000007788 liquid Substances 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 238000012805 post-processing Methods 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- QVUBIQNXHRPJKK-UHFFFAOYSA-N 2-(3,4-difluorophenyl)cyclopropan-1-amine Chemical compound NC1CC1C1=CC=C(F)C(F)=C1 QVUBIQNXHRPJKK-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 3
- 210000001367 artery Anatomy 0.000 description 3
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- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 3
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- 239000000843 powder Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
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- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-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
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
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- 229940127219 anticoagulant drug Drugs 0.000 description 2
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- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 2
- XAAHAAMILDNBPS-UHFFFAOYSA-L calcium hydrogenphosphate dihydrate Chemical compound O.O.[Ca+2].OP([O-])([O-])=O XAAHAAMILDNBPS-UHFFFAOYSA-L 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
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- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
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- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
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- 150000001720 carbohydrates Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000000306 component Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000003605 opacifier Substances 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 229940023488 pill Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000009702 powder compression Methods 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000013094 purity test Methods 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 229940098466 sublingual tablet Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960000790 thymol Drugs 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- YWBFPKPWMSWWEA-UHFFFAOYSA-O triazolopyrimidine Chemical class BrC1=CC=CC(C=2N=C3N=CN[N+]3=C(NCC=3C=CN=CC=3)C=2)=C1 YWBFPKPWMSWWEA-UHFFFAOYSA-O 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to organic chemistry and pharmaceutical field, it is specifically related to a kind of content high-purity ticagrelor being not less than 99.0% and preparation method thereof, this preparation method is to be crystallized in the solvent containing esters and amide containing class successively by ticagrelor, or crystallizes in amide containing class and the solvent containing esters successively；The invention still further relates to the pharmaceutical preparation containing this high-purity ticagrelor, and this high-purity ticagrelor application in preparing anticoagulation or antithrombotic reagent.
Description
Technical field
The present invention relates to organic chemistry and pharmaceutical field, be specifically related to a kind of highly purified ticagrelor and preparation side thereof
Method.
Background technology
Ticagrelor (Ticagrelor, once with code name: AZD6140, ARC126532), belongs to cyclopenta triazolo pyrimidine
Compounds, chemistry is entitled: (1S, 2S, 3R, 5S)-3-[7-{ [(1R, 2S)-2-(3,4-difluorophenyl) cyclopropyl] amino }-
5-rosickyite base-3H-1,2,3-triazols [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyl-oxethyl)-1,2-ring pentanediol, molecule
Formula: C23H28F2N6O4S, No. CAS: 274693-27-5, there is the chemical constitution shown in following formula I:
Ticagrelor is a kind of novel, has selective anticoagulant, is also first reversible conjunction type P2Y12 gland
Glycosides diphosphonic acid receptor (ADP) antagonist, can reversibly purine 2 receptor subtype on vasoactive smooth muscle cell (VSMC)
P2Y12, the platelet aggregation causing ADP has obvious inhibitory action, can effectively reduce acute coronary syndrome (unstable
Sizing angina pectoris, non-ST section myocardial infarction, ST section myocardial infarction) incidence rate of thrombotic cardiovascular event of patient.Because of for lattice
The antiplatelet effects of auspicious Lip river is reversible, and it need to go the patient performed the operation particularly for those after carrying out anticoagulant therapy in advance again
It is suitable for.This product is developed by AstraZeneca (AstraZeneca), and trade name Brilinta, in December, 2010 obtains first in European Union
Must list approval, February next year and August are approved listing approval in Britain and the U.S. the most respectively, and up to the present this medicine is in the whole world 40
Multiple countries go through to list.This product clinical efficacy is obvious, and safety is good, is an outstanding person in anticoagulation medicine.
Patent CN1334816A, CN1432017A, CN102149716A, CN102659815A, CN102675321A,
CN102731467A, WO2011017108 or WO2012138981 etc. disclose the multiple synthetic route of ticagrelor.At these
In synthetic route, final step reaction is ticagrelor (II) deprotection in hydrochloric acid/methanol solution of propylidene protection and obtains
Ticagrelor (I), pyrimidine ring position a, benzyl position b equipotential in the ticagrelor (II) protected due to propylidene or ticagrelor (I) structure
Putting and have higher reactivity, therefore these positions are it may happen that react and produce some impurity, and then are incorporated into product
In ticagrelor (I).The impurity that prior art is all not directed in ticagrelor is studied and controls.
Preparing highly purified crude drug, the impurity controlled in crude drug and corresponding preparations is in drug development to certain limit
Emphasis and difficult point.These impurity are probably in preparation technology generation, it is also possible to produced by product degraded.At crude drug and
The method controlling these impurity in preparation is the most unpredictalbe, needs through substantial amounts of experiment and gropes.
In order to overcome the deficiencies in the prior art and improve the quality of product ticagrelor further, effectively control therein miscellaneous
Matter, the impurity in ticagrelor is studied, is found under study for action by the present invention, has several content relatively in ticagrelor
High impurity, and these impurity not easily pass through existing process for purification (as with ethyl acetate/isobutyltrimethylmethane. equal solvent recrystallization)
Effectively reduce or remove.For these problems found in research, the present invention has prepared this several major impurities, it is determined that it
The structure of matter, provide the improvement new method of a kind of purification ticagrelor simultaneously, this purification process can effectively reduce or remove
Remove these impurity, obtain highly purified ticagrelor.
Summary of the invention
It is an object of the invention to provide a kind of highly purified ticagrelor.
Another object of the present invention is to provide the preparation method of above-mentioned high-purity ticagrelor.
A further object of the present invention is to provide the pharmaceutical preparation of the above-mentioned high-purity ticagrelor comprising therapeutically effective amount.
A further object of the present invention is to provide above-mentioned high-purity ticagrelor preparing anticoagulation or antithrombotic medicine
In application.
According to goal of the invention, the invention provides a kind of highly purified ticagrelor compositions, said composition comprises formula III
Shown impurity (1S, 2S, 3R, 5S)-3-[7-methoxyl group-5-(rosickyite base)-3H-1,2,3-triazol [4,5-d] pyrimidine-3-
Base]-5-(2-hydroxyl-oxethyl)-1,2-Pentamethylene. glycol (it is called for short: impurity TCGA) and/or shown in formula IV (1S, 2S, 3R,
5S)-3-[7-[[(1R, 2R)-2-(3,4-difluorophenyl) cyclopropyl] amino]-5-(rosickyite base)-3H-1,2,3-triazol [4,
5-d] pyrimidin-3-yl]-5-(2-hydroxyl-oxethyl)-1,2-ring pentanediol (is called for short: TCGB), wherein the content of ticagrelor is not
Less than 99.0%, impurity shown in formula III is not higher than 0.5% relative to the content of ticagrelor, 0.3%, 0.2%, 0.15%,
0.1% or 0.05%, impurity shown in formula IV relative to the content of ticagrelor be not higher than 0.2%, 0.15%, 0.1% or
0.05%.
