CN104557975A - 依维莫司中间体及其降解杂质的制备方法 - Google Patents
依维莫司中间体及其降解杂质的制备方法 Download PDFInfo
- Publication number
- CN104557975A CN104557975A CN201410812149.XA CN201410812149A CN104557975A CN 104557975 A CN104557975 A CN 104557975A CN 201410812149 A CN201410812149 A CN 201410812149A CN 104557975 A CN104557975 A CN 104557975A
- Authority
- CN
- China
- Prior art keywords
- everolimus
- preparation
- formula
- reaction
- preferred
- 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.)
- Granted
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- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[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 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 title claims abstract description 51
- 229960005167 everolimus Drugs 0.000 title claims abstract description 38
- 239000012535 impurity Substances 0.000 title claims abstract description 18
- 238000000034 method Methods 0.000 title claims abstract description 6
- 230000015556 catabolic process Effects 0.000 title abstract description 14
- 238000006731 degradation reaction Methods 0.000 title abstract description 14
- 239000000543 intermediate Substances 0.000 title abstract 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims description 4
- 235000005074 zinc chloride Nutrition 0.000 claims description 4
- 239000011592 zinc chloride Substances 0.000 claims description 4
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 claims description 4
- PCSWWKIGJZLKHG-UHFFFAOYSA-N O(S(=O)(=O)C(F)(F)F)CC.[O] Chemical compound O(S(=O)(=O)C(F)(F)F)CC.[O] PCSWWKIGJZLKHG-UHFFFAOYSA-N 0.000 claims description 3
- 235000010290 biphenyl Nutrition 0.000 claims description 3
- 239000004305 biphenyl Substances 0.000 claims description 3
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 3
- 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 description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- 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 description 3
- 229960002930 sirolimus Drugs 0.000 claims description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 2
- 238000012544 monitoring process Methods 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 229940102001 zinc bromide Drugs 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 229960003444 immunosuppressant agent Drugs 0.000 abstract 1
- 230000001861 immunosuppressant effect Effects 0.000 abstract 1
- 239000003018 immunosuppressive agent Substances 0.000 abstract 1
- 238000007142 ring opening reaction Methods 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 229940042992 afinitor Drugs 0.000 description 9
- 238000011282 treatment Methods 0.000 description 9
- 239000011734 sodium Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 0 C[C@@]1C(C[C@@]([C@@](*)C[C@](CCC2)C[C@]2OC)OC([C@](CCCC2)N2C(C(C2(C(C)CC*CCC(C)=CC=CC=C[C@@](C)C[C@@](C)C(C[C@@]3O)=O)OC2)=O)=O)=O)=*C3=C1 Chemical compound C[C@@]1C(C[C@@]([C@@](*)C[C@](CCC2)C[C@]2OC)OC([C@](CCCC2)N2C(C(C2(C(C)CC*CCC(C)=CC=CC=C[C@@](C)C[C@@](C)C(C[C@@]3O)=O)OC2)=O)=O)=O)=*C3=C1 0.000 description 4
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
- 208000033383 Neuroendocrine tumor of pancreas Diseases 0.000 description 3
- 208000006265 Renal cell carcinoma Diseases 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 230000007717 exclusion Effects 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 208000029340 primitive neuroectodermal tumor Diseases 0.000 description 3
- 201000004059 subependymal giant cell astrocytoma Diseases 0.000 description 3
- 238000002054 transplantation Methods 0.000 description 3
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 2
- 229960000255 exemestane Drugs 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000011519 second-line treatment Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 229940043785 zortress Drugs 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 101150029707 ERBB2 gene Proteins 0.000 description 1
- 206010019315 Heart transplant rejection Diseases 0.000 description 1
