CN1505620A - Process for purification of warfarin acid, warfarin alkali metal salts and corresponding clathrates - Google Patents
Process for purification of warfarin acid, warfarin alkali metal salts and corresponding clathrates Download PDFInfo
- Publication number
- CN1505620A CN1505620A CNA018231594A CN01823159A CN1505620A CN 1505620 A CN1505620 A CN 1505620A CN A018231594 A CNA018231594 A CN A018231594A CN 01823159 A CN01823159 A CN 01823159A CN 1505620 A CN1505620 A CN 1505620A
- Authority
- CN
- China
- Prior art keywords
- neodicoumarin
- acid
- water
- pure
- salt
- 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.)
- Pending
Links
- 239000002253 acid Substances 0.000 title claims abstract description 145
- 238000000034 method Methods 0.000 title claims abstract description 106
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 title claims abstract description 59
- -1 warfarin alkali metal salts Chemical class 0.000 title claims abstract description 21
- 230000008569 process Effects 0.000 title claims description 15
- 238000000746 purification Methods 0.000 title abstract description 10
- 229960005080 warfarin Drugs 0.000 title abstract description 8
- 229910052783 alkali metal Inorganic materials 0.000 title description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 81
- 239000002904 solvent Substances 0.000 claims abstract description 34
- 239000000243 solution Substances 0.000 claims abstract description 33
- 239000000725 suspension Substances 0.000 claims abstract description 32
- 239000007864 aqueous solution Substances 0.000 claims abstract description 18
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 15
- 238000001914 filtration Methods 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 229910052751 metal Inorganic materials 0.000 claims abstract description 9
- 239000002184 metal Substances 0.000 claims abstract description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000008346 aqueous phase Substances 0.000 claims abstract description 7
- 238000001816 cooling Methods 0.000 claims abstract description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 4
- SEGSDVUVOWIWFX-UHFFFAOYSA-N ethyl biscoumacetate Chemical compound C1=CC=C2C(=O)C(C(C=3C(C4=CC=CC=C4OC=3O)=O)C(=O)OCC)=C(O)OC2=C1 SEGSDVUVOWIWFX-UHFFFAOYSA-N 0.000 claims description 176
- 229960002822 ethyl biscoumacetate Drugs 0.000 claims description 151
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 82
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 43
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- 238000002360 preparation method Methods 0.000 claims description 28
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 27
- 239000012043 crude product Substances 0.000 claims description 26
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical group CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 23
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- 235000017550 sodium carbonate Nutrition 0.000 claims description 17
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 17
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 16
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 14
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical group [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- ZGFASEKBKWVCGP-UHFFFAOYSA-N cyclocoumarol Chemical compound C12=CC=CC=C2OC(=O)C2=C1OC(OC)(C)CC2C1=CC=CC=C1 ZGFASEKBKWVCGP-UHFFFAOYSA-N 0.000 claims description 9
- 238000010790 dilution Methods 0.000 claims description 9
- 239000012895 dilution Substances 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 8
- 229950002423 cyclocoumarol Drugs 0.000 claims description 8
- 230000002378 acidificating effect Effects 0.000 claims description 7
- 239000011260 aqueous acid Substances 0.000 claims description 7
- 230000008859 change Effects 0.000 claims description 7
- 238000009835 boiling Methods 0.000 claims description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 5
- 239000012071 phase Substances 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 239000012454 non-polar solvent Substances 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 2
- 239000002245 particle Substances 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 7
- 239000003125 aqueous solvent Substances 0.000 claims 7
- 239000004215 Carbon black (E152) Substances 0.000 claims 2
- 238000009472 formulation Methods 0.000 claims 2
- 229930195733 hydrocarbon Natural products 0.000 claims 2
- 150000002430 hydrocarbons Chemical class 0.000 claims 2
- RRQQLORBQGPFOQ-UHFFFAOYSA-N propan-2-ol;sulfuric acid Chemical compound CC(C)O.OS(O)(=O)=O RRQQLORBQGPFOQ-UHFFFAOYSA-N 0.000 claims 1
- 239000013589 supplement Substances 0.000 claims 1
- 239000003826 tablet Substances 0.000 claims 1
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 claims 1
- 235000001892 vitamin D2 Nutrition 0.000 claims 1
- 239000011653 vitamin D2 Substances 0.000 claims 1
- 238000001035 drying Methods 0.000 abstract description 7
- 229910052708 sodium Inorganic materials 0.000 abstract description 6
- 239000011734 sodium Substances 0.000 abstract description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 abstract description 5
- 229910052700 potassium Inorganic materials 0.000 abstract description 5
- 239000011591 potassium Substances 0.000 abstract description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 abstract description 4
- 125000005233 alkylalcohol group Chemical group 0.000 abstract description 3
- 238000007865 diluting Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 18
- 239000000047 product Substances 0.000 description 13
- 239000007787 solid Substances 0.000 description 12
- 238000010992 reflux Methods 0.000 description 11
- 238000004821 distillation Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 8
- 239000000126 substance Substances 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 229960004756 ethanol Drugs 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 238000001556 precipitation Methods 0.000 description 6
- 239000003637 basic solution Substances 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 239000001211 (E)-4-phenylbut-3-en-2-one Substances 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 4
- 238000013019 agitation Methods 0.000 description 4
- 229930008407 benzylideneacetone Natural products 0.000 description 4
- 239000013256 coordination polymer Substances 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000002798 polar solvent Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 235000015320 potassium carbonate Nutrition 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- BWHOZHOGCMHOBV-BQYQJAHWSA-N trans-benzylideneacetone Chemical compound CC(=O)\C=C\C1=CC=CC=C1 BWHOZHOGCMHOBV-BQYQJAHWSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 3
- 239000003146 anticoagulant agent Substances 0.000 description 3
- 229940127219 anticoagulant drug Drugs 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000001103 potassium chloride Substances 0.000 description 3
- 235000011164 potassium chloride Nutrition 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- MJKVTPMWOKAVMS-UHFFFAOYSA-N 3-hydroxy-1-benzopyran-2-one Chemical compound C1=CC=C2OC(=O)C(O)=CC2=C1 MJKVTPMWOKAVMS-UHFFFAOYSA-N 0.000 description 2
- OWBBAPRUYLEWRR-UHFFFAOYSA-N 4-hydroxycoumarin Chemical compound C1=CC=C2OC(O)=CC(=O)C2=C1 OWBBAPRUYLEWRR-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- 102000009839 Endothelial Protein C Receptor Human genes 0.000 description 2
- 108010009900 Endothelial Protein C Receptor Proteins 0.000 description 2
- 238000006957 Michael reaction Methods 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- VXIXUWQIVKSKSA-UHFFFAOYSA-N benzotetronic acid Natural products C1=CC=CC2=C1OC(=O)C=C2O VXIXUWQIVKSKSA-UHFFFAOYSA-N 0.000 description 2
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000005115 demineralization Methods 0.000 description 2