In one embodiment, the high-purity ticagrelor compositions that invention provides is selected from:
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.0%, and impurity shown in formula III is relative to for lattice
The content of auspicious Lip river is not higher than 0.5%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05%, and impurity shown in formula IV is relative to for lattice
The content of auspicious Lip river is not higher than 0.2%, 0.15%, 0.1% or 0.05%；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.1%, and impurity shown in formula III is relative to for lattice
The content of auspicious Lip river is not higher than 0.5%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05%, and impurity shown in formula IV is relative to for lattice
The content of auspicious Lip river is not higher than 0.2%, 0.15%, 0.1% or 0.05%；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.2%, and impurity shown in formula III is relative to for lattice
The content of auspicious Lip river is not higher than 0.3%, 0.2%, 0.15%, 0.1% or 0.05%, and shown in formula IV, impurity is relative to ticagrelor
Content is not higher than 0.2%, 0.15%, 0.1% or 0.05%；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.3%, and impurity shown in formula III is relative to for lattice
The content of auspicious Lip river is not higher than 0.3%, 0.2%, 0.15%, 0.1% or 0.05%, and shown in formula IV, impurity is relative to ticagrelor
Content is not higher than 0.2%, 0.15%, 0.1% or 0.05%；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.4%, and impurity shown in formula III is relative to for lattice
The content of auspicious Lip river is not higher than 0.2%, 0.15%, 0.1% or 0.05%, impurity shown in formula IV relative to ticagrelor content not
Higher than 0.2%, 0.15%, 0.1% or 0.05%；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.5%, and impurity shown in formula III is relative to for lattice
The content of auspicious Lip river is not higher than 0.2%, 0.15%, 0.1% or 0.05%, impurity shown in formula IV relative to ticagrelor content not
Higher than 0.15%, 0.1% or 0.05%；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.6%, and impurity shown in formula III is relative to for lattice
The content of auspicious Lip river is not higher than 0.15%, 0.1% or 0.05%, and impurity shown in formula IV is not higher than relative to the content of ticagrelor
0.15%, 0.1% or 0.05%；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.7%, and impurity shown in formula III is relative to for lattice
The content of auspicious Lip river is not higher than 0.1% or 0.05%, impurity shown in formula IV relative to the content of ticagrelor be not higher than 0.1% or
0.05%；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.8%, and impurity shown in formula III is relative to for lattice
The content of auspicious Lip river is not higher than 0.05%, and impurity shown in formula IV is not higher than 0.05% relative to the content of ticagrelor.
In another embodiment, the high-purity ticagrelor compositions that invention provides is selected from:
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.0%, and impurity shown in formula III is relative to for lattice
The content of auspicious Lip river is not higher than 0.5%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05%, and impurity shown in formula IV is relative to for lattice
The content of auspicious Lip river is not higher than 0.2%, 0.15%, 0.1% or 0.05%, other single impurity relative to ticagrelor content not
Higher than 0.15%, 0.1% or 0.05%；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.1%, and impurity shown in formula III is relative to for lattice
The content of auspicious Lip river is not higher than 0.5%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05%, and impurity shown in formula IV is relative to for lattice
The content of auspicious Lip river is not higher than 0.2%, 0.15%, 0.1% or 0.05%, other single impurity relative to ticagrelor content not
Higher than 0.15%, 0.1% or 0.05%；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.2%, and impurity shown in formula III is relative to for lattice
The content of auspicious Lip river is not higher than 0.3%, 0.2%, 0.15%, 0.1% or 0.05%, and shown in formula IV, impurity is relative to ticagrelor
Content is not higher than 0.2%, 0.15%, 0.1% or 0.05%, and other single impurity is not higher than relative to the content of ticagrelor
0.15%, 0.1% or 0.05%；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.3%, and impurity shown in formula III is relative to for lattice
The content of auspicious Lip river is not higher than 0.3%, 0.2%, 0.15%, 0.1% or 0.05%, and shown in formula IV, impurity is relative to ticagrelor
Content is not higher than 0.2%, 0.15%, 0.1% or 0.05%, and other single impurity is not higher than relative to the content of ticagrelor
0.15%, 0.1% or 0.05%；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.4%, and impurity shown in formula III is relative to for lattice
The content of auspicious Lip river is not higher than 0.2%, 0.15%, 0.1% or 0.05%, impurity shown in formula IV relative to ticagrelor content not
Higher than 0.2%, 0.15%, 0.1% or 0.05%, other single impurity is not higher than 0.15% relative to the content of ticagrelor,
0.1% or 0.05%；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.5%, and impurity shown in formula III is relative to for lattice
The content of auspicious Lip river is not higher than 0.2%, 0.15%, 0.1% or 0.05%, impurity shown in formula IV relative to ticagrelor content not
Higher than 0.15%, 0.1% or 0.05%, other single impurity relative to the content of ticagrelor be not higher than 0.15%, 0.1% or
0.05%；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.6%, and impurity shown in formula III is relative to for lattice
The content of auspicious Lip river is not higher than 0.15%, 0.1% or 0.05%, and impurity shown in formula IV is not higher than relative to the content of ticagrelor
0.15%, 0.1% or 0.05%, other single impurity is not higher than 0.1% or 0.05% relative to the content of ticagrelor；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.7%, and impurity shown in formula III is relative to for lattice
The content of auspicious Lip river is not higher than 0.1% or 0.05%, impurity shown in formula IV relative to the content of ticagrelor be not higher than 0.1% or
0.05%, other single impurity is not higher than 0.1% or 0.05% relative to the content of ticagrelor；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.8%, and impurity shown in formula III is relative to for lattice
The content of auspicious Lip river is not higher than 0.05%, and impurity shown in formula IV is not higher than 0.05% relative to the content of ticagrelor, and other is single
Impurity is not higher than 0.1% or 0.05% relative to the content of ticagrelor.
Described " ticagrelor compositions " refers to the mixture of ticagrelor and impurity.Described " impurity " refers to auspicious with for lattice
The organic impurities that Lip river structure is relevant, including the raw material in preparation technology, intermediate, byproduct of reaction, the catabolite of product, light
Learn isomer etc..
Described " relative to the content of ticagrelor " refers to the content content divided by ticagrelor of impurity in the composition；
Described " content of ticagrelor " refers to that ticagrelor in the composition accounts for the percentage ratio of ticagrelor and total impurities.Real one
Execute in scheme, measure ticagrelor and impurity in ticagrelor compositions by high performance liquid chromatography (HPLC) area normalization method
Content, TCGA relative to the chromatographic peak area that content is TCGA of ticagrelor divided by the chromatographic peak area of ticagrelor, TCGB
Relative to the chromatographic peak area that content is TCGB of ticagrelor divided by the chromatographic peak area of ticagrelor, the content of ticagrelor
For ticagrelor chromatographic peak area divided by ticagrelor and all impurity chromatographic peak area and.The numerical value of content can be after testing
Or calculate data and round up process.The selection of the condition determination of high performance liquid chromatography (HPLC) can be according to the routine in this area
Technology is carried out, and such as, this condition determination may be selected to be: [the Agilent with octadecylsilane chemically bonded silica as filler
ZORBAX SB-C18Post (150mm × 4.6mm, 1.8 μm)]；(regulate with phosphoric acid with the phosphate sodium dihydrogen buffer solution of 0.01mol/L
PH to 3.5) be mobile phase A, acetonitrile be Mobile phase B；Flow velocity is 1.0ml/ minute, and column temperature is 40 DEG C, and detection wavelength is 242nm,
According to the form below carries out gradient elution.
| Time (minute) | A% (V/V) | B% (V/V) |
| 0 | 80 | 20 |
| 20 | 55 | 45 |
| 25 | 55 | 45 |
| 45 | 30 | 70 |
| 50 | 30 | 70 |
| 55 | 80 | 20 |
| 60 | 80 | 20 |
According to goal of the invention, the preparation method that the invention provides a kind of above-mentioned high-purity ticagrelor compositions (is called for short
" method one "), the method includes:
(1), ticagrelor is dissolved in esters solvent, adds anti-solvent and separate out solid, point isolated solid；
(2), the solid of step (1) gained is dissolved in amide solvent or amide solvent with another or multiple suitably
In the mixed solvent of solvent composition, cool down or add anti-solvent precipitation solid, point isolated solid；
(3), optionally, the solid that step (2) is separated is dried.
