CN110003193B - 一种制备易于粉碎的利伐沙班及其制备方法 - Google Patents
一种制备易于粉碎的利伐沙班及其制备方法 Download PDFInfo
- Publication number
- CN110003193B CN110003193B CN201910263184.3A CN201910263184A CN110003193B CN 110003193 B CN110003193 B CN 110003193B CN 201910263184 A CN201910263184 A CN 201910263184A CN 110003193 B CN110003193 B CN 110003193B
- Authority
- CN
- China
- Prior art keywords
- rivaroxaban
- cooling
- crystallization
- acetic acid
- crystallizing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- KGFYHTZWPPHNLQ-AWEZNQCLSA-N rivaroxaban Chemical compound S1C(Cl)=CC=C1C(=O)NC[C@@H]1OC(=O)N(C=2C=CC(=CC=2)N2C(COCC2)=O)C1 KGFYHTZWPPHNLQ-AWEZNQCLSA-N 0.000 title claims abstract description 64
- 229960001148 rivaroxaban Drugs 0.000 title claims abstract description 64
- 238000002360 preparation method Methods 0.000 title abstract description 12
- 239000002245 particle Substances 0.000 claims abstract description 55
- 238000000034 method Methods 0.000 claims abstract description 42
- 238000001816 cooling Methods 0.000 claims abstract description 20
- 238000010902 jet-milling Methods 0.000 claims abstract description 17
- 239000012043 crude product Substances 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 239000013078 crystal Substances 0.000 claims abstract description 10
- 238000010438 heat treatment Methods 0.000 claims abstract description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 53
- 238000002425 crystallisation Methods 0.000 claims description 42
- 230000008025 crystallization Effects 0.000 claims description 41
- 229960000583 acetic acid Drugs 0.000 claims description 25
- 239000012362 glacial acetic acid Substances 0.000 claims description 22
- 238000010298 pulverizing process Methods 0.000 claims description 10
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- 238000004321 preservation Methods 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- 239000000110 cooling liquid Substances 0.000 claims description 3
- 239000012264 purified product Substances 0.000 claims description 3
- 239000012535 impurity Substances 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 229940079593 drug Drugs 0.000 description 18
- 239000003814 drug Substances 0.000 description 18
- 238000003756 stirring Methods 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 238000002386 leaching Methods 0.000 description 12
- 238000009826 distribution Methods 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- 238000004090 dissolution Methods 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 9
- 239000000843 powder Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000010586 diagram Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 206010014522 Embolism venous Diseases 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 239000007779 soft material Substances 0.000 description 4
- 238000001356 surgical procedure Methods 0.000 description 4
- 208000004043 venous thromboembolism Diseases 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 208000007536 Thrombosis Diseases 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 229940088679 drug related substance Drugs 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000004537 pulping Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- -1 (5S) -5- (aminomethyl) -2-oxo-1, 3-oxazolidin-3-yl Chemical group 0.000 description 2
- BMPDCQVRKDNUAP-UHFFFAOYSA-N 5-chlorothiophene-2-carbonyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)S1 BMPDCQVRKDNUAP-UHFFFAOYSA-N 0.000 description 2
- 206010051055 Deep vein thrombosis Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 208000010378 Pulmonary Embolism Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 206010047249 Venous thrombosis Diseases 0.000 description 2
- 238000000635 electron micrograph Methods 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000001788 irregular Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000003701 mechanical milling Methods 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 238000009736 wetting Methods 0.000 description 2