- 230000002328 demineralizing effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 229910003002 lithium salt Inorganic materials 0.000 description 2
- 159000000002 lithium salts Chemical class 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000003128 rodenticide Substances 0.000 description 2
- 238000005185 salting out Methods 0.000 description 2
- 229960000883 warfarin potassium Drugs 0.000 description 2
- 238000009736 wetting Methods 0.000 description 2
- ZWVHTXAYIKBMEE-UHFFFAOYSA-N 2-hydroxyacetophenone Chemical compound OCC(=O)C1=CC=CC=C1 ZWVHTXAYIKBMEE-UHFFFAOYSA-N 0.000 description 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- 208000031295 Animal disease Diseases 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- 244000187656 Eucalyptus cornuta Species 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 229930003448 Vitamin K Natural products 0.000 description 1
- GHVZOJONCUEWAV-UHFFFAOYSA-N [K].CCO Chemical compound [K].CCO GHVZOJONCUEWAV-UHFFFAOYSA-N 0.000 description 1
- WJEIYVAPNMUNIU-UHFFFAOYSA-N [Na].OC(O)=O Chemical compound [Na].OC(O)=O WJEIYVAPNMUNIU-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- WPUJEWVVTKLMQI-UHFFFAOYSA-N benzene;ethoxyethane Chemical compound CCOCC.C1=CC=CC=C1 WPUJEWVVTKLMQI-UHFFFAOYSA-N 0.000 description 1
- LPRSRULGRPUBTD-UHFFFAOYSA-N butan-2-one;hydrate Chemical compound O.CCC(C)=O LPRSRULGRPUBTD-UHFFFAOYSA-N 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 229940072645 coumadin Drugs 0.000 description 1
- 229960000956 coumarin Drugs 0.000 description 1
- 235000001671 coumarin Nutrition 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N cycloheptane Chemical compound C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000012925 reference material Substances 0.000 description 1
- 239000012492 regenerant Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- IGLNJRXAVVLDKE-UHFFFAOYSA-N rubidium atom Chemical compound [Rb] IGLNJRXAVVLDKE-UHFFFAOYSA-N 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- KYITYFHKDODNCQ-UHFFFAOYSA-M sodium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [Na+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 KYITYFHKDODNCQ-UHFFFAOYSA-M 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 235000019168 vitamin K Nutrition 0.000 description 1
- 239000011712 vitamin K Substances 0.000 description 1
- 150000003721 vitamin K derivatives Chemical class 0.000 description 1
- 229940046010 vitamin k Drugs 0.000 description 1
- 229960002647 warfarin sodium Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
- C07D311/44—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3
- C07D311/46—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3 unsubstituted in the carbocyclic ring
Abstract
An improved procedure for the purification of warfarin acid. Sodium, potassium and lithium warfarin salts and the corresponding clathrates are prepared in high, pharmacopeial grade purity and good yields from the pure warfarin acid and the respective metal salt bases in suitable media. The process for preparing pure warfarin acid from crude warfarin acid starts by suspending the crude acid in a water immiscible solvent, extracting the acid into an aqueous solution of dilute base, separating the resulting aqueous phase and diluting it with a lower alkyl alcohol. The aqueous solution is filtered before being diluted with the lower alkyl alcohol. The solution is acidified to a pH of about 2 to 5 using a suitable acid, such as hydrochloric, sulfuric or phosphoric acid. The resulting suspension is stirred at a temperature of from about to 20 DEG C to about 60 DEG C, cooling the suspension below room temperature, filtering the pure warfarin acid and drying.
Description
Background of invention
Invention field
The present invention relates to the synthetic of pure neodicoumarin acid and derivative thereof.Specifically, the neodicoumarin acid that the present invention relates to purify prepares the method for tintorane, tintorane 2-propyl alcohol clathrate, Warfarin Potassium salt and the neodicoumarin lithium 2-propyl alcohol clathrate of high pharmacopeia level purity from it.
Background
Tintorane, tintorane 2-propyl alcohol clathrate, Warfarin Potassium salt and neodicoumarin lithium 2-propyl alcohol clathrate are effectively anti-coagulants, orally use usually, are widely used as active pharmaceutical ingredient (APIs).These compounds also are widely used as rodenticide with various dose and prescription.
The industrial production of APIs preferably adopts the system and the method that the pure intermediate of high quality can be provided and satisfy the product of pharmacopeia requirement.Numerous synthetic neodicoumarin acid (warfarin acid), its salt and the method for clathrate are arranged, but pharmaceutical industry still need prepare the method for these compounds with high quality, this had both comprised that intermediate also comprised product, particularly prepared high-purity neodicoumarin acid.
Neodicoumarin acid and an alkali metal salt thereof are the coumarin type derivatives with powerful anti-coagulant performance.They are useful anticoagulant medicaments of being used for the treatment of human and animal disease relevant with vitamin K of having established.For example:
Tintorane and 2-propyl alcohol clathrate thereof are with extensive stock name Coumadin for example; Marevan; Prothromadin; Tintorane; Warfarin sodium; Warfilone; Waran sells.
Warfarin Potassium salt salt is supplied with title Athrombin K.
These materials are activeconstituentss in common rodenticide.
Neodicoumarin acid, chemically be called racemic 4-hydroxyl-3-(3-oxo-benzene butyl)-2H-1-chromen-2-one, or 3-(α-acetonyl benzyl)-4 hydroxy coumarin, it typically adds through Michael reaction by 4 hydroxy coumarin commercial offers or that make in the original place becomes 4-phenyl-3-butene-2-ketone (benzylidene-acetone) and makes.The synthetic method of describing in reference has adopted the condition of wide scope, as the change of solvent, and the change of an acidic catalyst and basic catalyst, different temperature, or the like.Though neodicoumarin acid is famous chemical entity, the industrial simply neodicoumarin acid for preparing pure state was not notably reported feasiblely and directly as yet.
Early people such as Ikawa (United States Patent (USP) 2,427,578, also see J.Am.Chem Soc.1944,66,902) or by people such as Siedman (J.Am.Chem.Soc.1950,72,5193) and much the method for purification described of other author is that crude product is carried out recrystallization with acetone-water mixture.
People such as Badran are at United States Patent (USP) 4,113, a kind of method for preparing pure crystallite shape neodicoumarin acid has been described in 744, this method is that the impure neodicoumarin acid with industry is dissolved in the special amine buffering-aqueous systems, filter, by the pH that adjusts filtrate again will be pure the sour recrystallize of crystallite shape neodicoumarin.
Bush and Trage have described a kind of method for preparing pure neodicoumarin acid, comprise with ether benzene and get the acid of crude product neodicoumarin, strip with dilute sodium hydroxide, filter this basic solution, and with 5NHCl solution redeposition (J.of Pharm.Sci.1983,72 (7), 830-831.), promptly get pure neodicoumarin acid with the acetone-water recrystallization again.
Nearer reference (people such as Ivanov for example, Arch.Pharm (Weinheim) 1990,323,521-522; People WO 97/24347 such as Uwaydah) extraction/recrystallization method that uses Glacial acetic acid or ethyl acetate has been described.
The neodicoumarin an alkali metal salt, chemically be called 4-hydroxyl-3-(3-oxo-benzene butyl) 2H-1-chromen-2-one an alkali metal salt, or 3-(2-acetonyl phenyl)-4 hydroxy coumarin sodium, potassium or lithium salts, usually by neodicoumarin acid and the corresponding basic metal bases in water medium molar equivalent or that lack some; Or with the reaction of metal alkoxide class in lower alkyl alcohol and make.