In said method one step (1), described " esters solvent " includes ethyl acetate, methyl acetate, Ethyl formate, acetic acid
Isopropyl ester, n-butyl acetate etc. or their mixture, wherein ethyl acetate or isopropyl acetate.
In said method one step (1), described " esters solvent " is generally higher than 1/ with the volume ratio of described " anti-solvent "
1.5, preferably greater than 1/1.2.
In said method one step (1), described " separation " can use and filter the conventional method waited in the art, can
Selection of land, can be dried isolated solid.
In said method one step (2), described " amide solvent " includes DMF, N, N-dimethyl second
Amide etc..
In said method one step (2), described " suitable solvent " includes methanol, ethanol, isopropanol, the tert-butyl alcohol, acetic acid second
Ester, methyl acetate, dichloromethane, chloroform, acetone, acetonitrile, toluene, water etc. or their mixed solvent, preferably methanol, ethanol,
Isopropanol, ethyl acetate, dichloromethane, acetone, acetonitrile, water or their mixture.Described " amide solvent " is " suitable with described
Preferably solvent " volume ratio be generally higher than 5/1, preferably greater than 10/1.
In said method one step (2), described " amide solvent " is generally higher than 1/ with the volume ratio of described " anti-solvent "
25, preferably greater than 1/20.
In said method one step (2), described " cooling " refers generally to reduce by more than 20 DEG C than solution temperature, preferably reduces by 30
More than DEG C.
In said method one step (1) and (2), dissolve the solvent load of ticagrelor and the selection of solution temperature is ability
The routine techniques in territory, in order to obtain higher purification yield, generally uses less amount of solvent and carries out molten at a higher temperature
Solve.The consumption of solvent is usually from just meltage to excess 1 times；Solution temperature is generally 10 DEG C to solvent boiling point.
In said method one step (1) and (2), described " anti-solvent " refers at normal temperatures to the dissolubility of ticagrelor not
The solvent got well and can be miscible with the solvent dissolving ticagrelor, such as ether, methyl tertiary butyl ether(MTBE), diisopropyl ether, positive propyl ether, 2-methoxy
Methylmethane, 1,1-dimethoxy-ethane, methyl phenyl ethers anisole, water, n-hexane, normal heptane, normal octane, isobutyltrimethylmethane. etc. or their mixing
Thing, wherein preferred methyl tertiary butyl ether(MTBE), n-hexane or isobutyltrimethylmethane..
In said method one step (1) and (2), described " separation " can use and filter the routine side waited in the art
Method.
In said method one step (3), the temperature of described " being dried " is generally 20～120 DEG C, preferably 50～100 DEG C；Can
With constant pressure and dry, it is also possible to drying under reduced pressure.
Further, the preparation method that the invention provides another kind of above-mentioned high-purity ticagrelor compositions (is called for short " side
Method two "), the method includes:
(1), ticagrelor is dissolved in amide solvent or amide solvent and another or multiple suitable solvent composition
Mixed solvent in, cool down or add anti-solvent and separate out solid, point isolated solid；
(2), the solid of step (1) gained is dissolved in esters solvent, adds anti-solvent and separate out solid, divide isolated solid
Body；
(3), optionally, the solid that step (2) is separated is dried.
In said method two step (1), described " amide solvent " includes DMF, N, N-dimethyl second
Amide etc..
In said method two step (1), described " suitable solvent " includes methanol, ethanol, isopropanol, the tert-butyl alcohol, acetic acid second
Ester, methyl acetate, dichloromethane, chloroform, acetone, acetonitrile, toluene, water etc. or their mixed solvent, preferably methanol, ethanol,
Isopropanol, ethyl acetate, dichloromethane, acetone, acetonitrile, water or their mixture.Described " amide solvent " is " suitable with described
Preferably solvent " volume ratio be generally higher than 5/1, preferably greater than 10/1.
In said method two step (1), described " amide solvent " is generally higher than 1/ with the volume ratio of described " anti-solvent "
25, preferably greater than 1/20.
In said method two step (1), described " cooling " refers generally to reduce by more than 20 DEG C than solution temperature, preferably reduces by 30
More than DEG C.
In said method two step (2), described " esters solvent " includes ethyl acetate, methyl acetate, Ethyl formate, acetic acid
Isopropyl ester, n-butyl acetate etc. or their mixture, wherein ethyl acetate or isopropyl acetate.
In said method two step (2), described " esters solvent " is generally higher than 1/ with the volume ratio of described " anti-solvent "
1.5, preferably greater than 1/1.2.
In said method two step (1) and (2), dissolve the solvent load of ticagrelor and the selection of solution temperature is ability
The routine techniques in territory, in order to obtain higher purification yield, generally uses less amount of solvent and carries out molten at a higher temperature
Solve.The consumption of solvent is usually from just meltage to excess 1 times；Solution temperature is generally 10 DEG C to solvent boiling point.
In said method two step (1) and (2), described " anti-solvent " refers at normal temperatures to the dissolubility of ticagrelor not
The solvent got well and can be miscible with the solvent dissolving ticagrelor, such as ether, methyl tertiary butyl ether(MTBE), diisopropyl ether, positive propyl ether, 2-methoxy
Methylmethane, 1,1-dimethoxy-ethane, methyl phenyl ethers anisole, water, n-hexane, normal heptane, normal octane, isobutyltrimethylmethane. etc. or their mixing
Thing, wherein preferred methyl tertiary butyl ether(MTBE), n-hexane or isobutyltrimethylmethane..
In said method two step (1) and (2), described " separation " can use and filter the routine side waited in the art
Method.
In said method two step (3), the temperature of described " being dried " is generally 20～120 DEG C, preferably 50～100 DEG C；Can
With constant pressure and dry, it is also possible to drying under reduced pressure.
Above-mentioned purification process (method one or method two) can effectively reduce or remove the impurity content in ticagrelor.?
In one embodiment, before purification in ticagrelor TCGA relative to the content of ticagrelor be about 0.7%, TCGB is relative to replacing
The content of Ge Ruiluo is about 0.3%, as stated above, selects ethyl acetate/isobutyltrimethylmethane. and methyl tertiary butyl ether(MTBE)/N, N-successively
Dimethylformamide recrystallization or select methyl tertiary butyl ether(MTBE)/N,N-dimethylformamide and ethyl acetate/isobutyltrimethylmethane. weight successively
Crystallization, in gained ticagrelor, TCGA and TCGB is respectively lower than 0.1% relative to the content of ticagrelor, and other impurity content is also
Not higher than 0.15%.If pressing literature method purification ticagrelor, it is used alone ethyl acetate/isobutyltrimethylmethane. recrystallization operation the most right
TCGB purification effect is preferable, poor to the purification effect of TCGA；It is used alone methyl tertiary butyl ether(MTBE)/N,N-dimethylformamide heavily to tie
Brilliant operation is only preferable to TCGA purification effect, poor to the purification effect of TCGB.If being used alone these purification process, its knot
Fruit necessarily needs recrystallization repeatedly could obtain the ticagrelor that purity is higher, and this will cause product yield to reduce, and industry becomes
Originally it is greatly increased.Therefore, the ticagrelor purification process that the present invention provides is a kind of easy and simple to handle, and efficiency is higher, it is easy to industry
The ticagrelor Novel purification method changed.
