WO2015079455A2 - A recycling process for preparing tenofovir alafenamide diastereomers - Google Patents
A recycling process for preparing tenofovir alafenamide diastereomers Download PDFInfo
- Publication number
- WO2015079455A2 WO2015079455A2 PCT/IN2014/000734 IN2014000734W WO2015079455A2 WO 2015079455 A2 WO2015079455 A2 WO 2015079455A2 IN 2014000734 W IN2014000734 W IN 2014000734W WO 2015079455 A2 WO2015079455 A2 WO 2015079455A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- diastereomer
- tenofovir alafenamide
- mixtures
- sodium
- base
- Prior art date
Links
- LDEKQSIMHVQZJK-CAQYMETFSA-N tenofovir alafenamide Chemical compound O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 LDEKQSIMHVQZJK-CAQYMETFSA-N 0.000 title claims abstract description 96
- 229960004946 tenofovir alafenamide Drugs 0.000 title claims abstract description 95
- 238000004064 recycling Methods 0.000 title description 8
- 238000004519 manufacturing process Methods 0.000 title description 6
- 238000000034 method Methods 0.000 claims abstract description 72
- 239000000203 mixture Substances 0.000 claims abstract description 61
- 230000006340 racemization Effects 0.000 claims abstract description 17
- 238000000926 separation method Methods 0.000 claims abstract description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 39
- 239000002585 base Substances 0.000 claims description 25
- 238000004587 chromatography analysis Methods 0.000 claims description 25
- 239000003480 eluent Substances 0.000 claims description 20
- 239000003960 organic solvent Substances 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 15
- 238000002953 preparative HPLC Methods 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 239000000725 suspension Substances 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 229910052783 alkali metal Inorganic materials 0.000 claims description 8
- -1 alkaline earth metal carbonates Chemical class 0.000 claims description 8
- 150000007529 inorganic bases Chemical class 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- MGAXYKDBRBNWKT-UHFFFAOYSA-N (5-oxooxolan-2-yl)methyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCC1OC(=O)CC1 MGAXYKDBRBNWKT-UHFFFAOYSA-N 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 5
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 5
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-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
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 4
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 4
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 150000002170 ethers Chemical class 0.000 claims description 4
- 150000002334 glycols Chemical class 0.000 claims description 4
- 150000008282 halocarbons Chemical class 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- 229940090181 propyl acetate Drugs 0.000 claims description 4
- 150000003457 sulfones Chemical class 0.000 claims description 4
- 150000003462 sulfoxides Chemical class 0.000 claims description 4
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- AYJRCSIUFZENHW-DEQYMQKBSA-L barium(2+);oxomethanediolate Chemical compound [Ba+2].[O-][14C]([O-])=O AYJRCSIUFZENHW-DEQYMQKBSA-L 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000920 calcium hydroxide Substances 0.000 claims description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 2
- 239000001095 magnesium carbonate Substances 0.000 claims description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 2
- 239000000347 magnesium hydroxide Substances 0.000 claims description 2
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 2
- 229960005235 piperonyl butoxide Drugs 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229960003975 potassium Drugs 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 229940086066 potassium hydrogencarbonate Drugs 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims 2
- 150000007530 organic bases Chemical class 0.000 claims 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000004296 chiral HPLC Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
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- 238000000746 purification Methods 0.000 description 4
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 3
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- 239000007858 starting material Substances 0.000 description 3
- SVUJNSGGPUCLQZ-FQQAACOVSA-N tenofovir alafenamide fumarate Chemical compound OC(=O)\C=C\C(O)=O.O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1.O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 SVUJNSGGPUCLQZ-FQQAACOVSA-N 0.000 description 3
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- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 2
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960004556 tenofovir Drugs 0.000 description 1
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 1
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Classifications
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
Definitions
- step b) reacting the step a) mixture with a suitable base to obtain a racemate, c) separating the (R,S,S)-diastereomer of tenofovir alafenamide;
- the present invention provides a process for separation of diastereomers of tenofovir alafenamide, comprising: subjecting the mixture having (R,S,S) & (R,R,S)-diastereomer of tenofovir alafenamide to simulated moving bed chromatography or Preparative HPLC, and separating the (R,S,S)- ' diastereomer of tenofovir alafenamide.
- the present invention provides a process for the racemization of (R,R,S)-diastereomer or a mixture having (R,S,S) & (R,R,S)- diastereomer of tenofovir alafenamide, said method comprising treating the (R,R,S)- diastereomer or a mixture having (R,S,S) & (R,R,S)-diastereomer with a suitable base in a suitable organic solvent.
