CN104327094B - 一种米尔贝肟的分离纯化方法 - Google Patents
一种米尔贝肟的分离纯化方法 Download PDFInfo
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- CN104327094B CN104327094B CN201410606012.9A CN201410606012A CN104327094B CN 104327094 B CN104327094 B CN 104327094B CN 201410606012 A CN201410606012 A CN 201410606012A CN 104327094 B CN104327094 B CN 104327094B
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- milbemycin oxime
- silica gel
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- CKVMAPHTVCTEMM-ALPQRHTBSA-N milbemycin oxime Chemical compound O1[C@H](C)[C@@H](C)CC[C@@]11O[C@H](C\C=C(C)\C[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)C(=N/O)/[C@H]3OC\2)O)C[C@H]4C1.C1C[C@H](C)[C@@H](CC)O[C@@]21O[C@H](C\C=C(C)\C[C@@H](C)\C=C\C=C/1[C@]3([C@H](C(=O)O4)C=C(C)C(=N/O)/[C@H]3OC\1)O)C[C@H]4C2 CKVMAPHTVCTEMM-ALPQRHTBSA-N 0.000 title claims abstract description 66
- 229940099245 milbemycin oxime Drugs 0.000 title claims abstract description 66
- 238000000034 method Methods 0.000 title claims abstract description 35
- 238000000746 purification Methods 0.000 title claims abstract description 22
- 238000002955 isolation Methods 0.000 title claims abstract description 14
- 239000000047 product Substances 0.000 claims abstract description 60
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims abstract description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000001035 drying Methods 0.000 claims abstract description 16
- 238000002425 crystallisation Methods 0.000 claims abstract description 15
- 230000008025 crystallization Effects 0.000 claims abstract description 15
- 238000001914 filtration Methods 0.000 claims abstract description 14
- 239000012528 membrane Substances 0.000 claims abstract description 12
- 239000000706 filtrate Substances 0.000 claims abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000011068 loading method Methods 0.000 claims abstract description 9
- 239000003208 petroleum Substances 0.000 claims abstract description 9
- 238000010898 silica gel chromatography Methods 0.000 claims abstract description 9
- 238000010298 pulverizing process Methods 0.000 claims abstract description 7
- 238000000926 separation method Methods 0.000 claims abstract description 6
- BWDBEAQIHAEVLV-UHFFFAOYSA-N 6-methylheptan-1-ol Chemical compound CC(C)CCCCCO BWDBEAQIHAEVLV-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000012141 concentrate Substances 0.000 claims abstract description 3
- 238000001816 cooling Methods 0.000 claims abstract description 3
- 239000007791 liquid phase Substances 0.000 claims abstract description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 66
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 28
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 20
- 239000000741 silica gel Substances 0.000 claims description 16
- 229910002027 silica gel Inorganic materials 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 14
- 238000001291 vacuum drying Methods 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 9
- 239000000945 filler Substances 0.000 claims description 8
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 239000012046 mixed solvent Substances 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 claims description 4
- BQFCCCIRTOLPEF-UHFFFAOYSA-N chembl1976978 Chemical compound CC1=CC=CC=C1N=NC1=C(O)C=CC2=CC=CC=C12 BQFCCCIRTOLPEF-UHFFFAOYSA-N 0.000 claims description 4
- 238000010828 elution Methods 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 238000005374 membrane filtration Methods 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 238000012856 packing Methods 0.000 claims description 4
- 229920001661 Chitosan Polymers 0.000 claims description 2
- 239000004952 Polyamide Substances 0.000 claims description 2
- 239000004695 Polyether sulfone Substances 0.000 claims description 2
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 229920002647 polyamide Polymers 0.000 claims description 2
- 229920006393 polyether sulfone Polymers 0.000 claims description 2
- 239000000523 sample Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000010438 heat treatment Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 21
- 235000015170 shellfish Nutrition 0.000 description 7
- 239000012043 crude product Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 150000002923 oximes Chemical class 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 4
- 239000008213 purified water Substances 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 2
- 241000209094 Oryza Species 0.000 description 2
- 235000007164 Oryza sativa Nutrition 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