Present invention also offers the major impurity in ticagrelor: TCGA and TCGB.Its purity is all not less than 90%, preferably
It is not less than 95%.
Further, the invention provides the preparation method of the two compound.
The preparation method of TCGA:
In Formula V, X is the halogen groups such as F, Cl, Br, I.
The method preparing TCGA that the present invention provides includes:
(1), by 2-, [[[7-halogen-5-(rosickyite base)-3H-1,2,3-triazol [4,5-d] is phonetic for (3aR, 4S, 6R, 6aS)-6-
Pyridine-3-base]-tetrahydrochysene-2,2-dimethyl-4H-cyclopenta-1,3-dioxane amyl-4-yl] epoxide]-ethanol (change by formula V
Compound) with methylate compound react compound 2-[[(3aR, 4S, 6R, 6aS)-6-[7-methoxyl group-5-(rosickyite base)-
3H-1,2,3-triazol [4,5-d] pyrimidin-3-yl]-tetrahydrochysene-2,2-dimethyl-4H-cyclopenta-1,3-dioxane
Amyl-4-yl] epoxide]-ethanol (formula VI compound).Wherein, described " Formula V compound " can by CN1432017A or
Prepared by the method disclosed in CN103965198A；Described " methylate compound " includes lithium methoxide, Feldalat NM, Feldalat KM etc.,
Preferably Feldalat NM；The preferred methanol of solvent of described " reaction ", oxolane etc., reaction temperature preferably 60 DEG C～solvent boiling point；Instead
By the routine techniques in this area, reaction can be carried out post processing after Ying, remove as this can carry out concentrating under reduced pressure after completion of the reaction
Go solvent, residue add water and organic solvent extraction, organic facies carry out successively washing, are dried, filter and concentrating under reduced pressure.
(2), formula VI compound is hydrolyzed in the presence of acid (1S, 2S, 3R, 5S)-3-[7-methoxyl group-5-(rosickyite
Base)-3H-1,2,3-triazol [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyl-oxethyl)-1,2-Pentamethylene. glycol (formula III chemical combination
Thing, TCGA).Wherein, described " sour " preferably hydrochloric acid, sulphuric acid, phosphoric acid, p-methyl benzenesulfonic acid etc.；The solvent of described " reaction " is preferably
Methanol, oxolane etc., reaction temperature preferably 60 DEG C～solvent boiling point；After completion of the reaction can be by the routine techniques pair in this area
Reaction carries out post processing, as this can carry out adding water and organic solvent extracting in decompression removing organic solvent, residue after completion of the reaction
Take, organic facies carries out washing successively, be dried, filter and concentrating under reduced pressure；Products obtained therefrom can be further purified through column chromatography.
The preparation method of TCGB:
In Formula V, X is the halogen groups such as F, Cl, Br, I.
The method preparing TCGB that the present invention provides includes:
(1), by 2-, [[[7-halogen-5-(rosickyite base)-3H-1,2,3-triazol [4,5-d] is phonetic for (3aR, 4S, 6R, 6aS)-6-
Pyridine-3-base]-tetrahydrochysene-2,2-dimethyl-4H-cyclopenta-1,3-dioxane amyl-4-yl] epoxide]-ethanol (change by formula V
Compound) and 2-(3,4-difluorophenyl) cyclopropylamine (formula VII compound) react in the presence of a base compound 2-[[(3aR, 4S,
6R, 6aS)-6-[7-[[(1R, 2R)-2-(3,4-difluorophenyl) cyclopropyl] amino]-5-(rosickyite base)-3H-1,2,3-triazole
And [4,5-d] pyrimidin-3-yl] tetrahydrochysene-2,2-dimethyl-4H-cyclopenta-1,3-Dioxol-4-yl] epoxide]-
Ethanol (formula VIII compound).Wherein, described " formula VII compound " can prepare by the method disclosed in CN102775314A；Described
" alkali " preferably triethylamine, N, N-diisopropyl ethyl amine, potassium carbonate etc.；The preferred toluene of solvent of described " reaction ", acetonitrile etc. with
The mixed solvent of water, reaction temperature preferably-10 DEG C～40 DEG C；After completion of the reaction can by the routine techniques in this area to react into
Row post processing, separates organic facies as this can carry out system after completion of the reaction, organic facies is adjusted after pH value, again separatory organic after adding water
Wash mutually.
(2), by formula VIII compound hydrolyze in the presence of acid (1S, 2S, 3R, 5S)-3-[7-[[(1R, 2R)-2-(3,
4-difluorophenyl) cyclopropyl] amino]-5-(rosickyite base)-3H-1,2,3-triazol [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyl
Ethyoxyl)-1,2-ring pentanediol (formula IV compound, TCGB).Wherein, described " sour " preferably hydrochloric acid, p-methyl benzenesulfonic acid, trifluoro second
Acid etc.；The solvent of described " reaction " is preferably methanol, ethanol, acetonitrile etc., reaction temperature preferably-10～20 DEG C；After completion of the reaction
By the routine techniques in this area, reaction can be carried out post processing, as this can carry out there was added in separatory, aqueous phase after completion of the reaction
Machine solvent extraction washes, neutralize with alkali, add that organic solvent carries out extracting, organic facies carries out washing, be dried, filter and subtracting successively again
Pressure concentrates；Products obtained therefrom can be further purified through preparing post.
It is still another object of the present invention to provide and above-mentioned high-purity ticagrelor compositions is applied to pharmaceutical preparation and system
Medicinal way.
In order to realize this purpose, on the one hand the invention provides a kind of above-mentioned high-purity comprising effective therapeutic dose auspicious for lattice
Lip river compositions and the pharmaceutical preparation of pharmaceutic adjuvant.
On the other hand, the invention provides above-mentioned high-purity ticagrelor compositions and prepare anticoagulation or antithrombotic reagent
In application.It is usually and the above-mentioned high-purity ticagrelor compositions of therapeutically effective amount is made with one or more pharmaceutic adjuvants
Pharmaceutical preparation, this pharmaceutical preparation be known in the art in the way of be prepared.
Said medicine preparation can be mainly used in treatment as a kind of anticoagulation or antithrombotic reagent or prevention have crown dynamic
Arteries and veins, cerebrovascular or the artery thrombosis of peripheral blood vessel patient and complication thereof, particularly, be used for reducing acute coronary and move
The incidence rate of the thrombotic cardiovascular event of arteries and veins syndrome patient.
The dosage form of said medicine preparation includes: tablet, capsule, pill, granule, syrup, powder, sublingual tablet,
Suspensoid, solution, injectable formulation, aerosol, dry powder doses, suppository, ointment, ointment, gel etc..They are according to each
From the feature of dosage form, route of administration includes being administered orally, Sublingual, parenterally (such as intravenous injection, intramuscular injection, subcutaneous injection etc.), warp
Lung/trachea or percutaneous etc..