- step b) reacting the step a) mixture with a suitable base to obtain a racemate, c) subjecting the resultant racemate to simulated moving bed chromatography or Preparative HPLC, and
- the starting compound either (R,R,S)-diastereomer or a mixture having (R,S,S) & (R,R,S)-diastereomer of tenofovir alafenamide can be prepared by any known methods, for example starting compound may be obtained by chromatography fractions according to U.S. patent No's 7,390,791.
- Step a) of the foregoing process includes providing a solution or suspension of (R,R,S)-diastereomer or a mixture having (R,S,S) & (R,R,S)-diastereomer of tenofovir alafenamide in a suitable organic solvent.
- a solution or suspension may be obtained directly from a reaction mixture in which (R,R,S)-diastereomer or a mixture having (R,S,S) & (R,R,S)-diastereomer is formed and used as such without isolation or it may be obtained after separation of diastereomers by chromatographic separation.
- bases for use in step b) of the foregoing process includes but are not limited to organic amine bases such as primary, secondary, tertiary amines, cyclic amines and the like; or inorganic bases such as alkali metal hydroxide, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal alkoxides, alkali metal aryloxides and the like.
- Suitable organic amines include but are not limited to trimethylamine, butylamine, isopropylamine, diethylamine, ethanolamine, dicyclohexylamine and the like.
- the particles of the support material advantageously have an average diameter (based on the particle size) of 5 ⁇ to 500mm, preferably ⁇ to 100 ⁇ , more preferably 20 ⁇ .
- the present invention also provides a process for purification of tenofovir alafenamide, comprising subjecting the racemic mixtures of tenofovir alafenamide diastereomers obtained by the process described as above to a Preparative FIPLC using suitable eluent.
- the process unlike conventional resolution methods, yields, after recycle over several batches, the desired (R,S,S)-diastereomer in high yields with high diastereomeric purity.
- Such racemization is environmentally desirable, and permits direct recycle of the undesired diastereomer, thus ultimately resulting in virtually complete conversion of undesired diastereomer to the desired diastereomer.
- the present invention also provides preparation of pharmaceutically acceptable salts of tenofovir alafenamide, the process comprising reacting tenofovir alafenamide, as starting material or as an intermediate, with pharmaceutically acceptable salts as per saltification procedure known in the art.
- the present invention provides tenofovir alafenamide, obtained by the process described herein, as analyzed using the chiral high performance liquid chromatography ("chiral HPLC”) with the conditions described below:
- Acetone (142 gms) was charged to the residue and concentrated under reduced pressure to obtained an oily residue which was purified by column chromatography over silica gel by eluting with acetone (100%). Pure product fractions were concentrated under reduced pressure to get residue. Acetonitrile was charged to the residue and the mixture was distilled under reduced pressure to get 47 gms of racemic Tenofovir alafenamide diastereomers as foamy solid.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN5455/CHE/2013 | 2013-11-27 | ||
