CN101805339B - 一种制备恩替卡韦化合物的方法 - Google Patents
一种制备恩替卡韦化合物的方法 Download PDFInfo
- Publication number
- CN101805339B CN101805339B CN2010101435873A CN201010143587A CN101805339B CN 101805339 B CN101805339 B CN 101805339B CN 2010101435873 A CN2010101435873 A CN 2010101435873A CN 201010143587 A CN201010143587 A CN 201010143587A CN 101805339 B CN101805339 B CN 101805339B
- Authority
- CN
- China
- Prior art keywords
- midbody
- reduced pressure
- under reduced
- stirring
- concentrating under
- 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.)
- Expired - Fee Related
Links
- 229960000980 entecavir Drugs 0.000 title claims abstract description 26
- -1 Entecavir compound Chemical class 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 16
- 238000003756 stirring Methods 0.000 claims description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 32
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 30
- 239000000243 solution Substances 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 13
- 239000012312 sodium hydride Substances 0.000 claims description 13
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 13
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 6
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 5
- 238000004440 column chromatography Methods 0.000 claims description 5
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 239000011259 mixed solution Substances 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 238000007670 refining Methods 0.000 claims description 5
- 239000011347 resin Substances 0.000 claims description 5
- 229920005989 resin Polymers 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 235000002639 sodium chloride Nutrition 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000010828 elution Methods 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 239000010410 layer Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- 239000008213 purified water Substances 0.000 claims description 3
- 150000003385 sodium Chemical class 0.000 claims description 3
- 235000010265 sodium sulphite Nutrition 0.000 claims description 3
- 238000010521 absorption reaction Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- AZFQCTBZOPUVOW-UHFFFAOYSA-N methyl(triphenyl)phosphanium Chemical compound C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 AZFQCTBZOPUVOW-UHFFFAOYSA-N 0.000 claims 2
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 abstract 1
- 239000011814 protection agent Substances 0.000 abstract 1
- 238000006467 substitution reaction Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 5
- 229960001627 lamivudine Drugs 0.000 description 4
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 4
- WLEDPHKFODFOIV-UHFFFAOYSA-N [methyl(diphenyl)-$l^{4}-phosphanyl]benzene Chemical compound C=1C=CC=CC=1[P](C=1C=CC=CC=1)(C)C1=CC=CC=C1 WLEDPHKFODFOIV-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 0 C*(c1nc(**)nc2c1N=IN2)=C Chemical compound C*(c1nc(**)nc2c1N=IN2)=C 0.000 description 2
- DCSOPUDOZMRWRP-UHFFFAOYSA-N Cc1cc(C)cc([SiH2]Cl)c1 Chemical compound Cc1cc(C)cc([SiH2]Cl)c1 DCSOPUDOZMRWRP-UHFFFAOYSA-N 0.000 description 2
- 241000700721 Hepatitis B virus Species 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 1
- VAKWQVQXOMMHSG-RMILHFBTSA-N OCC([C@@H]1O[C@@H]1C1)[C@H]1O Chemical compound OCC([C@@H]1O[C@@H]1C1)[C@H]1O VAKWQVQXOMMHSG-RMILHFBTSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- NUUNDIOOYFEMQN-UHFFFAOYSA-N cyclopenta-1,3-diene;sodium Chemical compound [Na].C1C=CC=C1 NUUNDIOOYFEMQN-UHFFFAOYSA-N 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