The dosage of said medicine preparation is according to conditions of patients character and seriousness, route of administration and patient age, body weight
Etc. being adjusted, general daily dose is between 1mg to 1g, between preferably 30mg to 300mg；Every day can be with single administration, it is possible to
With multiple dosing.
Said medicine preparation can also comprise other suitable active component.
In one embodiment, the medicine that the present invention provides is oral solid formulation, preferred tablet or capsule.This is administered orally
Solid preparation is in addition to active component high-purity ticagrelor compositions, and possibly together with pharmaceutic adjuvant, described pharmaceutic adjuvant is all this
The pharmaceutic adjuvant that field is conventional, including filler, disintegrating agent, binding agent, lubricant etc..
Described filler generally comprise mannitol, calcium hydrogen phosphate, microcrystalline Cellulose, pregelatinized Starch, lactose, Icing Sugar,
Calcium sulfate, micropowder silica gel etc..They can be used alone and can also be used in mixed way, wherein preferred mannitol, calcium hydrogen phosphate, crystallite
Cellulose.
Described disintegrating agent generally comprises carboxymethyl starch sodium, sodium carboxymethyl cellulose, cross-linked carboxymethyl cellulose sodium, crystallite
Cellulose, crospolyvinylpyrrolidone, polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, agar, calcium carbonate and carbonic acid
Hydrogen sodium etc..They can be used alone and can also be used in mixed way, the most preferably carboxymethyl starch sodium, sodium carboxymethyl cellulose,
Cross-linked carboxymethyl cellulose sodium, microcrystalline Cellulose.
Described binding agent generally comprises hydroxypropyl cellulose, hydroxypropyl methyl cellulose, Polyethylene Glycol, polyvidone, micro-
Crystalline cellulose, starch slurry, water, the ethanol solution etc. of various concentration, they can be used alone and can also be used in mixed way.The most excellent
Select hydroxypropyl cellulose, hydroxypropyl methyl cellulose, Polyethylene Glycol, polyvidone.
Described lubricant generally comprises magnesium stearate, Pulvis Talci, stearic acid, calcium stearate, Palmic acid, aluminium silicate, hard
Acyl amine, solid polyethylene glycol etc..They can be used alone and can also be used in mixed way, wherein preferred magnesium stearate, Pulvis Talci.
If necessary, it is also possible in above-mentioned composition or preparation, add other adjuvants, if sweeting agent is (such as A Sipa
Smooth, steviosin etc.), coloring agent (such as ferrous oxide, titanium dioxide etc.), stabilizer is (such as vitamin E, thymol, glycine
Deng), surfactant (such as sodium laurylsulfate etc.) etc..
The preparation of above-mentioned oral solid formulation can be according to the conventional method preparing oral solid formulation in the art
Carry out, such as: tablet can be prepared to use the mode such as wet granule compression tablet, direct powder compression, and capsule can use powder directly to fill
Prepared by the modes such as capsule, wet granulation are encapsulated.When described oral solid formulation is tablet, can be further to it as required
Coating, makes film coated tablet or sugar coated tablet.Coated substrate includes cellulose family, crylic acid resin, saccharide, such as hydroxypropyl level
Methylcellulose, sucrose etc., the most also can add plasticizer, antiplastering aid, opacifier.
Specific embodiment
Below in conjunction with embodiment, the invention will be further described, can make professional and technical personnel in the field more fully
Understand the present invention, but limit the scope of the present invention never in any form.
Nuclear-magnetism test in following example is using deuterated dimethyl sulfoxide as test solvent, in making with tetramethylsilane
Mark, at room temperature measures by BrukeAV-II 400MHz nuclear magnetic resonance analyser；Mass spectrometric measurement is to use Agilent Quadrupole
LC/MS 6120B, ESI holotype completes；Liquid chromatograph purity testing is to complete with Agilent1260 high performance liquid chromatograph
's.
Embodiment 1
(1S, 2S, 3R, 5S)-3-[7-methoxyl group-5-(rosickyite base)-3H-1,2,3-triazol [4,5-d] pyrimidine-3-
Base] preparation of-5-(2-hydroxyl-oxethyl)-1,2-Pentamethylene. glycol (TCGA)
By 2-[[(3aR, 4S, 6R, 6aS)-6-[the bromo-5-of 7-(rosickyite base)-3H-1,2,3-triazol [4,5-d] pyrimidine-
3-yl]-tetrahydrochysene-2,2-dimethyl-4H-cyclopenta-1,3-dioxane amyl-4-yl] epoxide]-ethanol (V) 5.87g is molten
Solution, in methanol 100ml, adds Feldalat NM 1.6g, is heated to about 65 DEG C, stirring reaction about 4.5 hours.Reactant liquor cools to room
Temperature, removal of solvent under reduced pressure, residue adds water 100ml, extracts with ethyl acetate 80ml × 3, merge organic facies；Organic facies depends on
Secondary through saturated sodium-chloride water solution 80ml washing, anhydrous sodium sulfate is dried, and filters, and filtrate reduced in volume obtains intermediate 2-
[[(3aR, 4S, 6R, 6aS)-6-[7-methoxyl group-5-(rosickyite base)-3H-1,2,3-triazol [4,5-d] pyrimidin-3-yl]-four
Hydrogen-2,2-dimethyl-4H-cyclopenta-1,3-dioxane amyl-4-yl] epoxide]-ethanol (VI) 3.68g.
Above-mentioned intermediate (VI) 1.00g obtained is dissolved in methanol 26ml, is added dropwise to 1mol/L hydrochloric acid 2ml, heating
To about 65 DEG C, stirring reaction about 5 hours.Reactant liquor cools to room temperature, and decompression removes organic solvent, adds water in residue
50ml, extracts with ethyl acetate 40ml × 3, merges organic facies；Organic facies is washed through saturated sodium-chloride water solution 60ml successively, nothing
Aqueous sodium persulfate is dried, filter, filtrate reduced in volume, column chromatography (dichloromethane: methanol=30:1) separate (1S, 2S, 3R,
5S)-3-[7-methoxyl group-5-(rosickyite base)-3H-1,2,3-triazol [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyl-oxethyl)-
1,2-Pentamethylene. glycol (III, TCGA).
HPLC purity: 99.20%.
1H-NMR (400MHz, DMSO-d6) δ (ppm): 1.007-1.043 (t, 3H), 1.714-1.805 (m, 2H),
2.086-2.156 (m, 1H), 2.672-2.748 (m, 1H), 3.152-3.231 (m, 2H), 3.502-3.559 (m, 4H),
3.788-3.823 (m, 1H), 3.990 (br, 1H), 4.179 (s, 3H), 4.590-4.648 (m, 2H), 5.057-5.102 (m,
2H), 5.147-5.163 (d, 1H).
13C-NMR (100MHz, DMSO-d6) δ (ppm): 13.65,22.66,33.16,33.59,55.41,60.78,
61.77,71.31,74.19,74.92,82.22,124.18,151.98,160.63,169.85.