| IN5455CH2013 IN2013CH05455A (enrdf_load_stackoverflow) | 2013-11-27 | 2014-11-27 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2015079455A2 true WO2015079455A2 (en) | 2015-06-04 |
| WO2015079455A3 WO2015079455A3 (en) | 2015-08-27 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2014/000734 WO2015079455A2 (en) | 2013-11-27 | 2014-11-27 | A recycling process for preparing tenofovir alafenamide diastereomers |
Country Status (2)
| Country | Link |
|---|---|
| IN (1) | IN2013CH05455A (enrdf_load_stackoverflow) |
| WO (1) | WO2015079455A2 (enrdf_load_stackoverflow) |
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| CN107179355A (zh) * | 2016-03-11 | 2017-09-19 | 广东东阳光药业有限公司 | 一种分离检测替诺福韦艾拉酚胺及其有关物质的方法 |
| CN107655987A (zh) * | 2017-09-08 | 2018-02-02 | 安徽灵药业有限公司 | 一种替诺福韦艾拉酚胺及其异构体的hplc检测方法 |
| CN111189947A (zh) * | 2020-03-30 | 2020-05-22 | 济南新科医药科技有限公司 | 一种分离检测富马酸丙酚替诺福韦异构体的分析方法 |
| CN111239285A (zh) * | 2020-02-20 | 2020-06-05 | 北京阳光诺和药物研究有限公司 | 一种替诺呋韦艾拉酚胺中基因毒性杂质的含量检测方法 |
| CN113075307A (zh) * | 2021-03-08 | 2021-07-06 | 瑞阳制药股份有限公司 | 富马酸丙酚替诺福韦异构体的检测方法 |
| CN113970612A (zh) * | 2020-07-22 | 2022-01-25 | 北京四环制药有限公司 | 一种高效液相色谱法测定丙酚替诺福韦有关物质的方法 |
| CN114137092A (zh) * | 2020-09-03 | 2022-03-04 | 北京四环制药有限公司 | 一种测定丙酚替诺福韦异构体的方法 |
| CN116609445A (zh) * | 2022-12-01 | 2023-08-18 | 上海医药工业研究院有限公司 | 无环核苷膦酸酯类化合物及其制备方法、分析方法和应用 |
| CN118883741A (zh) * | 2024-07-05 | 2024-11-01 | 福建广生堂药业股份有限公司 | 一种富马酸丙酚替诺福韦及其对映异构体的分离检测方法及其应用 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT2682397T (pt) * | 2000-07-21 | 2017-05-31 | Gilead Sciences Inc | Pró-fármacos de análogos de nucleótido fosfonato e métodos para selecionar e produzir os mesmos |
| SI3333173T1 (sl) * | 2011-10-07 | 2019-08-30 | Gilead Sciences, Inc. | Postopki za pripravo analogov protivirusnega nukleotida |
| CN104105484A (zh) * | 2012-02-03 | 2014-10-15 | 吉联亚科学公司 | 用于治疗病毒感染的包含替诺福韦艾拉酚胺半反丁烯二酸盐和可比西他的组合疗法 |
-
2014
- 2014-11-27 IN IN5455CH2013 patent/IN2013CH05455A/en unknown
- 2014-11-27 WO PCT/IN2014/000734 patent/WO2015079455A2/en active Application Filing
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107179355A (zh) * | 2016-03-11 | 2017-09-19 | 广东东阳光药业有限公司 | 一种分离检测替诺福韦艾拉酚胺及其有关物质的方法 |
| CN107655987A (zh) * | 2017-09-08 | 2018-02-02 | 安徽灵药业有限公司 | 一种替诺福韦艾拉酚胺及其异构体的hplc检测方法 |
| CN111239285A (zh) * | 2020-02-20 | 2020-06-05 | 北京阳光诺和药物研究有限公司 | 一种替诺呋韦艾拉酚胺中基因毒性杂质的含量检测方法 |
| CN111239285B (zh) * | 2020-02-20 | 2020-10-09 | 北京阳光诺和药物研究有限公司 | 一种替诺呋韦艾拉酚胺中基因毒性杂质的含量检测方法 |
| CN111189947A (zh) * | 2020-03-30 | 2020-05-22 | 济南新科医药科技有限公司 | 一种分离检测富马酸丙酚替诺福韦异构体的分析方法 |
| CN111189947B (zh) * | 2020-03-30 | 2022-06-17 | 济南新科医药科技有限公司 | 一种分离检测富马酸丙酚替诺福韦异构体的分析方法 |
| CN113970612A (zh) * | 2020-07-22 | 2022-01-25 | 北京四环制药有限公司 | 一种高效液相色谱法测定丙酚替诺福韦有关物质的方法 |
| CN114137092A (zh) * | 2020-09-03 | 2022-03-04 | 北京四环制药有限公司 | 一种测定丙酚替诺福韦异构体的方法 |
| CN114137092B (zh) * | 2020-09-03 | 2025-02-11 | 北京四环制药有限公司 | 一种测定丙酚替诺福韦异构体的方法 |
| CN113075307A (zh) * | 2021-03-08 | 2021-07-06 | 瑞阳制药股份有限公司 | 富马酸丙酚替诺福韦异构体的检测方法 |
| CN116609445A (zh) * | 2022-12-01 | 2023-08-18 | 上海医药工业研究院有限公司 | 无环核苷膦酸酯类化合物及其制备方法、分析方法和应用 |
| CN118883741A (zh) * | 2024-07-05 | 2024-11-01 | 福建广生堂药业股份有限公司 | 一种富马酸丙酚替诺福韦及其对映异构体的分离检测方法及其应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2015079455A3 (en) | 2015-08-27 |
| IN2013CH05455A (enrdf_load_stackoverflow) | 2015-08-07 |
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