KR20030014222A - 클라불란산의 염의 정제 방법 - Google Patents
클라불란산의 염의 정제 방법 Download PDFInfo
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- KR20030014222A KR20030014222A KR1020027015169A KR20027015169A KR20030014222A KR 20030014222 A KR20030014222 A KR 20030014222A KR 1020027015169 A KR1020027015169 A KR 1020027015169A KR 20027015169 A KR20027015169 A KR 20027015169A KR 20030014222 A KR20030014222 A KR 20030014222A
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- KR
- South Korea
- Prior art keywords
- salt
- clavulanic acid
- amine
- acid
- medium
- Prior art date
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- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 title claims abstract description 136
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 title claims abstract description 129
- 229960003324 clavulanic acid Drugs 0.000 title claims abstract description 121
- 150000003839 salts Chemical class 0.000 title claims abstract description 113
- 238000000034 method Methods 0.000 title claims abstract description 100
- 238000000746 purification Methods 0.000 title claims description 6
- -1 amine salts Chemical class 0.000 claims abstract description 68
- 239000012535 impurity Substances 0.000 claims abstract description 36
- 238000005406 washing Methods 0.000 claims abstract description 13
- 238000001953 recrystallisation Methods 0.000 claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- NDSQGOBLOMHGLG-UHFFFAOYSA-N 2-(2,5-dioxopyrrolidin-1-yl)-3-(4-hydroxyphenyl)propanoic acid Chemical group O=C1CCC(=O)N1C(C(=O)O)CC1=CC=C(O)C=C1 NDSQGOBLOMHGLG-UHFFFAOYSA-N 0.000 claims description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 40
- 239000002609 medium Substances 0.000 claims description 39
- 239000000047 product Substances 0.000 claims description 31
- 150000001412 amines Chemical class 0.000 claims description 30
- ABVRVIZBZKUTMK-JSYANWSFSA-M potassium clavulanate Chemical compound [K+].[O-]C(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 ABVRVIZBZKUTMK-JSYANWSFSA-M 0.000 claims description 30
- 239000003960 organic solvent Substances 0.000 claims description 23
- 229910052751 metal Inorganic materials 0.000 claims description 19
- 239000002184 metal Substances 0.000 claims description 19
- 239000008346 aqueous phase Substances 0.000 claims description 16
- 239000007788 liquid Substances 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 14
- 239000012071 phase Substances 0.000 claims description 13
- 239000002243 precursor Substances 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 9
- 238000000855 fermentation Methods 0.000 claims description 8
- 230000004151 fermentation Effects 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 238000001556 precipitation Methods 0.000 claims description 6
- 239000012467 final product Substances 0.000 claims description 5
- 239000012736 aqueous medium Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 239000012266 salt solution Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 244000005700 microbiome Species 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims 1
- 229910052783 alkali metal Inorganic materials 0.000 abstract description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
- 239000000243 solution Substances 0.000 description 29
- 229910052757 nitrogen Inorganic materials 0.000 description 23
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 22
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 18
- 229960000583 acetic acid Drugs 0.000 description 11
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 11
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 229940090805 clavulanate Drugs 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 150000002576 ketones Chemical class 0.000 description 6
- 238000000605 extraction Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- MFIGJRRHGZYPDD-UHFFFAOYSA-N n,n'-di(propan-2-yl)ethane-1,2-diamine Chemical compound CC(C)NCCNC(C)C MFIGJRRHGZYPDD-UHFFFAOYSA-N 0.000 description 5