People's such as Schroeder United States Patent (USP) 2,765,321 has been described a kind of method for preparing the crystalline tintorane, and it is with aqueous sodium hydroxide solution and excessive neodicoumarin acid-respons, adds ethanol and filtration subsequently, removes excessive acid.Final tintorane salt obtains by salting-out process, and this salting-out process adopts lithium chloride is added in the ethanol-water solution of tintorane salt, cooling, and the tintorane that is settled out with reclaiming by filtration.
People's such as Link United States Patent (USP) 2,777,859 have described a kind of method for preparing the aqueous solution of neodicoumarin alkali metal derivant, this method is that alkali metal hydroxide aqueous solution is added in the wet neodicoumarin acid of excessive water, heating, and remove excessive neodicoumarin acid with filtration method.
People's such as Schroeder United States Patent (USP) 3,077,481 has described the method for the band look tintorane of purifying, and this method is that amorphous salt is dissolved in the 2-propyl alcohol of heat, the solution of cooling gained, and reclaim crystalline tintorane 2-propyl alcohol clathrate product.
Yates and Thomson have described a kind of improved method for preparing tintorane in French Patent 1397213, and this method is with the suspension of neodicoumarin acid in anhydrous low-grade alkane alcohol and the solution reaction that is dissolved in the sodium hydroxide that contains molar equivalent in the same solvent.After the flux evaporation, thick product goes out with the pulpous state isolated in form, and it must further be purified and carry out finish-drying or lyophilized.This product is not drug quality usually.Tintorane can be by being dissolved in the 2-propyl alcohol, the crystalline clathrate is separated and purifies with filtration method.Captive 2-propyl alcohol can be by removing the solution evaporation of this crystal salt in methyl alcohol, ethanol or acetone in a vacuum to doing.In order to obtain the pharmaceutical grade material, need further to purify.
The United States Patent (USP) 3 of Schroeder and Link, 192,232 have described a kind of method for preparing tintorane and Warfarin Potassium salt salt, and this method is at room temperature the thin pulp of neodicoumarin acid in acetone-water and sodium hydroxide or potassium hydroxide less than equivalents in water to be reacted.Tell by capable person's salt by stirring, be evaporated to gac for this crude salt solution, spraying drying or drum dried are purified.
People's such as Weiner United States Patent (USP) 3,246,013 has described a kind of method for preparing crystalline tintorane 2-propyl alcohol clathrate, by using sodium hydroxide that neodicoumarin acid/2-propyl alcohol thin pulp is neutralized to pH about 9～10, perhaps for fear of the color of common existence, select for use sodium alkoxide as an alternative thing neutralize at 50-80 ℃.
People such as Ohnishi have described a kind of method for preparing the neodicoumarin an alkali metal salt, and this method is that neodicoumarin acid is dissolved among the aqueous solution that contains the corresponding alkali metal hydroxide of equivalent (lithium, sodium, potassium, rubidium and caesium).Biosci.Biotech.Biochem.1995,59 (6), 995-1006 (seeing CA123:105246 (1996)).Separate corresponding salt with freeze-drying.
In recent patent publications WO 97/24347 (publication on July 10th, 1997), people such as Uwaydah have described a kind of integrated approach that is begun to prepare neodicoumarin an alkali metal salt (sodium and potassium) and clathrate by 2-hydroxy acetophenone and carbonic ether.The Hydroxycoumarin that so makes to react with benzylidene-acetone with described those similar methods of Ivanov (seeing top reference), generates neodicoumarin acid again in the presence of phase-transfer catalyst.Back one intermediate again in dehydrated alcohol or 2-propyl alcohol with sodium hydroxide or potassium hydroxide or yellow soda ash or salt of wormwood reaction, perhaps preferred and sodium methylate or potassium methylate or sodium ethylate or potassium ethylate react, and finally generate required product.
As from what can see to existing preparation method's description, in this field huge interest is arranged, exist the route of a lot of synthetic neodicoumarin acid and salt thereof.But, still need a kind of industrial feasible method of economy to produce the neodicoumarin acid and the related salts thereof of high-quality pharmacopeia level.
General introduction of the present invention
Considered above-mentioned explanation and non-limiting example described here, other purposes of the present invention and advantage will become clear.
The present invention is a kind of method from the pure neodicoumarin acid of crude product neodicoumarin acid preparation, this method be the acid of crude product neodicoumarin be suspended in the preferred toluene of the immiscible solvent of water among, the neodicoumarin acid extraction is advanced in the dilute alkaline aqueous solution, separate the water that obtains, with for example methyl alcohol, ethanol or preferred 2-propyl alcohol dilution of low-grade alkane alcohol.Preferably, before this aqueous solution being diluted, the aqueous solution is filtered with low-grade alkane alcohol.Preferably low-grade alkane alcohol is joined about 50% concentration.For example hydrochloric acid, sulfuric acid or phosphoric acid etc. are acidified to pH with this solution and are about 2～5 with suitable acid.Sulfuric acid is preferred.Gained suspension is stirred under about 20 ℃～60 ℃, preferred about 40 ℃～50 ℃ temperature, suspension is cooled to is lower than room temperature, preferred about 5 ℃～10 ℃, filter this pure neodicoumarin acid, and carry out drying.
The crude product neodicoumarin acid that is used to purify, preferably by the Methopyranorin hydrolysis is made, during hydrolysis, toward the solution of Methopyranorin in the mixture of miscible solvent of polar water and water, add about 2%～10% an acidic catalyst, preferred 4-toluenesulphonic acids, temperature are the boiling point from room temperature to solvent approximately.An acidic catalyst is invalid usually less than 2%, then may make product impure and possible uneconomical greater than 10-15%.Reaction is preferred at the water that contains about 35%～65%, carries out in the butanone of preferred about 40%～50% water or the acetone, most preferably carries out under reflux temperature.
On the other hand, the present invention is a kind of method for preparing tintorane 2-propyl alcohol clathrate, is included in the 2-propyl alcohol pure neodicoumarin acid and yellow soda ash reaction.The 2-propyl alcohol preferably contains the water of 0.5%～5% volume of having an appointment, and more preferably contains the water of 1%～3% volume of having an appointment.It is about 0.9～2 that the mol ratio of yellow soda ash and neodicoumarin acid is preferably, more preferably about 1.0～1.3, to guarantee the productive rate and the quality of final product.The preparation of tintorane 2-propyl alcohol clathrate is preferably carried out to the temperature of about solvent boiling point in about room temperature.More preferably, be reflected under the reflux temperature and carry out.Reaction is typically finished in about 1～5 hour time, more preferably finishes in about 2～3 hours.In preferred embodiments, the solid filtering of mainly being made up of unreacted carbonic acid sodium that still keeps after reaction is finished is removed.Remove with the azeotropic distn of two components or three component system and to anhydrate.Preferred two component component distillation system is 2-propyl alcohol-water.Preferred three component component distillation systems are 2-propyl alcohol-hexanaphthene-water, 2-propyl alcohol-hexane-water or 2-propyl alcohol-heptane-water, preferred 2-propyl alcohol-hexane-water.Pure neodicoumarin acid 2-propyl alcohol clathrate goes out with the pure solid precipitation of crystalline from reaction mixture, it is filtered collect.
