TW200948361A - Method for synthesizing Biolimus A9 and the like and method for improving stability of the same - Google Patents
Method for synthesizing Biolimus A9 and the like and method for improving stability of the same Download PDFInfo
- Publication number
- TW200948361A TW200948361A TW097119375A TW97119375A TW200948361A TW 200948361 A TW200948361 A TW 200948361A TW 097119375 A TW097119375 A TW 097119375A TW 97119375 A TW97119375 A TW 97119375A TW 200948361 A TW200948361 A TW 200948361A
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- Prior art keywords
- moss
- formula
- bayer
- synthesizing
- alkyl
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Links
- 238000000034 method Methods 0.000 title claims abstract description 28
- 230000002194 synthesizing effect Effects 0.000 title claims 6
- YYSFXUWWPNHNAZ-PKJQJFMNSA-N umirolimus Chemical compound C1[C@@H](OC)[C@H](OCCOCC)CC[C@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 YYSFXUWWPNHNAZ-PKJQJFMNSA-N 0.000 title abstract description 4
- -1 alkyl benzenesulfonate Chemical compound 0.000 claims abstract description 23
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229960002930 sirolimus Drugs 0.000 claims abstract description 12
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 claims abstract description 11
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 7
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 7
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims abstract description 3
- 229940077388 benzenesulfonate Drugs 0.000 claims abstract 3
- 239000000203 mixture Substances 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 235000006708 antioxidants Nutrition 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims description 4
- 125000004946 alkenylalkyl group Chemical group 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 125000005038 alkynylalkyl group Chemical group 0.000 claims description 3
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims 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 claims description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims description 2
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 2
- 235000001815 DL-alpha-tocopherol Nutrition 0.000 claims description 2
- 239000011627 DL-alpha-tocopherol Substances 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 229930003268 Vitamin C Natural products 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 239000000473 propyl gallate Substances 0.000 claims description 2
- 235000010388 propyl gallate Nutrition 0.000 claims description 2
- 229940075579 propyl gallate Drugs 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 235000019154 vitamin C Nutrition 0.000 claims description 2
- 239000011718 vitamin C Substances 0.000 claims description 2
- 125000005270 trialkylamine group Chemical group 0.000 claims 3
- 239000004322 Butylated hydroxytoluene Substances 0.000 claims 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims 2
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 claims 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 claims 1
- 150000004996 alkyl benzenes Chemical class 0.000 claims 1
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Substances [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims 1
- 229910052786 argon Inorganic materials 0.000 claims 1
- 235000010385 ascorbyl palmitate Nutrition 0.000 claims 1
- 229940095259 butylated hydroxytoluene Drugs 0.000 claims 1
- 230000002708 enhancing effect Effects 0.000 claims 1
- 239000001530 fumaric acid Substances 0.000 claims 1
- 125000005842 heteroatom Chemical group 0.000 claims 1
- 229940097411 palm acid Drugs 0.000 claims 1
- 125000004076 pyridyl group Chemical group 0.000 claims 1
- 238000001308 synthesis method Methods 0.000 claims 1
- 238000010189 synthetic method Methods 0.000 claims 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims 1
- 235000021419 vinegar Nutrition 0.000 claims 1
- 239000000052 vinegar Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 238000003860 storage Methods 0.000 abstract description 4
- 238000010521 absorption reaction Methods 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract 1
- 238000013341 scale-up Methods 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000007792 addition Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 230000003321 amplification Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 238000003199 nucleic acid amplification method Methods 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000013517 stratification Methods 0.000 description 3
- XPDWGBQVDMORPB-UHFFFAOYSA-N trifluoromethane acid Natural products FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 3
- HPYNZHMRTTWQTB-UHFFFAOYSA-N 2,3-dimethylpyridine Chemical compound CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 2
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 2