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- 238000005516 engineering process Methods 0.000 description 2
- 230000002964 excitative effect Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000003120 macrolide antibiotic agent Substances 0.000 description 2
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- 239000013558 reference substance Substances 0.000 description 2
- 235000009566 rice Nutrition 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- 241000238421 Arthropoda Species 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 241000002163 Mesapamea fractilinea Species 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 241001655322 Streptomycetales Species 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical group CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 230000000507 anthelmentic effect Effects 0.000 description 1
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- 210000004556 brain Anatomy 0.000 description 1
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- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
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- 244000079386 endoparasite Species 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
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- 230000036749 excitatory postsynaptic potential Effects 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
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- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
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- 210000005171 mammalian brain Anatomy 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000028161 membrane depolarization Effects 0.000 description 1
- 238000003808 methanol extraction Methods 0.000 description 1
- 210000000107 myocyte Anatomy 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
Description
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CN201410606012.9A CN104327094B (zh) | 2014-10-30 | 2014-10-30 | 一种米尔贝肟的分离纯化方法 |
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CN201410606012.9A CN104327094B (zh) | 2014-10-30 | 2014-10-30 | 一种米尔贝肟的分离纯化方法 |
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CN104327094A CN104327094A (zh) | 2015-02-04 |
CN104327094B true CN104327094B (zh) | 2016-08-17 |
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Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
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CN105254644B (zh) * | 2015-11-04 | 2017-07-18 | 湖北宏中药业股份有限公司 | 一种米尔贝肟的制备方法 |
CN107586301A (zh) * | 2016-07-06 | 2018-01-16 | 浙江海正药业股份有限公司 | 米尔贝a3肟晶型a及其制备方法 |
CN108948047A (zh) * | 2017-05-20 | 2018-12-07 | 鲁南制药集团股份有限公司 | 一种替西罗莫司的纯化方法 |
CN111094296A (zh) * | 2017-07-24 | 2020-05-01 | 浙江海正药业股份有限公司 | 一种米尔贝a4肟晶型a及其制备方法 |
CN109970758A (zh) * | 2019-05-05 | 2019-07-05 | 浙江海正药业股份有限公司 | 5-酮基米尔贝霉素晶型及其制备方法 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
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JPS59108785A (ja) * | 1982-11-25 | 1984-06-23 | Sankyo Co Ltd | ミルベマイシン類の5−オキシム誘導体 |
JPS6289685A (ja) * | 1985-05-31 | 1987-04-24 | Sankyo Co Ltd | 13−ハロゲンミルベマイシン誘導体 |
JP4314337B2 (ja) * | 1999-03-29 | 2009-08-12 | 三井化学アグロ株式会社 | ミルベマイシン類及びアベルメクチン類の精製法 |
CN103896961A (zh) * | 2014-03-25 | 2014-07-02 | 武汉大学 | 一种米尔贝肟类化合物及其制备方法 |
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Address after: 435300 Li Shizhen Pharmaceutical Industrial Park, Qichun, Huanggang, Hubei Patentee after: HUBEI HONCH PHARMACEUTICAL Co.,Ltd. Address before: 435300 Li Shizhen Pharmaceutical Industrial Park, Qichun, Huanggang, Hubei Patentee before: HUBEI HONCH PHARMACEUTICAL Co.,Ltd. |
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PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A Method for Separation and Purification of Milbeoxime Effective date of registration: 20230105 Granted publication date: 20160817 Pledgee: Bank of China Limited Huanggang branch Pledgor: HUBEI HONCH PHARMACEUTICAL Co.,Ltd. Registration number: Y2023420000006 |
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Date of cancellation: 20230823 Granted publication date: 20160817 Pledgee: Bank of China Limited Huanggang branch Pledgor: HUBEI HONCH PHARMACEUTICAL Co.,Ltd. Registration number: Y2023420000006 |
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PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A Method for Separation and Purification of Milbeoxime Effective date of registration: 20230825 Granted publication date: 20160817 Pledgee: Bank of China Limited Huanggang branch Pledgor: HUBEI HONCH PHARMACEUTICAL Co.,Ltd. Registration number: Y2023980053856 |
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