On the other hand, the present invention is a kind of by pure neodicoumarin acid and salt of wormwood (replacement yellow soda ash) reaction being prepared the method for Warfarin Potassium salt.The reaction parameter of formation sylvite is similar to formation tintorane 2-propyl alcohol clathrate.
On the other hand, the present invention is a kind of method for preparing neodicoumarin lithium 2-propyl alcohol clathrate, comprises pure neodicoumarin acid and the solution reaction of 2-lithium propoxide in anhydrous 2-propyl alcohol.Its preferred reaction parameter, though must use anhydrous 2-propyl alcohol, other parameters are similar to preparation tintorane 2-propyl alcohol clathrate.
Also have an aspect, the present invention be a kind of comprise with pure neodicoumarin acid and yellow soda ash water can miscible polar solvent rather than the 2-propyl alcohol in the method for preparing tintorane of reacting.Preferably, with water can miscible polar solvent be acetone, ethanol, acetonitrile or butanone, and butanone most preferably.Desolvate or add low polar solvent such as hexane, heptane or suberane are collected pure tintorane by removing.
Succeed by the synthetic pure neodicoumarin acid of providing convenience on the basis that the present invention formerly makes great efforts to fail.The present invention is superior especially providing from pure neodicoumarin acid aspect the neodicoumarin derivative: it can directly use these derivatives and needn't additional purification.
The invention solves the previous not problem of understanding, a kind of method for preparing pure neodicoumarin acid is provided, described pure neodicoumarin can prepare high-quality salt and clathrate, and needn't additional purification.
The present invention provides the method for a kind of improved synthetic neodicoumarin acid and derivative thereof with many proven technique, and comprising provides a kind of neodicoumarin acid for preparing the pure shape that is not easy to obtain with existing method and needn't additional purification.
The previous not advantage of understanding that the present invention has is, more effectively synthesis of high purity neodicoumarin an alkali metal salt and clathrate.
The advantage that the present invention has is, the shape of the neodicoumarin acid of preparation is big crystallization, and this is easier to filter, and is easy to drying, shortens time of drying.
The present invention has satisfied easily, industrial synthetic pure effectively neodicoumarin acid reaches and prepares the long-term needs of its sodium salt, sylvite and lithium salts and clathrate by it.
Detailed description of the present invention
When describing the preferred embodiments of the invention, for clarity sake used concrete term.But the present invention does not plan to be limited in the selected concrete term.All reference of here being quoted all are cited as a reference, just as their each piece of writing is quoted as a reference separately.
" pure " just as used herein refers to a kind of at least a material that meets at least in American Pharmacopeia (USP), British Pharmacopoeia, these standards of European Pharmacopoeia (Ph.Eur).EPCRS refers to European reference material committee of pharmacopeia, and USPRS refers to United States Pharmacopoeia Reference Standards.EPCRS and USPRS all provide the reference standard of tintorane and neodicoumarin acid.
The non-limitative example of the non-polar solvent that is suitable for comprises aliphatic hydrocarbon and aromatic hydrocarbon, for example hexane, heptane, hexanaphthene, toluene and benzene, and toluene is particularly preferred.
The non-limitative example of the solvent that water is miscible comprises lower molecular weight alcohols (methyl alcohol, ethanol, Virahol, or the like), acetonitrile, ketone (acetone, butanone, or the like), and ethers (tetrahydrofuran (THF), 1, the 4-dioxane, or the like).
Deep research proves, is used to prepare the purity of the neodicoumarin acid of derivative, has a strong impact on for the quality of final neodicoumarin salt and as the purposes of APIs.Therefore, provide the pure neodicoumarin acid of a kind of preparation as key intermediate fully repeatably, industrial feasible method.
The method of the pure neodicoumarin acid of preparation according to the present invention comprises the following steps:
1) adopt currently known methods, in methyl alcohol under refluxing by the Michael reaction of 4 hydroxy coumarin at benzylidene-acetone, make the Methopyranorin derivative.
2) in butanone-water or acetone-water system, utilize the acidic catalyst hydrolysis of Methopyranorin, the acid of preparation crude product neodicoumarin.Preferred an acidic catalyst is the 4-toluenesulphonic acids.Preferred acid concentration is about 2%～10%, more preferably about 4%～6%.It is invalid being generally less than about 2% acid, then causes many impurity and can be uneconomic greater than 10～15%.Butanone and acetone can contain have an appointment 30%～60%, preferred about 40%～50% water.Reaction can carried out under the temperature from room temperature to the solvent refluxing temperature approximately.Preferably, reaction is carried out under reflux temperature.Though can adopt on the methodological principle of other preparation crude product neodicoumarin acid, the inventor finds that when preparing the acid of crude product neodicoumarin with this method, following method of purification is the most effective.
3) novelly prepare pure neodicoumarin acid with improvement, method is that the acid of crude product neodicoumarin is suspended in the solvent of low polarity, water immiscibility, dissolving and the acid of extraction neodicoumarin make it to enter alkaline aqueous phase with neodicoumarin salt, separate, with optional this alkaline aqueous solution that filters, with the low-grade alkane alcohol dilution, this preferably carries out more than room temperature subsequently.The immiscible solvent of this low polar water preferably is non-chlorating, most preferably is toluene.This basic solution is the dilute alkaline soln aqueous solution of sodium hydroxide for example preferably.Preferred low-grade alkane alcohol solvent is the 2-propyl alcohol, though for example methyl alcohol, ethanol also can use other low-grade alkane alcohols.Preferably filter pure crystalline neodicoumarin acid is separated by the material that will be settled out.The acid that is used to precipitate neodicoumarin acid can be the aqueous acids that is selected from hydrochloric acid, sulfuric acid, phosphoric acid or the like.Sulfuric acid is preferred.
Shockingly find already, the deposition condition of the diluting condition of the aqueous solution of salt and the neodicoumarin acid of having purified, sour but needn't carry out expensive time-consuming additional purification to obtaining the high purity neodicoumarin, all be helpful.After the aqueous solution of neodicoumarin salt being separated and filters, preferably in room temperature or to be higher than the dilution of carrying out under the room temperature of the aqueous solution being carried out with low-grade alkane alcohol be strict.Therefore, before adding acid, solution stirring, preferably about 25 ℃～60 ℃, more preferably under about 40 ℃～50 ℃ temperature, carry out.With low-grade alkane alcohol, preferably the 2-propyl alcohol is in room temperature or be higher than under the room temperature and add.Though the quantity of alcohol is not strict, the solution of gained preferably contains 30%～60% the Virahol of having an appointment, and more preferably contains the Virahol between about 40% to about 50%, to prevent the loss of pure neodicoumarin acid.Then acid is added to the about 2-5 of pH in room temperature in being higher than under the room temperature.In room temperature or be higher than that to precipitate under the room temperature be crucial, it causes neodicoumarin acid to produce with high purity and big crystallization.