- 229940093475 2-ethoxyethanol Drugs 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- WACNXHCZHTVBJM-UHFFFAOYSA-N 1,2,3,4,5-pentafluorobenzene Chemical compound FC1=CC(F)=C(F)C(F)=C1F WACNXHCZHTVBJM-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JWNWROOIPXQQNT-UHFFFAOYSA-N 2-ethoxyethyl 2,3,4,5,6-pentafluorobenzenesulfonate Chemical compound CCOCCOS(=O)(=O)C1=C(F)C(F)=C(F)C(F)=C1F JWNWROOIPXQQNT-UHFFFAOYSA-N 0.000 description 1
- RJYPTKAJRGPMMM-UHFFFAOYSA-N 2-ethoxyethyl trifluoromethanesulfonate Chemical compound CCOCCOS(=O)(=O)C(F)(F)F RJYPTKAJRGPMMM-UHFFFAOYSA-N 0.000 description 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- 101100181929 Caenorhabditis elegans lin-3 gene Proteins 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- 241000282320 Panthera leo Species 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 240000005809 Prunus persica Species 0.000 description 1
- 235000006040 Prunus persica var persica Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- GNUKKQRZURGDEK-UHFFFAOYSA-N ethyl 2,3,4,5,6-pentafluorobenzenesulfonate Chemical compound CCOS(=O)(=O)c1c(F)c(F)c(F)c(F)c1F GNUKKQRZURGDEK-UHFFFAOYSA-N 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000009728 shiwei Substances 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000009941 weaving Methods 0.000 description 1
- 238000003466 welding Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TW097119375A TW200948361A (en) | 2008-05-26 | 2008-05-26 | Method for synthesizing Biolimus A9 and the like and method for improving stability of the same |
| US12/387,754 US7872122B2 (en) | 2008-05-26 | 2009-05-08 | Process for making Biolimus A9 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TW097119375A TW200948361A (en) | 2008-05-26 | 2008-05-26 | Method for synthesizing Biolimus A9 and the like and method for improving stability of the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW200948361A true TW200948361A (en) | 2009-12-01 |
| TWI360417B TWI360417B (https=) | 2012-03-21 |
Family
ID=41342583
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW097119375A TW200948361A (en) | 2008-05-26 | 2008-05-26 | Method for synthesizing Biolimus A9 and the like and method for improving stability of the same |
Country Status (2)
| Country | Link |
|---|---|
| US (1) | US7872122B2 (https=) |
| TW (1) | TW200948361A (https=) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108864149A (zh) * | 2013-03-15 | 2018-11-23 | 生物传感器国际集团有限公司 | 雷帕霉素衍生物的纯化 |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2601201B1 (en) | 2010-08-04 | 2014-09-24 | Meril Life Sciences Pvt. Ltd. | Process for preparation of novel 42-0-(heteroalkoxyalkyl) rapamycin compounds with anti-proliferative properties" |
| CN102464668B (zh) * | 2010-11-17 | 2015-04-29 | 浙江海正药业股份有限公司 | 雷帕霉素或其衍生物的制备色谱纯化方法 |
| CN102731527A (zh) * | 2012-07-12 | 2012-10-17 | 浙江医药股份有限公司新昌制药厂 | 一种西罗莫司42－醚衍生物的合成方法 |
| JP6401713B2 (ja) | 2013-01-22 | 2018-10-10 | バイオセンサーズ インターナショナル グループ、リミテッド | ラパマイシン誘導体の低温合成 |
| EP3010926B1 (en) | 2013-06-20 | 2019-11-20 | Novartis AG | Alkylation with an alkyl fluoroalkyl sulfonate |
| WO2016040806A1 (en) | 2014-09-11 | 2016-03-17 | The Regents Of The University Of California | mTORC1 INHIBITORS |
| CN106146535B (zh) * | 2015-04-25 | 2019-07-26 | 山东新时代药业有限公司 | 一种依维莫司的制备方法 |
| JP6793651B2 (ja) * | 2015-08-28 | 2020-12-02 | 日本化薬株式会社 | ラパマイシン又はその誘導体を含有する医薬組成物 |
| JP6884881B2 (ja) * | 2017-04-12 | 2021-06-09 | ナイキ イノベイト シーブイ | 取り外し可能なモジュールを有する着用可能な物品 |
| IL300091A (en) | 2018-05-01 | 2023-03-01 | Revolution Medicines Inc | C40-, c28-, and c-32-linked rapamycin analogs as mtor inhibitors |
| CN112368289B (zh) | 2018-05-01 | 2024-02-20 | 锐新医药公司 | 作为mtor抑制剂的c26-连接的雷帕霉素类似物 |
| AU2023275778A1 (en) | 2022-05-25 | 2024-12-12 | Revolution Medicines, Inc. | Methods of treating cancer with an mtor inhibitor |
| CN117327093B (zh) * | 2023-08-23 | 2025-11-25 | 福建省微生物研究所 | 一种Biolimus A9的合成方法 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1571151B1 (en) * | 2004-03-01 | 2008-12-24 | Terumo Kabushiki Kaisha | Process for production of O-alkylated rapamycin derivatives |
-
2008
- 2008-05-26 TW TW097119375A patent/TW200948361A/zh not_active IP Right Cessation
-
2009
- 2009-05-08 US US12/387,754 patent/US7872122B2/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108864149A (zh) * | 2013-03-15 | 2018-11-23 | 生物传感器国际集团有限公司 | 雷帕霉素衍生物的纯化 |
| US11046711B2 (en) | 2013-03-15 | 2021-06-29 | Biosensors International Group, Ltd. | Purification of rapamycin derivatives using temperature induced phase separation |
| CN108864149B (zh) * | 2013-03-15 | 2022-04-05 | 生物传感器国际集团有限公司 | 雷帕霉素衍生物的纯化 |
| US11780850B2 (en) | 2013-03-15 | 2023-10-10 | Biosensors International Group, Ltd. | Purification of rapamycin derivatives using temperature induced phase separation |
Also Published As
| Publication number | Publication date |
|---|---|
| US20090292118A1 (en) | 2009-11-26 |
| US7872122B2 (en) | 2011-01-18 |
| TWI360417B (https=) | 2012-03-21 |
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