(+)-ESI-MS:386.0
Embodiment 2
(1S, 2S, 3R, 5S)-3-[7-[[(1R, 2R)-2-(3,4-difluorophenyl) cyclopropyl] amino]-5-(rosickyite base)-
3H-1,2,3-triazol [4,5-d] pyrimidin-3-yl] preparation of-5-(2-hydroxyl-oxethyl)-1,2-ring pentanediol (TCGB)
By 2-[[(3aR, 4S, 6R, 6aS)-6-[the bromo-5-of 7-(rosickyite base)-3H-1,2,3-triazol [4,5-d] pyrimidine-
3-yl] tetrahydrochysene-2,2-dimethyl-4H-cyclopenta-1,3-Dioxol-4-yl] epoxide]-ethanol (V) 0.45g,
Toluene 5.0ml and water 1.6ml mixing, the toluene being sequentially added into 2-(3,4-difluorophenyl) cyclopropylamine (VII) 0.16g under room temperature is molten
Liquid 1.0ml and triethylamine 0.24g, separates organic facies after being then stirred at room temperature 6 hours, add water 5ml, use vinegar in organic facies
Acid for adjusting pH is about 7.Separatory, organic facies saturated sodium-chloride water solution 5ml washs, and separates organic facies and is cooled to 0～10 DEG C, adds
Enter the methanol 1.50ml solution of hydrochloric acid 0.75ml, then react 2 hours at about 0～10 DEG C, separate hydrochloric acid methanol phase, use toluene
5ml × 3 extract hydrochloric acid methanol phase, and the hydrochloric acid methanol separated is middle mutually adds water 5ml, neutralizes with triethylamine, then uses ethyl acetate
10ml × 2 extract, and the most purified water 5ml × 2 are washed, and anhydrous sodium sulfate is dried, and filter, and filtrate reduced in volume is dry obtains oily
Liquid, column chromatography for separation (dichloromethane: methanol=20:1) obtains (1S, 2S, 3R, 5S)-3-[7-[[(1R, 2R)-2-(3,4-
Difluorophenyl) cyclopropyl] amino]-5-(rosickyite base)-3H-1,2,3-triazol [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyl second
Epoxide)-1,2-ring pentanediol (IV, TCGB).
HPLC purity: 97.50%.
1H-NMR (400MHz, DMSO-d6) δ (ppm): 0.943-1.038 (m, 3H), 1.407-1.464 (q, 2H),
1.594-1.766 (m, 2H), 1.972-2.052 (m, 1H), 2.366-2.489 (m, 1H), 2.572-2.648 (m, 1H),
2.966-3.198 (m, 2H), 3.356-3.417 (m, 1H), 3.449-3.526 (m, 4H), 3.741-3.771 (m, 1H), 3.941
(s, 1H), 4.501-4.595 (m, 2H), 4.896-4.973 (m, 1H), 5.009-5.019 (d, 1H), 5.067-5.083 (d,
1H), 6.928-7.040 (m, 1H), 7.070-7.249 (m, 2H), 8.804-9.127 (m, 1H).
(+)-ESI-MS:523.2
Embodiment 3
The preparation of high-purity ticagrelor
By ticagrelor 200g (HPLC area normalization method: ticagrelor content is 97.9%, and TCGA is relative to ticagrelor
Content be 0.65%, TCGB is 0.35% relative to the content of ticagrelor) join in ethyl acetate 2L, temperature control 40～50
Stirring and dissolving at DEG C, adds isobutyltrimethylmethane. 3.0L, finishes continuation stir about 1 hour, is then cooled to 0～8 DEG C of stirring and crystallizing about 2 little
Time.Filtering, filter cake is drying under reduced pressure 5 hours at 40～50 DEG C, obtain ticagrelor crude product 183.0g.HPLC area normalization method: replace
Ge Ruiluo content is 98.9%, and TCGA is 0.58% relative to the content of ticagrelor, and TCGB is relative to the content of ticagrelor
It is 0.11%.
Above-mentioned ticagrelor crude product 5g and DMF 6ml is mixed, is warming up at 40～50 DEG C dissolve, so
Rear addition methyl tertiary butyl ether(MTBE) 100ml, stirring is cooled to 5～10 DEG C, continues stirring and crystallizing about 3 hours, filters, filter cake 50～
Drying under reduced pressure 8 hours at 55 DEG C, obtain ticagrelor 4.7g.HPLC area normalization method: ticagrelor content is 99.7%, TCGA phase
Content for ticagrelor is 0.08%, and TCGB is 0.07% relative to the content of ticagrelor, and other single impurity is relative
Content in ticagrelor is not higher than 0.1%.
Embodiment 4
The preparation of high-purity ticagrelor
By ticagrelor 180g (HPLC area normalization method: ticagrelor content is 97.9%, and TCGA is relative to ticagrelor
Content be 0.65%, TCGB is 0.35% relative to the content of ticagrelor) join in isopropyl acetate 1.8L, temperature control 40
～stirring and dissolving at 50 DEG C, add normal hexane 2.2L, finish continuation stir about 1 hour, be then cooled to 0～8 DEG C of stirring and crystallizing
About 2 hours.Filtering, filter cake is drying under reduced pressure 5 hours at 40～50 DEG C, obtain ticagrelor crude product 165.1g.HPLC area normalization
Method: ticagrelor content is 99.1%, TCGA is 0.51% relative to the content of ticagrelor, and TCGB is relative to ticagrelor
Content is 0.08%.
Above-mentioned ticagrelor crude product 100g, N,N-dimethylformamide 120ml are mixed.It is warming up at 40～50 DEG C molten
Solving, be subsequently adding methyl tertiary butyl ether(MTBE) 1.8L, stirring is cooled to 5～10 DEG C, continues stirring and crystallizing about 3 hours, filters, and filter cake exists
Drying under reduced pressure 8 hours at 60～65 DEG C, obtain ticagrelor 90.3g.HPLC area normalization method: ticagrelor content is 99.8%,
TCGA is 0.05% relative to the content of ticagrelor, and TCGB is 0.04% relative to the content of ticagrelor, and other is single miscellaneous
Matter is not higher than 0.05% relative to the content of ticagrelor.
Embodiment 5
The preparation of high-purity ticagrelor
By ticagrelor crude product 10g (embodiment 3 prepares gained crude product) and DMAC N,N' dimethyl acetamide 12ml and methanol
1.2ml mixing.Being warming up at 40～45 DEG C dissolve, be subsequently adding methyl tertiary butyl ether(MTBE) 300ml, stirring is cooled to 5～10 DEG C, continues
Continuous stirring and crystallizing about 3 hours, filters, and filter cake is drying under reduced pressure 8 hours at 50～55 DEG C, obtain ticagrelor 8.8g.HPLC area
Normalization method: ticagrelor content is 99.2%, TCGA is 0.28% relative to the content of ticagrelor, and TCGB is auspicious relative to for lattice
The content of Lip river is 0.10%, and other single impurity is not higher than 0.15% relative to the content of ticagrelor.
Embodiment 6
The preparation of high-purity ticagrelor
By ticagrelor crude product 20g (embodiment 4 prepares gained crude product), N,N-dimethylformamide 20ml and methanol 4ml
Mixing.Being warming up at 40～50 DEG C dissolve, be subsequently adding diisopropyl ether 400ml, stirring is cooled to 5～10 DEG C, continues stirring and crystallizing
About 6 hours, filtering, filter cake is drying under reduced pressure 10 hours at 65～70 DEG C, obtain ticagrelor 18.1g.HPLC area normalization method: replace
Ge Ruiluo content is 99.6%, and TCGA is 0.17% relative to the content of ticagrelor, and TCGB is relative to the content of ticagrelor
It is 0.06%.Other single impurity is not higher than 0.1% relative to the content of ticagrelor.