Add after the acid, with suspension in room temperature or be higher than under the room temperature and stir.Be lower than room temperature by suspension is cooled to, preferably to about 5 ℃～10 ℃, and further promote precipitation, filter by the material that will be settled out then and pure crystalline neodicoumarin acid separated.
The invention still further relates to and prepare the method that pure neodicoumarin derivative comprises its salt and clathrate thereof.The neodicoumarin derivative specifically comprises tintorane, tintorane 2-propyl alcohol clathrate, Warfarin Potassium salt and the neodicoumarin lithium 2-propyl alcohol clathrate that derives from above-mentioned pure neodicoumarin acid.It will be understood that according to the present invention, other ionic neodicoumarin salt can make, and the clathrate that contains other solvents except that the 2-propyl alcohol can make.
These methods comprise:
1) tintorane is by making pure neodicoumarin acid and excess of sodium carbonate backflow in polar solvent such as acetone or butanone, and solvent can be anhydrous, or contains about 1%～10% water.Unreacted yellow soda ash is preferably removed by filtration.Product, or by adding non-polar solvent for example hexane, hexanaphthene, heptane etc. and salt is settled out, separates sedimentation and filtration and drying to doing by evaporating solvent.
2) tintorane 2-propyl alcohol clathrate is by making pure neodicoumarin acid and equivalent or excess of sodium carbonate backflow in the 2-propyl alcohol.The 2-propyl alcohol can be to have an appointment 0.5%～10% anhydrous maybe can containing, and preferably contains about 1%～3% water.The ratio of yellow soda ash and neodicoumarin acid is between about 0.9 and about 2, preferably between about 1.0 and about 1.3.Be reflected in the temperature range from room temperature to solvent boiling point and carry out, the time is from about 1 hour to about 5 hours.Preferably, this is reflected under the reflux temperature and carries out, and the preferred reaction time is from about 2 hours to about 3 hours.Unreacted yellow soda ash is with removing by filter, and excessive water is removed with binary (2-propanol/water) or ternary (heptane, hexanaphthene or preferred hexane are with 2-propyl alcohol and water) component distillation.The pure tintorane 2-propyl alcohol clathrate that is settled out is by filtering and dry and further separated with pure crystalline solid.
3) Warfarin Potassium salt salt is by making pure neodicoumarin acid and salt of wormwood backflow in the 2-propyl alcohol.Those of reaction conditions and preparation tintorane 2-propyl alcohol clathrate are similar.But, when preparation sylvite, do not generate clathrate.With method of cooling this salt directly is settled out from reaction medium, and adopts to filter it is separated with dry.
4) neodicoumarin lithium 2-propyl alcohol clathrate reacts in the 2-propyl alcohol by the 2-lithium propoxide (making in the original place with lithium bar or lithium rod) that pure neodicoumarin is sour and excessive slightly and makes.By cooling, precipitation, filtration and the dry product of isolating.
Concerning the method for having described, can change some reaction conditionss, and this can produce some Different Results.It may be the characteristic that preferred some condition variation is change time and temperature, stirring extent and reaction vessel.For any special equipment of supplying and desirable each the finished product, these changes can be studied again.Be provided with for special laboratory, the change method can decide by normal experiment with optimal conditions.Concerning the person skilled in the art,, can be conspicuous to these methods according to instruction of the present invention.
The neodicoumarin derivative that makes according to the present invention can be made pharmaceutical dosage form with suitable pharmaceutically acceptable carrier or thinner.If it is suitable, pharmaceutical dosage form can be mixed with various preparations with usual method, they include but not limited to solid, semisolid, liquid or gas shape, for example sheet, capsule, pulvis, particle, ointment, solution, suppository, injection liquid, inhalation and aerosol are to adapt to their route of administration separately.The prior art known method can adopt, and is released or is absorbed before arriving destination organization to prevent it, or guarantee that this pharmaceutical composition discharges on time.Should adopt the pharmaceutically acceptable shape that can not make the present composition invalid.Aspect pharmaceutical dosage form, these compositions can use separately, also can cooperate suitably with the other drug active compound and make up.
In order to explain the present invention and its special purposes, following indefiniteness embodiment is provided, they explain the present invention, but do not limit its four corner.
Embodiment
Embodiment 1: the preparation of pure neodicoumarin acid
Whole two-step reaction and the method for purification that begins from the Methopyranorin methyl ether below described.
A. Methopyranorin hydrolysis crude product neodicoumarin acid
Methopyranorin methyl ether (1720g before made in methyl alcohol with the 1.2kg benzylidene-acetone by currently known methods, productive rate 72%) is added in butanone (6.5L) solution that contains 4-toluenesulphonic acids monohydrate (170g).Add entry (4L), and with this mixture stir about 4 hours under refluxing.
Then this reaction soln is concentrated into half of volume originally with butanone/water azeotropic distn, therein, the acid of crude product neodicoumarin begins precipitation.Suspension is cooled off gradually, through filtering and with suddenly ketone with the crude product neodicoumarin acid that obtains wetting after washing.
Output: count 1320-1390g (counting 80-85%) with butt with Methopyranorin.(this wet thing contains about 15-25% moisture content, is directly used in next step).
The physical properties of this crude product neodicoumarin acid is equal to real sample (neodicoumarin acid USP standard).
B. by the pure neodicoumarin acid of crude product neodicoumarin acid system
Crude product (wetting) the neodicoumarin acid that derives from embodiment 1 is added in the toluene (5.5L), this mixture is at room temperature stirred till obtaining unit for uniform suspension.Then 5% sodium hydroxide solution (about 4L) is added in the suspension that is stirred till reaching alkaline pH and obtaining almost limpid two phase liquid.Stop to stir and making it layering.Water below the suction filtration discards top organic phase.
To contain water filtered fluid returns in the molten device and slowly is heated to 40-50 ℃.Add 2-propyl alcohol (4L) and this solution stirring 1/2 hour is kept original temperature simultaneously.
A at leisure subsequently part adds sulfuric acid (20% aqueous solution) in solution heat, that be stirred, up to reaching the constant acid ph value.Need about 1.5～2L sulphuric acid soln altogether, and pure neodicoumarin acid simultaneously goes out with brilliant white crystalline solid precipitation.
With heavy-gravity suspension restir 1/2 hour, be cooled to then be lower than 10 ℃ another hour.
Filter this cold suspension, thoroughly wash, at last with cold 2-propyl alcohol washing with deionized water.
In vacuum oven, after dry 8-10 hour, obtain pure neodicoumarin acid with white crystalline powder.
Output: 1250-1300g (counting 90-95%) with the acid of crude product neodicoumarin
M.P: 159.6-161.2 ℃ (161 ℃ of literature values)
Limpid degree and color: transparent and almost colourless.
Be absorbed in the color that the 385nm place surveys with UV(the 10%W/V solution in 1NNaOH):＜0.30AU.
Related substances(TLC): do not detect.
The physical properties of product is identical with neodicoumarin acid USPRS.
Embodiment 2: the preparation of tintorane
Toward mechanical stirrer is housed, temperature is taken into account in the three neck round-bottomed flasks of backflow/distiller condenser, adds pure neodicoumarin acid (308g, 1 mole) continuously, yellow soda ash (Merck project 106398) (106g, 1 mole) and butanone (MEK, CP, 3100ml).