- ITMQDYQHNKXERQ-YDALLXLXSA-N 4-[4-[(5s)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholin-3-one;hydrochloride Chemical compound Cl.O=C1O[C@@H](CN)CN1C1=CC=C(N2C(COCC2)=O)C=C1 ITMQDYQHNKXERQ-YDALLXLXSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 102000047724 Member 2 Solute Carrier Family 12 Human genes 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 108091006621 SLC12A1 Proteins 0.000 description 1
- 108091006620 SLC12A2 Proteins 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 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 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000011540 hip replacement Methods 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 210000003127 knee Anatomy 0.000 description 1
- 238000013150 knee replacement Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000004886 process control Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 102220042174 rs141655687 Human genes 0.000 description 1
- 102220076495 rs200649587 Human genes 0.000 description 1
- 102220043159 rs587780996 Human genes 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000011541 total hip replacement Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
Description
时间(分钟) | 流动相A(%) | 流动相B(%) |
0 | 95 | 5 |
5 | 92 | 8 |
12 | 68 | 32 |
35 | 46 | 54 |
40 | 95 | 5 |
Claims (7)
Priority Applications (2)
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CN202211191174.1A CN115745984A (zh) | 2019-04-02 | 2019-04-02 | 一种制备易于粉碎的利伐沙班及其制备方法 |
CN201910263184.3A CN110003193B (zh) | 2019-04-02 | 2019-04-02 | 一种制备易于粉碎的利伐沙班及其制备方法 |
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CN201910263184.3A CN110003193B (zh) | 2019-04-02 | 2019-04-02 | 一种制备易于粉碎的利伐沙班及其制备方法 |
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CN110003193A CN110003193A (zh) | 2019-07-12 |
CN110003193B true CN110003193B (zh) | 2023-12-05 |
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CN201910263184.3A Active CN110003193B (zh) | 2019-04-02 | 2019-04-02 | 一种制备易于粉碎的利伐沙班及其制备方法 |
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CN115745984A (zh) * | 2019-04-02 | 2023-03-07 | 北京四环制药有限公司 | 一种制备易于粉碎的利伐沙班及其制备方法 |
CN114886867A (zh) * | 2022-06-16 | 2022-08-12 | 北京四环制药有限公司 | 一种高稳定性的利伐沙班药物组合物及其制备方法 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011012321A1 (en) * | 2009-07-31 | 2011-02-03 | Krka, D.D., Novo Mesto | Processes for crystallization of rivaroxaban |
CN105646470A (zh) * | 2014-11-21 | 2016-06-08 | 北大方正集团有限公司 | 一种利伐沙班的精制方法 |
CN105777738A (zh) * | 2014-12-16 | 2016-07-20 | 南京生命能科技开发有限公司 | 一种利伐沙班原料药及其制备方法 |
CN106008492A (zh) * | 2016-08-12 | 2016-10-12 | 杭州和泽医药科技有限公司 | 一种利伐沙班的合成方法 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN115745984A (zh) * | 2019-04-02 | 2023-03-07 | 北京四环制药有限公司 | 一种制备易于粉碎的利伐沙班及其制备方法 |
CN114685480A (zh) * | 2020-12-25 | 2022-07-01 | 江苏嘉逸医药有限公司 | 一种精制及粉碎利伐沙班原料药的方法 |
-
2019
- 2019-04-02 CN CN202211191174.1A patent/CN115745984A/zh active Pending
- 2019-04-02 CN CN201910263184.3A patent/CN110003193B/zh active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011012321A1 (en) * | 2009-07-31 | 2011-02-03 | Krka, D.D., Novo Mesto | Processes for crystallization of rivaroxaban |
CN105646470A (zh) * | 2014-11-21 | 2016-06-08 | 北大方正集团有限公司 | 一种利伐沙班的精制方法 |
CN105777738A (zh) * | 2014-12-16 | 2016-07-20 | 南京生命能科技开发有限公司 | 一种利伐沙班原料药及其制备方法 |
CN106008492A (zh) * | 2016-08-12 | 2016-10-12 | 杭州和泽医药科技有限公司 | 一种利伐沙班的合成方法 |
Non-Patent Citations (1)
Title |
---|
尚遂存."重结晶".《有机化学实验操作与技术》.西安地图出版社,1996,28-30. * |
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Publication number | Publication date |
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CN110003193A (zh) | 2019-07-12 |
CN115745984A (zh) | 2023-03-07 |
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