Embodiment 7
The preparation of high-purity ticagrelor
Ticagrelor crude product 20g (embodiment 3 prepares gained crude product) and DMAC N,N' dimethyl acetamide 20ml is mixed.Heat up
Dissolving at 40～50 DEG C, be subsequently adding diisopropyl ether 400ml, stirring is cooled to 5～10 DEG C, continues stirring and crystallizing about 6 hours, mistake
Filter, filter cake is drying under reduced pressure 10 hours at 70～75 DEG C, obtain ticagrelor 17.8g.HPLC area normalization method: ticagrelor content
Being 99.5%, TCGA is 0.16% relative to the content of ticagrelor, and TCGB is 0.11% relative to the content of ticagrelor, its
Its single impurity is not higher than 0.1% relative to the content of ticagrelor.
Embodiment 8
The preparation of high-purity ticagrelor
By ticagrelor 40g (HPLC area normalization method: ticagrelor content is 97.9%, and TCGA is relative to ticagrelor
Content be 0.65%, TCGB is 0.35% relative to the content of ticagrelor) and DMF 50ml mixing, rise
Temperature is dissolved at 40～50 DEG C, is subsequently adding methyl tertiary butyl ether(MTBE) 800ml, and stirring is cooled to 5～10 DEG C, continues stirring and crystallizing about
3 hours, filtering, filter cake is drying under reduced pressure 8 hours at 50～55 DEG C, obtain ticagrelor crude product 36.4g.HPLC area normalization method:
Ticagrelor content is 99.5%, and TCGA is 0.09% relative to the content of ticagrelor, TCGB containing relative to ticagrelor
Amount is 0.27%.
Above-mentioned solid 5g is joined in ethyl acetate 50ml, stirring and dissolving at temperature control 40～50 DEG C, add isobutyltrimethylmethane.
75ml, finishes continuation stir about 1 hour, is then cooled to 0～8 DEG C of stirring and crystallizing about 2 hours.Filtering, filter cake is at 40～50 DEG C
Lower drying under reduced pressure 5 hours, obtains ticagrelor crude product 4.5g.HPLC area normalization method: ticagrelor content is 99.7%, TCGA phase
Content for ticagrelor is 0.07%, and TCGB is 0.09% relative to the content of ticagrelor, and other single impurity is relative
Content in ticagrelor is not higher than 0.1%.
Embodiment 9
The preparation of high-purity ticagrelor
Ticagrelor crude product 10g (embodiment 8 prepares gained crude product) is joined in ethyl acetate 100ml, temperature control 40～
Stirring and dissolving at 50 DEG C, adds isobutyltrimethylmethane. 120ml, finishes continuation stir about 1 hour, is then cooled to 0～8 DEG C of stirring and crystallizing about
2 hours.Filtering, filter cake is drying under reduced pressure 5 hours at 40～50 DEG C, obtain ticagrelor crude product 8.9g.HPLC area normalization method: replace
Ge Ruiluo content is 99.8%, and TCGA is 0.05% relative to the content of ticagrelor, and TCGB is relative to the content of ticagrelor
Being 0.05%, other single impurity is not higher than 0.1% relative to the content of ticagrelor.
Embodiment 10
Ticagrelor tablet and preparation thereof
Prescription:
| Component | Content (mg/ sheet) |
| Ticagrelor compositions (is prepared by embodiment 4) | 90.0 |
| Mannitol | 126.0 |
| Calcium phosphate dibasic dihydrate | 63.0 |
| Hydroxypropyl cellulose | 9.0 |
| Carboxymethyl starch sodium | 9.0 |
| Magnesium stearate | 3.0 |
Preparation: by the ticagrelor compositions in upper table component, mannitol, calcium phosphate dibasic dihydrate, hydroxypropyl cellulose
Mix with carboxymethyl starch sodium, use water wet granulation, be dried, granulate, mix with magnesium stearate, tabletting, to obtain final product.
Products obtained therefrom, is measured by HPLC area normalization method: ticagrelor content is 99.8%, and TCGA is relative to ticagrelor
Content be 0.04%.TCGB is 0.04% relative to the content of ticagrelor, and other single impurity is relative to ticagrelor
Content is not higher than 0.1%.
Comparative example 1
Ticagrelor 10g (preparing gained ticagrelor crude product by embodiment 3) is joined in ethyl acetate 100ml, control
Stirring and dissolving at temperature 40～50 DEG C, adds isobutyltrimethylmethane. 150ml, finishes continuation stir about 1 hour, is then cooled to 0～8 DEG C of stirring
Crystallize about 2 hours.Filtering, filter cake is drying under reduced pressure 5 hours at 40～50 DEG C, obtain ticagrelor crude product 9.2g.HPLC area is returned
One method: ticagrelor content is 99.3%, TCGA is 0.53% relative to the content of ticagrelor, and TCGB is relative to ticagrelor
Content be 0.04%.
Comparative example 2
Ticagrelor 10g (preparing gained ticagrelor crude product by embodiment 8) and N,N-dimethylformamide 12ml is mixed
Closing, be warming up at 40～50 DEG C dissolve, be subsequently adding methyl tertiary butyl ether(MTBE) 200ml, stirring is cooled to 5～10 DEG C, continues stirring
Crystallize about 3 hours, filters, and filter cake is drying under reduced pressure 8 hours at 50～55 DEG C, obtain ticagrelor crude product 9.0g.HPLC area is returned
One method: ticagrelor content is 99.6%, TCGA is 0.02% relative to the content of ticagrelor, and TCGB is relative to ticagrelor
Content be 0.22%.
It will be understood by those skilled in the art that under the teaching of this specification, the present invention can be made some amendments
Or change.These modifications and variations should also be as within the scope of the claims in the present invention.
Claims (10)
1. (1 shown in formula IIIS,2S,3R,5S)-3-[7-methoxyl group-5-(rosickyite base)-3H-1,2,3-triazol [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyl-oxethyl)-1,2-Pentamethylene. glycol,
III。
2. (1S, 2S, 3R, 5S)-3-[7-[[(1R, 2R)-2-(3,4-difluorophenyl) cyclopropyl] the amino]-5-shown in formula IV
(rosickyite base)-3H-1,2,3-triazol [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyl-oxethyl)-1,2-ring pentanediol,
IV。
3. a ticagrelor compositions, wherein the content of ticagrelor is not less than 99.0%, and impurity shown in formula III is relative to replacing
The content of Ge Ruiluo is not higher than 0.5%, and impurity shown in formula IV is not higher than 0.2% relative to the content of ticagrelor.