Claims (8)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2010101435873A CN101805339B (zh) | 2010-04-12 | 2010-04-12 | 一种制备恩替卡韦化合物的方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2010101435873A CN101805339B (zh) | 2010-04-12 | 2010-04-12 | 一种制备恩替卡韦化合物的方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101805339A CN101805339A (zh) | 2010-08-18 |
CN101805339B true CN101805339B (zh) | 2012-01-11 |
Family
ID=42607307
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2010101435873A Expired - Fee Related CN101805339B (zh) | 2010-04-12 | 2010-04-12 | 一种制备恩替卡韦化合物的方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN101805339B (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2705953C (en) * | 2010-05-31 | 2018-05-01 | Alphora Research Inc. | Carbanucleoside synthesis and intermediate compounds useful therein |
WO2014000673A1 (en) * | 2012-06-29 | 2014-01-03 | Sunshine Lake Pharma Co., Ltd. | Process for preparation of entecavir |
CN108203435B (zh) * | 2016-12-16 | 2020-09-04 | 正大天晴药业集团股份有限公司 | 一种利用Boc保护基的恩替卡韦的制备方法 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PL212790B1 (pl) * | 2002-12-11 | 2012-11-30 | Bristol Myers Squibb Co | Sposób wytwarzania entekawiru, produkty posrednie, sposób wytwarzania produktu posredniego oraz pochodna metanosulfonianowa |
CN101210015B (zh) * | 2006-12-26 | 2010-09-22 | 上海国创医药有限公司 | 一种乙肝治疗药物恩替卡韦的制备方法 |
-
2010
- 2010-04-12 CN CN2010101435873A patent/CN101805339B/zh not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
CN101805339A (zh) | 2010-08-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105683209B (zh) | 2’-脱氧-2’,2’-二氟四氢尿苷的合成途径 | |
EP4043455A1 (en) | Bicyclic compound that acts as crbn protein regulator | |
CN106543252A (zh) | 核苷氨基磷酸酯类前药的制备方法及其中间体 | |
EP3351550B1 (en) | Phosphoramidate compound and preparation method and crystalline form thereof | |
CN105237452A (zh) | 一种度骨化醇的新结晶形式及其制备方法 | |
WO2022012630A1 (zh) | C-核苷化合物的合成方法 | |
CN102395591B (zh) | 一种合成普拉格雷的方法 | |
CN101402655B (zh) | 一种米铂的制备方法 | |
CN106565646A (zh) | 一种美白剂原料的合成方法 | |
CN101805339B (zh) | 一种制备恩替卡韦化合物的方法 | |
CN115947759A (zh) | 一种治疗新冠药物瑞德西韦的制备方法 | |
CN116640088A (zh) | 一种高纯度雷芬那辛的制备方法 | |
CN111646964B (zh) | 一种碱催化的合成2h-吡喃-2-酮衍生物新方法 | |
CN106749335B (zh) | 一种卤代氧头孢类中间体的制备方法和应用 | |
CN103145636B (zh) | 一种1,4-二酰基-3,6-二苯基-1,4-二氢均四嗪类化合物及其制备方法和应用 | |
CN103130708B (zh) | 一种n-叔丁氧羰基-4-硝基哌啶的制备方法 | |
CN109836465B (zh) | 一种制备盐酸表柔比星的方法 | |
CN113999164B (zh) | 常山酮中间体反式-n-苄氧羰基-(3-羟基-2-哌啶基)-2-丙酮的制备方法 | |
CN110128385A (zh) | 一种通过十二酰氯化学修饰的槲皮素衍生物及其合成方法 | |
CN112679570B (zh) | 一种泰地罗新的合成与纯化方法 | |
JP5496908B2 (ja) | ゼラレノンマクロライドアナログを作製するための中間体および方法 | |
KR102350002B1 (ko) | 탁산 화합물, 이들의 제조 방법, 및 이들의 용도 | |
KR100741310B1 (ko) | 젬시타빈의 합성에 유용한 신규한나프탈렌-2-카르복실레이트 유도체와 그의 제조방법 | |
CN110105361B (zh) | 一种Evodiakine及其衍生物的制备方法 | |
CN109053847B (zh) | 一种17β-咪唑烷基溴盐-去氢表雄烷衍生物及其制备方法和应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
ASS | Succession or assignment of patent right |
Owner name: HAINAN LINGKANG PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: WANG MING Effective date: 20130724 |
|
C41 | Transfer of patent application or patent right or utility model | ||
COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 570125 HAIKOU, HAINAN PROVINCE TO: 570216 HAIKOU, HAINAN PROVINCE |
|
TR01 | Transfer of patent right |
Effective date of registration: 20130724 Address after: 570216 Hainan Province, Haikou city Jinpan Industrial Development Zone Industrial Village No. 3-6 building Patentee after: Hainan Lingkang Pharmaceutical Co., Ltd. Address before: The new business building No. 48 570125 Hainan city of Haikou province China World Trade Center Road, room 2601 Patentee before: Wang Ming |
|
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20120111 Termination date: 20160412 |
|
CF01 | Termination of patent right due to non-payment of annual fee |