With mixture reflux 8 hours under agitation, be cooled to room temperature then and filter.
Clear solution is returned flask, distill and make solvent volume reduce to 1/3 of initial volume.
Residue in the flask adds heptane (3100ml) for a at leisure part, and this mixture is restir 4 hours at room temperature.
With the suction filtration method tintorane is separated with white powder, washing also is dried to constant weight under 35-40 ℃ and 1mmHg in vacuum oven.
Output: 298g (90%)
Basic solution
Limpid degree: limpid and colourless (meeting Ph.Eur and USP).
Survey with the UV absorption
Color(phenol ketone):＜0.1AU (meeting Ph.Eur and USP).
The pH:7.86 of 1% aqueous solution (meeting Ph.Eur and USP)
Related substances(using TLC): be not more than for 0.1% (meeting Ph.Eur and USP)
Identify: identical with tintorane EPCR standard.
Embodiment 3: the preparation of tintorane
As top embodiment 2, but use pure neodicoumarin acid (0.1 mole) and hexane (300ml) to replace heptane.
Output: 29g (88%)
Limpid degree, color (using UV) and related substances be identical with top embodiment 2
pH：7.8
Analyze: identical with the EPCR standard.
Embodiment 4: the preparation of Warfarin Potassium salt
In suitable glass flask, under nitrogen atmosphere, will (the CP level, 160ml) mixture of the pure neodicoumarin acid in (31g, 0.1 mole) and salt of wormwood (99%) (10.4g, 0.75 mole) stirs 2 hours down at 20-25 ℃ at the 2-propyl alcohol.
With suction method not limpid solution is filtered, filtrate being cooled to is lower than 5 ℃ and reaches 4-6 hour.
With nitrogen pressure the solid carefulness that is settled out is leached, with cold 2-propyl alcohol washing, and vacuum oven (40-50 ℃ 10mmHg) dry 6-8 hour, obtains white water absorbability crystalline solid Warfarin Potassium salt.
Output: 24.3g (70%)
Identify(adopting IR, contrast neodicoumarin acidity scale standard): meet
The potassium check: the positive
1 The H-NMR check: its spectrogram is in fact identical with Warfarin Potassium salt-EPCRs.
Heat is analyzed(using DSC): do not observe solvent and discharge the heat absorption (opposite) that causes with tintorane 2-propyl alcohol clathrate.
1The data of H-NMR and DSC are strong to be shown, Warfarin Potassium salt does not generate clathrate with the 2-propyl alcohol.
Embodiment 5: the preparation of neodicoumarin lithium 2-propyl alcohol clathrate
(0.42g, 0.06at.-g) (CP is anhydrous, 10ml) reaction and make the 2-propanol solution of 2-lithium propoxide with excessive-propyl alcohol by the lithium rod.In nitrogen atmosphere, this solution is dropwise added in the pure neodicoumarin acid in 2-propyl alcohol (60ml) (15.4g, the 0.05 mole) suspension that is stirred.
This clear solution at room temperature stirred 2 hours, till solid part is settled out.
Suspension is cooled to about 0 ℃ again reaches 4 hours, under nitrogen pressure,, wash with cold 2-propyl alcohol with the careful filtration of white solid precipitation, and (40-50 ℃ of vacuum oven, 10mmHg) dry 8-12 hour, obtain the pure neodicoumarin lithium of the powder 2-propyl alcohol clathrate of white crystals.
Output: 15g (80.2%)
Identify(using IR, contrast neodicoumarin acidity scale standard): meet
1 The H-NMR check: its figure is identical with real tintorane clathrate sample in fact, but show with respect to the proton integer of methyl, and IPA such as is at a molar content in clathrate.
IPA content(using GC): 15.1%
Heat is analyzed(using DSC): typical heat absorbing type and with observed similar 160 ℃ of appearance of the sour sodium 2-of real neodicoumarin propyl alcohol inclusion polymerization matter sample, shows to have clathrate.
Embodiment 6: the preparation of tintorane 2-propyl alcohol clathrate
In the suitable glasses container that distillation column and level part separator are housed, and the pure neodicoumarin acid of packing into (1000g, 3.25 moles), yellow soda ash (cp, 260g, 2.45 moles) and 2-propyl alcohol (technical grade, 5000ml).
This mixture heating up is reached 2 hours to refluxing, be cooled to room temperature then.
Add demineralization water (500ml), and at room temperature this reaction mixture was stirred 1/2 hour, be cooled to and be lower than 10 ℃, and suction filtration rapidly.
This limpid colourless solution is returned container, add hexane (1500ml), and this mixture under agitation is heated to boiling.
Ternary azeotropic compositions begins to be steamed, and water is removed from mixture gradually, and its distillation method of boiling is removed hexane with binary then, and tintorane 2-propyl alcohol clathrate is settled out.
With the solution suction strainer, solid washs with cold 2-propyl alcohol, and (vacuum oven, 10mmHg), obtained the pure products of white crystals by 45-50 ℃ in dry about 8 hours.
Output: 1030g (88%)
1% solution
PH: 8.25
Water(using the KF method): less than 0.1%
IPA content(using GC): 8.15%
Alkaline solution
Limpid degree: meet the requirements
Color(using the UV method):＜0.1AU
Related substances(TLC): do not detect
Product meets the pharmacopeia requirement.
Embodiment 7: the preparation of tintorane 2-propyl alcohol clathrate
In the suitable glasses container that distillation column is housed, add continuously the 2-propyl alcohol (technical grade, 7.7L), pure neodicoumarin acid (1.54kg, 5 moles), yellow soda ash (0.34kg, 3.2 moles) and demineralization water (0.22L).
Under agitation this mixture was refluxed 2 hours.
Stop heating then, and the mixture that this is hot filters rapidly.This limpid hot filtrate is returned in the container, the solution heating is stirred simultaneously, slowly remove under high reflux ratio with the binary azeotropic distillation method and anhydrate.The solvent removed of distillation is replaced by adding the 2-propyl alcohol, suspended substance restir hour or two hours under refluxing.
Stop heating, mixture is cooled to gradually is lower than 10 ℃.Leach solid, with cold solvent washing, and vacuum oven (45-50 ℃, 10mmHg) in dry 6-10 hour, the pure tintorane 2-of the powder propyl alcohol clathrate of white crystals.
Output: 1.5kg (83%)
1% solution
PH: 8.3
Basic solution
Limpid degree: meet the requirements
Color(using UV):＜0.1AU
Water(using the KF method): be not more than 0.1%
IPA content(using GC): 8.2%
Related substances(TLC): do not detect
Analyze: meet the pharmacopeia requirement
Embodiment 8: the preparation of tintorane 2-propyl alcohol clathrate
In the suitable glasses flask that distillation column is housed, add the 2-propyl alcohol (8L, technical grade or regenerant), yellow soda ash (CP, 175g, 1.16 moles) and the pure neodicoumarin acid (1kg, 3.25 moles) that contain about 1%～2% water (V/V).
This mixture is under agitation heated and refluxed 2 hours.
This not clear solution place and to be cooled to about 30 ℃ and suction filtration rapidly.
