CN100586946C - 一种阿加曲班的分离方法 - Google Patents
一种阿加曲班的分离方法 Download PDFInfo
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- CN100586946C CN100586946C CN200610129330A CN200610129330A CN100586946C CN 100586946 C CN100586946 C CN 100586946C CN 200610129330 A CN200610129330 A CN 200610129330A CN 200610129330 A CN200610129330 A CN 200610129330A CN 100586946 C CN100586946 C CN 100586946C
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- argatroban
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- methyl alcohol
- raw material
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- KXNPVXPOPUZYGB-XYVMCAHJSA-N argatroban Chemical compound OC(=O)[C@H]1C[C@H](C)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NC[C@H](C)C2 KXNPVXPOPUZYGB-XYVMCAHJSA-N 0.000 title claims abstract description 41
- 229960003856 argatroban Drugs 0.000 title claims abstract description 41
- 238000000926 separation method Methods 0.000 title claims description 9
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 239000000203 mixture Substances 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000013078 crystal Substances 0.000 claims abstract description 7
- 238000010992 reflux Methods 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 239000012452 mother liquor Substances 0.000 claims description 2
- 238000004811 liquid chromatography Methods 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 9
- 238000001035 drying Methods 0.000 abstract description 4
- 238000001914 filtration Methods 0.000 abstract description 4
- 238000004587 chromatography analysis Methods 0.000 abstract description 2
- 238000001816 cooling Methods 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- 239000007788 liquid Substances 0.000 abstract 1
- 239000007791 liquid phase Substances 0.000 abstract 1
- 238000009833 condensation Methods 0.000 description 12
- 230000005494 condensation Effects 0.000 description 12
- 238000001953 recrystallisation Methods 0.000 description 9
- DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- VJDOLBUUJRHCPC-UHFFFAOYSA-N quinoline;sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O.N1=CC=CC2=CC=CC=C21 VJDOLBUUJRHCPC-UHFFFAOYSA-N 0.000 description 7
- 239000003814 drug Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000004019 antithrombin Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 2
- 229930064664 L-arginine Natural products 0.000 description 2
- 235000014852 L-arginine Nutrition 0.000 description 2
- MRAUNPAHJZDYCK-BYPYZUCNSA-N L-nitroarginine Chemical compound OC(=O)[C@@H](N)CCCNC(=N)N[N+]([O-])=O MRAUNPAHJZDYCK-BYPYZUCNSA-N 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000010931 ester hydrolysis Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- IYLPVOSBXVRRJZ-QAKAPOOCSA-N (2R,4R)-1-[(2S)-5-(hydrazinylmethylideneamino)-2-[(3-methyl-1,2,3,4-tetrahydroquinolin-8-yl)sulfonylamino]pentanoyl]-4-methylpiperidine-2-carboxylic acid Chemical compound NN=CNCCC[C@@H](C(=O)N1[C@H](C[C@@H](CC1)C)C(=O)O)NS(=O)(=O)C=1C=CC=C2CC(CNC=12)C IYLPVOSBXVRRJZ-QAKAPOOCSA-N 0.000 description 1
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 description 1
- 206010003178 Arterial thrombosis Diseases 0.000 description 1
- 206010008132 Cerebral thrombosis Diseases 0.000 description 1
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 description 1
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 201000001429 Intracranial Thrombosis Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 229960004676 antithrombotic agent Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
Images
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200610129330A CN100586946C (zh) | 2006-11-10 | 2006-11-10 | 一种阿加曲班的分离方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200610129330A CN100586946C (zh) | 2006-11-10 | 2006-11-10 | 一种阿加曲班的分离方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1951936A CN1951936A (zh) | 2007-04-25 |
| CN100586946C true CN100586946C (zh) | 2010-02-03 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200610129330A Active CN100586946C (zh) | 2006-11-10 | 2006-11-10 | 一种阿加曲班的分离方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100586946C (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2824187A1 (en) | 2013-07-09 | 2015-01-14 | Euticals S.P.A. | Biocatalyzed synthesis of the optically pure (R) and (S) 3-methyl-1,2,3,4-tetrahydroquinoline and their use as chiral synthons for the preparation of the antithrombotic (21R)- and (21S)-argatroban |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100467022C (zh) * | 2007-04-13 | 2009-03-11 | 天津市炜杰科技有限公司 | 21(s)阿加曲班的应用 |
| CN101362746B (zh) * | 2007-08-06 | 2011-12-28 | 博瑞生物医药技术(苏州)有限公司 | 阿加曲班单一立体异构体的分离方法及多晶型物 |
| CN102329371B (zh) * | 2007-08-06 | 2013-07-10 | 博瑞生物医药技术(苏州)有限公司 | 阿加曲班单一立体异构体的分离方法及多晶型物 |
| CN101560244B (zh) * | 2009-04-21 | 2011-05-25 | 深圳翰宇药业股份有限公司 | 一种固相法和液相法结合合成阿加曲班的新方法 |
| CN102228677A (zh) * | 2011-06-17 | 2011-11-02 | 天津市炜杰科技有限公司 | 以酸作为增溶剂的21(r)阿加曲班静脉注射液 |
| CN102228426A (zh) * | 2011-06-17 | 2011-11-02 | 天津市炜杰科技有限公司 | 以醇作为增溶剂的21(r)阿加曲班静脉注射液 |
| CN103923168B (zh) * | 2013-01-14 | 2018-08-24 | 山东新时代药业有限公司 | 一种阿加曲班一水合物的制备方法 |
| CN104558103B (zh) * | 2013-10-24 | 2019-02-26 | 四川科瑞德制药股份有限公司 | 一种阿加曲班中间体的制备方法 |
| CN103772486B (zh) * | 2014-01-06 | 2016-01-20 | 天津大学 | 一种阿加曲班新晶型及其制备方法 |
-
2006
- 2006-11-10 CN CN200610129330A patent/CN100586946C/zh active Active
Non-Patent Citations (6)
| Title |
|---|
| A short syntheis of argatroban: a potent selective thrombininhibitor. Janine Cossy, et al.Bioorganic & medicinal chemistry,Vol.11 . 2001 |
| A short syntheis of argatroban: a potent selective thrombininhibitor. Janine Cossy,et al.Bioorganic & * |
| medicinal chemistry,Vol.11. 2001 * |
| Potent inhibition of thrombin by the newly synthesizedargininederivative No. 805. the importance of stereostructureof its hydrophobic carboxamide portion.. Shosuke Okamoto, et al.Biochemical and biophysical research communications,Vol.101 No.2. 1981 |
| Potent inhibition of thrombin by the newly synthesizedargininederivative No.805.the importance of stereostructureof its hydrophobic carboxamide portion. Shosuke Okamoto,et al.Biochemical and biophysical research communications,Vol.101 No.2. 1981 * |
| Separation of 21-(R)- and 21-(S)-argatroban: solubility andactivity of the individual diastereoisomers. Thomas e. rawson, et al.Journal of Pharmaceutical Sciences,Vol.82 No.6. 1993 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2824187A1 (en) | 2013-07-09 | 2015-01-14 | Euticals S.P.A. | Biocatalyzed synthesis of the optically pure (R) and (S) 3-methyl-1,2,3,4-tetrahydroquinoline and their use as chiral synthons for the preparation of the antithrombotic (21R)- and (21S)-argatroban |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1951936A (zh) | 2007-04-25 |
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