- 241000237502 Ostreidae Species 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 108091008039 hormone receptors Proteins 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000020636 oyster Nutrition 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 210000001835 viscera Anatomy 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
Claims (9)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410812149.XA CN104557975B (zh) | 2014-12-23 | 2014-12-23 | 依维莫司中间体及其降解杂质的制备方法 |
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CN201410812149.XA CN104557975B (zh) | 2014-12-23 | 2014-12-23 | 依维莫司中间体及其降解杂质的制备方法 |
Publications (2)
Publication Number | Publication Date |
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CN104557975A true CN104557975A (zh) | 2015-04-29 |
CN104557975B CN104557975B (zh) | 2017-06-20 |
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CN201410812149.XA Active CN104557975B (zh) | 2014-12-23 | 2014-12-23 | 依维莫司中间体及其降解杂质的制备方法 |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104530112A (zh) * | 2014-12-23 | 2015-04-22 | 连云港恒运医药科技有限公司 | 依维莫司中间体及其乙基化杂质的制备方法 |
CN109206441A (zh) * | 2017-06-30 | 2019-01-15 | 正大天晴药业集团股份有限公司 | 一种依维莫司的纯化方法 |
CN113929703A (zh) * | 2020-07-13 | 2022-01-14 | 鲁南制药集团股份有限公司 | 一种依维莫司有关物质d的合成方法 |
CN115028658A (zh) * | 2022-07-06 | 2022-09-09 | 国药集团川抗制药有限公司 | 雷帕霉素硅醇酯及其制备方法和应用 |
CN115716839A (zh) * | 2022-11-15 | 2023-02-28 | 无锡福祈制药有限公司 | 一种依维莫司杂质的合成方法 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102127092A (zh) * | 2010-01-18 | 2011-07-20 | 东南大学 | 依维莫斯的制备 |
WO2012066502A1 (en) * | 2010-11-19 | 2012-05-24 | Biocon Limited | Processes for preparation of everolimus and intermediates thereof |
WO2014082286A1 (en) * | 2012-11-30 | 2014-06-05 | Hangzhou Zylox Pharma Co., Ltd. | Rafamycin analogs and methods for making same |
CN104530112A (zh) * | 2014-12-23 | 2015-04-22 | 连云港恒运医药科技有限公司 | 依维莫司中间体及其乙基化杂质的制备方法 |
-
2014
- 2014-12-23 CN CN201410812149.XA patent/CN104557975B/zh active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102127092A (zh) * | 2010-01-18 | 2011-07-20 | 东南大学 | 依维莫斯的制备 |
WO2012066502A1 (en) * | 2010-11-19 | 2012-05-24 | Biocon Limited | Processes for preparation of everolimus and intermediates thereof |
WO2014082286A1 (en) * | 2012-11-30 | 2014-06-05 | Hangzhou Zylox Pharma Co., Ltd. | Rafamycin analogs and methods for making same |
CN104530112A (zh) * | 2014-12-23 | 2015-04-22 | 连云港恒运医药科技有限公司 | 依维莫司中间体及其乙基化杂质的制备方法 |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104530112A (zh) * | 2014-12-23 | 2015-04-22 | 连云港恒运医药科技有限公司 | 依维莫司中间体及其乙基化杂质的制备方法 |
CN104530112B (zh) * | 2014-12-23 | 2018-01-09 | 连云港恒运药业有限公司 | 依维莫司中间体及其乙基化杂质的制备方法 |
CN109206441A (zh) * | 2017-06-30 | 2019-01-15 | 正大天晴药业集团股份有限公司 | 一种依维莫司的纯化方法 |
CN109206441B (zh) * | 2017-06-30 | 2022-05-20 | 正大天晴药业集团股份有限公司 | 一种依维莫司的纯化方法 |
CN113929703A (zh) * | 2020-07-13 | 2022-01-14 | 鲁南制药集团股份有限公司 | 一种依维莫司有关物质d的合成方法 |
CN113929703B (zh) * | 2020-07-13 | 2023-12-01 | 鲁南制药集团股份有限公司 | 一种依维莫司有关物质d的合成方法 |
CN115028658A (zh) * | 2022-07-06 | 2022-09-09 | 国药集团川抗制药有限公司 | 雷帕霉素硅醇酯及其制备方法和应用 |
CN115716839A (zh) * | 2022-11-15 | 2023-02-28 | 无锡福祈制药有限公司 | 一种依维莫司杂质的合成方法 |
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Effective date of registration: 20170519 Address after: 222200 Guanyun City, Jiangsu province Lingang Industrial Zone, the south side of the weft Road, eight Applicant after: Lianyungang Hengyun Pharmaceutical Co. Ltd. Address before: 222200 Jiangsu city of Lianyungang province Guanyun County Harbor Industrial Zone weft seven road No. 1 Applicant before: LIANYUNGANG HENGYUN MEDICAL TECHNOLOGY CO., LTD. |
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Address after: 222200 Guanyun City, Jiangsu province Lingang Industrial Zone, the south side of the weft Road, eight Patentee after: Lianyungang Hengyun Pharmaceutical Co. Ltd. Address before: 222200 Guanyun City, Jiangsu province Lingang Industrial Zone, the south side of the weft Road, eight Patentee before: Lianyungang Hengyun Pharmaceutical Co. Ltd. |