The filtered liquid that this is almost colourless returns flask, restarts heating, and the component distillation of beginning 2-propanol/water, and this distillation proceeds to the volume of material in the flask and reaches the about 1/3 of initial volume, obtains heavy-gravity suspension.
This suspension is cooled to is lower than 10 ℃, (embodiment 4-5) handles as mentioned above, obtains required pure tintorane 2-propyl alcohol clathrate with the solid of white crystals.
Output: 995g (85%)
1% solution
PH: 7.9-8.0
Basic solution
Limpid degree: meet the requirements
Color(using the UV method): less than 0.1AU
Water(using the KF method): 0.1%
Related substances(using TLC): do not detect
Analyze: meet the pharmacopeia requirement.
The embodiment that illustrates in this manual and discuss only is intended to instruct the use best method of the present invention known to the those skilled in the art inventor.Be considered to limit the scope of the invention without any thing in this manual.All implementation columns all are representational and nonrestrictive.Above-mentioned embodiment of the present invention can be improved or change, and its key element can add and can subtract, but does not all leave the present invention, because those skilled in the art all will appreciate that after according to above-mentioned instruction.Therefore should be understood that in the scope of claim and equivalent thereof that the present invention can also other modes implement except as describing especially.
Claims (48)
1. method for preparing pure neodicoumarin acid, it comprises the following steps:
(a) provide the crude product neodicoumarin acid that is suspended in the water immiscible solvent,
(b) water immiscible solvent is merged mutually with alkaline water,
(c) acid of crude product neodicoumarin is extracted into alkaline aqueous phase with the form of neodicoumarin salt,
(d) from the water immiscible solvent, isolate water,
(e) dilute water with low-grade alkane alcohol,
(f) water that will dilute with aqueous acids/low-grade alkane alcohol phase acidifying is to generate the suspension of pure neodicoumarin acid.
2. according to the method for claim 1, also comprise and after water immiscible solvent is isolated water, water being filtered.
3. according to the process of claim 1 wherein the aqueous phase as acidified that to have diluted under the temperature of room temperature being higher than.
4. according to the method for claim 1, also comprise suspension refrigerative with pure neodicoumarin acid.
5. according to the method for claim 1, also comprise pure neodicoumarin acid is filtered.
6. according to the process of claim 1 wherein that water immiscible solvent is a toluene.
7. according to the process of claim 1 wherein that alkaline water is a dilute sodium hydroxide.
According to the process of claim 1 wherein water be heated to before the low-grade alkane alcohol dilution from about 20 ℃ to about 60 ℃ temperature.
According to the process of claim 1 wherein water be heated to before the low-grade alkane alcohol dilution from about 40 ℃ to about 60 ℃ temperature.
10. according to the process of claim 1 wherein that low-grade alkane alcohol is added to about 50% concentration.
11. according to the process of claim 1 wherein that low-grade alkane alcohol is selected from a group of being made up of methyl alcohol, ethanol and 2-propyl alcohol.
12. according to the process of claim 1 wherein that low-grade alkane alcohol is the 2-propyl alcohol.
13. according to the process of claim 1 wherein that aqueous acids is selected from a group of being made up of hydrochloric acid, sulfuric acid and phosphoric acid.
14. according to the process of claim 1 wherein that aqueous acids is a sulfuric acid.
15. according to the method for claim 4, the suspension of wherein pure neodicoumarin acid is cooled to and is lower than room temperature.
16. according to the process of claim 1 wherein the suspension of pure neodicoumarin acid be cooled between about 5 ℃ to about 10 ℃ temperature.
17. according to the process of claim 1 wherein that the acid of crude product neodicoumarin prepares with the method that comprises the following steps:
An acidic catalyst is being added to the temperature of about solvent boiling point from about room temperature among Methopyranorin containing up to the solution in the miscible solvent of the water of about 50% water.
18. according to the method for claim 17, wherein an acidic catalyst is the 4-toluenesulphonic acids.
19. according to the method for claim 17, wherein the miscible solvent of water is butanone or acetone.
20. a method for preparing pure neodicoumarin salt and clathrate thereof comprises the following steps: the pure neodicoumarin acid that the method according to claim 1 makes is reacted in non-aqueous solvent with metal carbonate, and
Remove unreacted metal carbonate.
21. according to the method for claim 20, wherein non-aqueous solvent contains about 0.5%～10% water.
22. according to the method for claim 20, wherein non-aqueous solvent contains the water of about 0.5%～5% volume.
23. according to the method for claim 20, wherein non-aqueous solvent contains the water of about 1%～3% volume.
24. according to the method for claim 20, wherein the ratio of the molar equivalent of metal carbonate and neodicoumarin acid is about 0.9～2.
25. according to the method for claim 20, wherein the ratio of the molar equivalent of metal carbonate and neodicoumarin acid is about 1.0～1.3.
26. according to the method for claim 20, it also comprises pure neodicoumarin salt or the sedimentary step of its clathrate.
27. according to the method for claim 26, wherein pure neodicoumarin salt is precipitated by with azeotropic distn solvent being removed.
28. according to the method for claim 20, wherein pure neodicoumarin salt is selected from the non-polar solvent of a group of being made up of hexane, hexanaphthene and heptane by adding and is precipitated.
29. according to the method for claim 27, wherein this salt is precipitated by the azeotropic distn of the ternary azeotropic compositions of water, 2-propyl alcohol and hydrocarbon, and this hydrocarbon is selected from a group of being made up of hexane, heptane and hexanaphthene.
30. according to the method for claim 20, wherein neodicoumarin salt is tintorane, metal carbonate is a yellow soda ash, and non-aqueous solvent is selected from a group of being made up of ethanol, acetonitrile, acetone and butanone.
31. according to the method for claim 20, wherein neodicoumarin salt is Warfarin Potassium salt, metal carbonate is a yellow soda ash, and non-aqueous solvent is the 2-propyl alcohol.
32. according to the method for claim 20, wherein neodicoumarin salt clathrate is a tintorane 2-propyl alcohol clathrate, metal carbonate is a yellow soda ash, and non-aqueous solvent is the 2-propyl alcohol.
33. a method for preparing pure neodicoumarin lithium 2-propyl alcohol clathrate comprises following step: will react in anhydrous 2-propyl alcohol with the 2-lithium propoxide according to the pure neodicoumarin acid of claim 1 preparation.
34. the neodicoumarin acid of the following step preparation:
(a) provide the crude product neodicoumarin acid that is suspended in the water immiscible solvent,
(b) this suspension is merged mutually with alkaline water,
(c) neodicoumarin acid is extracted into aqueous phase with the form of neodicoumarin salt,
(d) isolate water,
(e) dilute water with low-grade alkane alcohol,
(f) water that will dilute with aqueous acids/low-grade alkane alcohol phase acidifying is to generate the suspension of pure neodicoumarin acid.
35. the pure neodicoumarin acid of claim 34, wherein this preparation also comprises: before with the low-grade alkane alcohol dilution water is filtered.
36. the pure neodicoumarin acid of claim 34 wherein with before the low-grade alkane alcohol dilution, is heated to room temperature with water or is higher than the temperature of room temperature.
37. the pure neodicoumarin acid of claim 34, wherein this preparation also comprises the suspension cooling with pure neodicoumarin acid.
