CN103848849A - 依维莫司的制备工艺 - Google Patents
依维莫司的制备工艺 Download PDFInfo
- Publication number
- CN103848849A CN103848849A CN201410111440.4A CN201410111440A CN103848849A CN 103848849 A CN103848849 A CN 103848849A CN 201410111440 A CN201410111440 A CN 201410111440A CN 103848849 A CN103848849 A CN 103848849A
- Authority
- CN
- China
- Prior art keywords
- acid
- preparation technology
- everolimus
- technology described
- reaction
- 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
Links
- 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 36
- 229960005167 everolimus Drugs 0.000 title claims abstract description 36
- 238000005516 engineering process Methods 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- 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 27
- 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 25
- 229960002930 sirolimus Drugs 0.000 claims abstract description 25
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims abstract description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 17
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000002253 acid Substances 0.000 claims abstract description 11
- 150000007530 organic bases Chemical class 0.000 claims abstract description 11
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 8
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 125000004494 ethyl ester group Chemical group 0.000 claims description 14
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 14
- 239000002585 base Substances 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 5
- 239000011707 mineral Substances 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 150000001336 alkenes Chemical class 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 13
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 abstract 1
- 239000012467 final product Substances 0.000 abstract 1
- 150000007522 mineralic acids Chemical class 0.000 abstract 1
- 230000000269 nucleophilic effect Effects 0.000 abstract 1
- AKRCTAVIEDMZGW-UHFFFAOYSA-N tert-butyl-dimethyl-(3,3,3-trifluoropropoxy)silane Chemical compound [Si](C)(C)(C(C)(C)C)OCCC(F)(F)F AKRCTAVIEDMZGW-UHFFFAOYSA-N 0.000 abstract 1
- 239000000047 product Substances 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- 238000011084 recovery Methods 0.000 description 7
- 230000002194 synthesizing effect Effects 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 235000010755 mineral Nutrition 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229910052710 silicon Inorganic materials 0.000 description 3
- 239000010703 silicon Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010052399 Neuroendocrine tumour Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000007039 two-step reaction 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)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
Claims (10)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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CN201410111440.4A CN103848849B (zh) | 2014-03-24 | 2014-03-24 | 依维莫司的制备工艺 |
Applications Claiming Priority (1)
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CN201410111440.4A CN103848849B (zh) | 2014-03-24 | 2014-03-24 | 依维莫司的制备工艺 |
Publications (2)
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CN103848849A true CN103848849A (zh) | 2014-06-11 |
CN103848849B CN103848849B (zh) | 2016-02-24 |
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104478898A (zh) * | 2014-11-18 | 2015-04-01 | 连云港恒运医药科技有限公司 | 依维莫司及其中间体的制备方法 |
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 |
CN104592254A (zh) * | 2015-02-08 | 2015-05-06 | 福建省微生物研究所 | 依维莫司的合成方法 |
EP3109250A1 (en) * | 2015-06-23 | 2016-12-28 | Synbias Pharma AG | Method for the synthesis of rapamycin derivatives |
CN108676014A (zh) * | 2018-06-15 | 2018-10-19 | 国药集团川抗制药有限公司 | 纯化依维莫司中间体的方法以及制备依维莫司的方法 |
CN115057874A (zh) * | 2022-07-06 | 2022-09-16 | 国药集团川抗制药有限公司 | 二雷帕霉素及其制备方法和应用 |
CN116813641A (zh) * | 2023-06-09 | 2023-09-29 | 杭州华东医药集团康润制药有限公司 | 一种依维莫司的制备方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994009010A1 (en) * | 1992-10-09 | 1994-04-28 | Sandoz Ltd. | O-alkylated rapamycin derivatives and their use, particularly as immunosuppressants |
CN102127092A (zh) * | 2010-01-18 | 2011-07-20 | 东南大学 | 依维莫斯的制备 |
CN102268015A (zh) * | 2011-08-30 | 2011-12-07 | 成都摩尔生物医药有限公司 | 一种依维莫司的合成方法 |
-
2014
- 2014-03-24 CN CN201410111440.4A patent/CN103848849B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994009010A1 (en) * | 1992-10-09 | 1994-04-28 | Sandoz Ltd. | O-alkylated rapamycin derivatives and their use, particularly as immunosuppressants |
CN102127092A (zh) * | 2010-01-18 | 2011-07-20 | 东南大学 | 依维莫斯的制备 |
CN102268015A (zh) * | 2011-08-30 | 2011-12-07 | 成都摩尔生物医药有限公司 | 一种依维莫司的合成方法 |
Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104478898A (zh) * | 2014-11-18 | 2015-04-01 | 连云港恒运医药科技有限公司 | 依维莫司及其中间体的制备方法 |
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 |
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 |
CN104592254A (zh) * | 2015-02-08 | 2015-05-06 | 福建省微生物研究所 | 依维莫司的合成方法 |
KR20180015257A (ko) * | 2015-06-23 | 2018-02-12 | 신바이어스 파마 아게 | 라파마이신 유도체의 합성 방법 |
WO2016207205A1 (en) * | 2015-06-23 | 2016-12-29 | Synbias Pharma Ag | Method for the synthesis of rapamycin derivatives |
EP3109250A1 (en) * | 2015-06-23 | 2016-12-28 | Synbias Pharma AG | Method for the synthesis of rapamycin derivatives |
CN107735398A (zh) * | 2015-06-23 | 2018-02-23 | 赛比亚斯药业股份公司 | 用于合成雷帕霉素衍生物的方法 |
TWI646100B (zh) * | 2015-06-23 | 2019-01-01 | 新拜爾斯製藥公司 | 合成雷帕黴素衍生物的方法 |
US10308665B2 (en) | 2015-06-23 | 2019-06-04 | Synbias Pharma Ag | Method for the synthesis of rapamycin derivatives |
RU2718058C2 (ru) * | 2015-06-23 | 2020-03-30 | Синбиас Фарма АГ | Способ синтеза производных рапамицина |
KR102621941B1 (ko) | 2015-06-23 | 2024-01-05 | 신바이어스 파마 아게 | 라파마이신 유도체의 합성 방법 |
CN108676014A (zh) * | 2018-06-15 | 2018-10-19 | 国药集团川抗制药有限公司 | 纯化依维莫司中间体的方法以及制备依维莫司的方法 |
CN115057874A (zh) * | 2022-07-06 | 2022-09-16 | 国药集团川抗制药有限公司 | 二雷帕霉素及其制备方法和应用 |
CN116813641A (zh) * | 2023-06-09 | 2023-09-29 | 杭州华东医药集团康润制药有限公司 | 一种依维莫司的制备方法 |
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Publication number | Publication date |
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CN103848849B (zh) | 2016-02-24 |
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