Ticagrelor compositions the most according to claim 3, it is selected from:
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.0%, and shown in formula III, impurity is relative to ticagrelor
Content be not higher than 0.5%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05%, impurity shown in formula IV is relative to the content of ticagrelor
Not higher than 0.2%, 0.15%, 0.1% or 0.05%；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.1%, and shown in formula III, impurity is relative to ticagrelor
Content be not higher than 0.5%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05%, impurity shown in formula IV is relative to the content of ticagrelor
Not higher than 0.2%, 0.15%, 0.1% or 0.05%；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.2%, and shown in formula III, impurity is relative to ticagrelor
Content be not higher than 0.3%, 0.2%, 0.15%, 0.1% or 0.05%, impurity shown in formula IV is the highest relative to the content of ticagrelor
In 0.2%, 0.15%, 0.1% or 0.05%；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.3%, and shown in formula III, impurity is relative to ticagrelor
Content be not higher than 0.3%, 0.2%, 0.15%, 0.1% or 0.05%, impurity shown in formula IV is the highest relative to the content of ticagrelor
In 0.2%, 0.15%, 0.1% or 0.05%；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.4%, and shown in formula III, impurity is relative to ticagrelor
Content be not higher than 0.2%, 0.15%, 0.1% or 0.05%, impurity shown in formula IV relative to ticagrelor content not higher than
0.2%, 0.15%, 0.1% or 0.05%；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.5%, and shown in formula III, impurity is relative to ticagrelor
Content be not higher than 0.2%, 0.15%, 0.1% or 0.05%, impurity shown in formula IV relative to ticagrelor content not higher than
0.15%, 0.1% or 0.05%；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.6%, and shown in formula III, impurity is relative to ticagrelor
Content be not higher than 0.15%, 0.1% or 0.05%, impurity shown in formula IV is not higher than 0.15% relative to the content of ticagrelor,
0.1% or 0.05%；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.7%, and shown in formula III, impurity is relative to ticagrelor
Content be not higher than 0.1% or 0.05%, impurity shown in formula IV is not higher than 0.1% or 0.05% relative to the content of ticagrelor；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.8%, and shown in formula III, impurity is relative to ticagrelor
Content be not higher than 0.05%, impurity shown in formula IV is not higher than 0.05% relative to the content of ticagrelor.
Ticagrelor compositions the most according to claim 3, it is selected from:
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.0%, and shown in formula III, impurity is relative to ticagrelor
Content be not higher than 0.5%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05%, impurity shown in formula IV is relative to the content of ticagrelor
Not higher than 0.2%, 0.15%, 0.1% or 0.05%, other single impurity is not higher than 0.15%, 0.1% relative to the content of ticagrelor
Or 0.05%；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.1%, and shown in formula III, impurity is relative to ticagrelor
Content be not higher than 0.5%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05%, impurity shown in formula IV is relative to the content of ticagrelor
Not higher than 0.2%, 0.15%, 0.1% or 0.05%, other single impurity is not higher than 0.15%, 0.1% relative to the content of ticagrelor
Or 0.05%；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.2%, and shown in formula III, impurity is relative to ticagrelor
Content be not higher than 0.3%, 0.2%, 0.15%, 0.1% or 0.05%, impurity shown in formula IV is the highest relative to the content of ticagrelor
In 0.2%, 0.15%, 0.1% or 0.05%, other single impurity relative to the content of ticagrelor be not higher than 0.15%, 0.1% or
0.05%；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.3%, and shown in formula III, impurity is relative to ticagrelor
Content be not higher than 0.3%, 0.2%, 0.15%, 0.1% or 0.05%, impurity shown in formula IV is the highest relative to the content of ticagrelor
In 0.2%, 0.15%, 0.1% or 0.05%, other single impurity relative to the content of ticagrelor be not higher than 0.15%, 0.1% or
0.05%；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.4%, and shown in formula III, impurity is relative to ticagrelor
Content be not higher than 0.2%, 0.15%, 0.1% or 0.05%, impurity shown in formula IV relative to ticagrelor content not higher than
0.2%, 0.15%, 0.1% or 0.05%, other single impurity relative to the content of ticagrelor be not higher than 0.15%, 0.1% or
0.05%；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.5%, and shown in formula III, impurity is relative to ticagrelor
Content be not higher than 0.2%, 0.15%, 0.1% or 0.05%, impurity shown in formula IV relative to ticagrelor content not higher than
0.15%, 0.1% or 0.05%, other single impurity is not higher than 0.15%, 0.1% or 0.05% relative to the content of ticagrelor；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.6%, and shown in formula III, impurity is relative to ticagrelor
Content be not higher than 0.15%, 0.1% or 0.05%, impurity shown in formula IV is not higher than 0.15% relative to the content of ticagrelor,
0.1% or 0.05%, other single impurity is not higher than 0.1% or 0.05% relative to the content of ticagrelor；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.7%, and shown in formula III, impurity is relative to ticagrelor
Content be not higher than 0.1% or 0.05%, impurity shown in formula IV is not higher than 0.1% or 0.05% relative to the content of ticagrelor, its
Its single impurity is not higher than 0.1% or 0.05% relative to the content of ticagrelor；Or,
Ticagrelor compositions, wherein the content of ticagrelor is not less than 99.8%, and shown in formula III, impurity is relative to ticagrelor
Content be not higher than 0.05%, impurity shown in formula IV is not higher than 0.05% relative to the content of ticagrelor, other single impurity phase
Content for ticagrelor is not higher than 0.1% or 0.05%.
6. a preparation method for ticagrelor compositions according to any one of claim 3 ~ 5, the method includes:
(1), ticagrelor is dissolved in esters solvent, adds anti-solvent and separate out solid, point isolated solid；
(2), the solid of step (1) gained is dissolved in amide solvent or amide solvent and another or multiple suitable solvent
In the mixed solvent of composition, cool down or add anti-solvent precipitation solid, point isolated solid；
(3), optionally, the solid that step (2) is separated is dried.
7. a preparation method for ticagrelor compositions according to any one of claim 3 ~ 5, the method includes:
(1), ticagrelor is dissolved in amide solvent or amide solvent mixed with what another or multiple suitable solvent formed
In bonding solvent, cool down or add anti-solvent precipitation solid, point isolated solid；
(2), the solid of step (1) gained is dissolved in esters solvent, adds anti-solvent and separate out solid, point isolated solid；
(3), optionally, the solid that step (2) is separated is dried.
8. according to the preparation method described in claim 6 or 7, wherein, the preparation method step (1) described in claim 6 or power
Profit requires that esters solvent described in the preparation method step (2) described in 7 is that ethyl acetate, methyl acetate, Ethyl formate, acetic acid are different
Propyl ester, n-butyl acetate or their mixture, ethyl acetate or isopropyl acetate；Preparation side described in claim 6
Amide solvent described in preparation method step (1) described in method step (2) or claim 7 be N,N-dimethylformamide,
DMAC N,N' dimethyl acetamide；Preparation method step (2) described in claim 6 or the preparation method step described in claim 7
(1) suitable solvent described in be methanol, ethanol, isopropanol, the tert-butyl alcohol, ethyl acetate, methyl acetate, dichloromethane, chloroform, third
Ketone, acetonitrile, toluene, water or their mixed solvent, preferably methanol, ethanol, isopropanol, ethyl acetate, dichloromethane, acetone,
Acetonitrile, water or their mixture；In preparation method step (1) described in claim 6 or claim 7 and (2), described instead
Solvent be ether, methyl tertiary butyl ether(MTBE), diisopropyl ether, positive propyl ether, 2-methoxyl group methane, 1,1-dimethoxy-ethane, methyl phenyl ethers anisole,
Water, n-hexane, normal heptane, normal octane, isobutyltrimethylmethane. or their mixture, preferably methyl tertiary butyl ether(MTBE), n-hexane or isobutyltrimethylmethane..
9. a pharmaceutical preparation, it comprises the ticagrelor compositions according to any one of the claim 3 ~ 5 of effective therapeutic dose
Or the ticagrelor compositions that preparation method according to any one of claim 6 ~ 8 prepares, and pharmaceutic adjuvant.
10. preparation side according to any one of ticagrelor compositions according to any one of claim 3 ~ 5 or claim 6 ~ 8
The ticagrelor compositions that method prepares application in preparing anticoagulation or antithrombotic reagent.
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