38. the pure neodicoumarin acid of claim 34, wherein this preparation also comprises pure neodicoumarin acid filtration.
39. the pure neodicoumarin acid of claim 34, it is in to have than pharmacopeia and requires more highly purified form.
40. a method for preparing pure neodicoumarin acid comprises:
The step of the suspension of preparation crude product neodicoumarin acid in water immiscible solvent,
Will be in the isolated step of neodicoumarin salt of alkaline aqueous phase,
The step that water is separated,
With the step of low-grade alkane alcohol dilution water,
Generate the step of pure neodicoumarin acid suspension by the water/low-grade alkane alcohol phase acidifying that will dilute with aqueous acids, and
Obtain the step of pure neodicoumarin acid from suspension.
41. according to the method for claim 40, wherein the step that obtains pure neodicoumarin acid from suspension comprises the step that obtains cold suspension.
42., also be included in before the step of water dilution, with the filtering step of water according to the method for claim 40.
43. the pure neodicoumarin acid that makes with the following step:
(a) acid of crude product neodicoumarin is suspended in the toluene,
(b) acid of crude product neodicoumarin is gone among the dilute sodium hydroxide aqueous solution with the neodicoumarin salt extraction,
(c) separate this aqueous solution,
(d) this aqueous solution is heated to from about 20 ℃ to about 60 ℃ temperature,
(e) with the 2-propyl alcohol water is diluted to from about 40% concentration to about 50%2-propyl alcohol, and simultaneously holding temperature from about 20 ℃ to about 60 ℃, and
(f) from about 20 ℃ to about 60 ℃ temperature, with sulfuric acid 2-propanol/water solution is acidified to constant pH, generate the suspension of pure neodicoumarin acid.
44. the pure neodicoumarin acid of claim 43, wherein this preparation also comprises the following steps:
(g) this suspension is cooled to is lower than about 10 ℃ temperature, and
(h) pure neodicoumarin acid is filtered.
45. a method for preparing medicinal neodicoumarin acid supplement comprises:, prepare pure neodicoumarin acid from the acid of crude product neodicoumarin by using the method that comprises the following steps:
(a) provide the crude product neodicoumarin acid that is suspended in the water immiscible solvent,
(b) water immiscible solvent is merged mutually with alkaline water,
(c) acid of crude product neodicoumarin is extracted into alkaline aqueous phase with the form of neodicoumarin salt,
(d) from the water immiscible solvent, isolate water,
(e) dilute water with low-grade alkane alcohol,
(f) water that will dilute with aqueous acids/low-grade alkane alcohol phase acidifying is to generate the suspension of pure neodicoumarin acid;
Change pure neodicoumarin acid into pharmaceutically acceptable neodicoumarin derivative; And preparation contains the medicine neodicoumarin formulation of this neodicoumarin derivative.
46. the method for claim 45, wherein pharmaceutically acceptable neodicoumarin derivative are selected from a group of being made up of neodicoumarin salt and clathrate.
47. the method for claim 46, wherein neodicoumarin salt and clathrate contain at least a neodicoumarin salt or the clathrate that is selected from a group of being made up of Warfarin Potassium salt, tintorane, tintorane 2-propyl alcohol clathrate, neodicoumarin lithium and neodicoumarin lithium 2-propyl alcohol clathrate.
48. the method for claim 45, wherein formulation is selected from a group of being made up of tablet, capsule, geltabs, pulvis, particle, solution and suspension.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US27173701P | 2001-02-28 | 2001-02-28 | |
| US60/271,737 | 2001-02-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1505620A true CN1505620A (en) | 2004-06-16 |
Family
ID=23036855
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA018231594A Pending CN1505620A (en) | 2001-02-28 | 2001-12-28 | Process for purification of warfarin acid, warfarin alkali metal salts and corresponding clathrates |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP1363893A1 (en) |
| CN (1) | CN1505620A (en) |
| BR (1) | BR0116919A (en) |
| CA (1) | CA2439488A1 (en) |
| IL (1) | IL157555A0 (en) |
| MX (1) | MXPA03007769A (en) |
| RU (1) | RU2003129000A (en) |
| WO (1) | WO2002070503A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109369450A (en) * | 2018-10-31 | 2019-02-22 | 江苏省农用激素工程技术研究中心有限公司 | The refining methd of tralkoxydim |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011143747A1 (en) * | 2010-05-20 | 2011-11-24 | Apotex Pharmachem Inc. | Polymorphic forms of warfarin potassium and preparations thereof |
| WO2011145007A1 (en) | 2010-05-20 | 2011-11-24 | Alembic Pharmaceuticals Limited | A process for the preparation of amorphous warfarin sodium |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2777859A (en) * | 1953-02-05 | 1957-01-15 | Wisconsin Alumni Res Found | Warfarin-alkali metal derivatives and processes of preparing the same |
| US2765321A (en) * | 1955-05-27 | 1956-10-02 | Wisconsin Alumni Res Found | Process of making crystalline warfarin sodium |
| FR1397213A (en) * | 1963-05-14 | 1965-04-30 | Frosst & Co Charles E | New method of preparing warfarin sodium |
| US4113744A (en) * | 1974-08-13 | 1978-09-12 | Nasri W. Badran | Microcrystalline 3-(alpha-acetonylbenzyl)-4-hydroxycoumarin (warfarin) and methods of making |
| US4826689A (en) * | 1984-05-21 | 1989-05-02 | University Of Rochester | Method for making uniformly sized particles from water-insoluble organic compounds |
| US5696274A (en) * | 1995-12-28 | 1997-12-09 | Hoechst Celanese Corporation | Syntheses based on 2-hydroxyacetophenone |
-
2001
- 2001-12-28 CA CA002439488A patent/CA2439488A1/en not_active Abandoned
- 2001-12-28 IL IL15755501A patent/IL157555A0/en unknown
- 2001-12-28 CN CNA018231594A patent/CN1505620A/en active Pending
- 2001-12-28 EP EP01985145A patent/EP1363893A1/en not_active Withdrawn
- 2001-12-28 MX MXPA03007769A patent/MXPA03007769A/en unknown
- 2001-12-28 RU RU2003129000/04A patent/RU2003129000A/en unknown
- 2001-12-28 WO PCT/US2001/050438 patent/WO2002070503A1/en not_active Application Discontinuation
- 2001-12-28 BR BR0116919-0A patent/BR0116919A/en not_active IP Right Cessation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109369450A (en) * | 2018-10-31 | 2019-02-22 | 江苏省农用激素工程技术研究中心有限公司 | The refining methd of tralkoxydim |
| CN109369450B (en) * | 2018-10-31 | 2021-07-27 | 江苏省农用激素工程技术研究中心有限公司 | Refining method of tralkoxydim |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2002070503A1 (en) | 2002-09-12 |
| MXPA03007769A (en) | 2005-07-01 |
| EP1363893A1 (en) | 2003-11-26 |
| RU2003129000A (en) | 2005-05-10 |
| IL157555A0 (en) | 2004-03-28 |
| BR0116919A (en) | 2004-10-13 |
| CA2439488A1 (en) | 2002-09-12 |
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