- ZUFQCVZBBNZMKD-UHFFFAOYSA-M potassium 2-ethylhexanoate Chemical compound [K+].CCCCC(CC)C([O-])=O ZUFQCVZBBNZMKD-UHFFFAOYSA-M 0.000 description 5
- 239000012453 solvate Substances 0.000 description 5
- GTEXIOINCJRBIO-UHFFFAOYSA-N 2-[2-(dimethylamino)ethoxy]-n,n-dimethylethanamine Chemical compound CN(C)CCOCCN(C)C GTEXIOINCJRBIO-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 229910017604 nitric acid Inorganic materials 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 3
- 125000005233 alkylalcohol group Chemical group 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 150000004985 diamines Chemical class 0.000 description 3
- MGHPNCMVUAKAIE-UHFFFAOYSA-N diphenylmethanamine Chemical class C=1C=CC=CC=1C(N)C1=CC=CC=C1 MGHPNCMVUAKAIE-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- JGVZJRHAZOBPMW-UHFFFAOYSA-N 1,3-bis(dimethylamino)propan-2-ol Chemical compound CN(C)CC(O)CN(C)C JGVZJRHAZOBPMW-UHFFFAOYSA-N 0.000 description 2
- LRKYLKBLUJXTFL-UHFFFAOYSA-N 1-(piperidin-1-ylmethyl)piperidine Chemical compound C1CCCCN1CN1CCCCC1 LRKYLKBLUJXTFL-UHFFFAOYSA-N 0.000 description 2
- OBETXYAYXDNJHR-UHFFFAOYSA-N 2-Ethylhexanoic acid Chemical compound CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 2
- GAHCNYHAKKGGHF-UHFFFAOYSA-N 5,5-dimethylhexan-1-amine Chemical compound CC(C)(C)CCCCN GAHCNYHAKKGGHF-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 241000187747 Streptomyces Species 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Chemical class 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- SBOJXQVPLKSXOG-UHFFFAOYSA-N o-amino-hydroxylamine Chemical class NON SBOJXQVPLKSXOG-UHFFFAOYSA-N 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- UYMQPNRUQXPLCY-UHFFFAOYSA-N 1-(2-piperidin-1-ylethyl)piperidine Chemical compound C1CCCCN1CCN1CCCCC1 UYMQPNRUQXPLCY-UHFFFAOYSA-N 0.000 description 1
- LAIUFBWHERIJIH-UHFFFAOYSA-N 3-Methylheptane Chemical class CCCCC(C)CC LAIUFBWHERIJIH-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 239000003781 beta lactamase inhibitor Substances 0.000 description 1
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- ACYBVNYNIZTUIL-UHFFFAOYSA-N n'-benzylethane-1,2-diamine Chemical compound NCCNCC1=CC=CC=C1 ACYBVNYNIZTUIL-UHFFFAOYSA-N 0.000 description 1
- TXXWBTOATXBWDR-UHFFFAOYSA-N n,n,n',n'-tetramethylhexane-1,6-diamine Chemical compound CN(C)CCCCCCN(C)C TXXWBTOATXBWDR-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Cephalosporin Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyrane Compounds (AREA)
Abstract
Description
t-BA 용액의 결정화 pH | 칼륨 클라불라네이트 중 % 총 불순물(클라불라네이트 기준, HPLC에 의해) |
중성 (pH 7.0 - 7.5) | 2.03 |
pH 4.5 | 0.03 |
용해 pH | Kclav 중 총 불순물의 %(클라불라네이트 기준) |
6.8 | 0.87 |
6.5 | 0.92 |
6.0 | 0.63 |
5.5 | 0.57 |
5.0 | 0.13 |
5.0* | 0.11 |
t-BA 용액의 결정화 pH | t-BA 클라불라네이트 중 % N-숙시닐 티로신(클라불라네이트 기준, HPLC에 의해) |
중성 (pH 8.5) | 3.48 |
pH 4.5 | 0.03 |
용해 pH | Kclav 중 N-숙시닐 티로신의 %(클라불라네이트 기준) |
6.8 | 0.62 |
6.5 | 0.65 |
6.0 | 0.44 |
5.5 | 0.40 |
5.0 | 0.04 |
5.0* | 0.07 |
Claims (32)
- 클라불란산의 염을 pH가 6.5 미만인 액체 매질에 노출시키는 단계를 포함하는 방법.
- 제 1 항에 있어서, pH가 3.5 - 5.5인 방법.
- 제 1 항 또는 제 2 항에 있어서, pH 6.0 이하의 세척 매질로 염을 세척하는 방법.
- 제 3 항에 있어서, 염이 클라불란산의 아민 염인 방법.
- 제 4 항에 있어서, 이어서 아민 염을 클라불란산의 최종 생성물 약학적으로 허용가능한 염으로 전환시키는 방법.
- 제 3 항에 있어서, 세척되는 염이 클라불란산의 금속염인 방법.
- 제 3 항 내지 제 6 항 중 어느 한 항에 있어서, 세척 매질이 pH가 6.0 이하인 물과 수용성 유기 용매의 혼합물인 방법.
- 제 3 항 내지 제 7 항 중 어느 한 항에 있어서, 1종 이상의 불순물을 함유하는 클라불란산의 출발 염을 제공하고, 상기 염을 세척 매질로 세척하여 상기 1종 이상의 불순물의 수준이 낮은 클라불란산의 생성물 염을 제조하는 방법을 포함하는 방법.
- 제 3 항 내지 제 8 항 중 어느 한 항에 있어서, 클라불란산의 출발 염을 세척 매질로 세척함으로써 상기 클라불란산의 출발 염으로부터 1종 이상의 불순물을 제거하는 방법을 포함하는 방법.
- 제 1 항 또는 제 2 항에 있어서, 클라불란산의 염을 pH가 6.0 이하인 재결정화 매질로부터 재결정화시키는 방법.
- 제 10 항에 있어서, 클라불란산의 염이 클라불란산의 아민 염인 방법.
- 제 11 항에 있어서, 이어서 아민 염을 클라불란산의 최종 생성물 약학적으로 허용가능한 염으로 전환시키는 방법.
- 제 10 항, 제 11 항 또는 제 12 항 중 어느 한 항에 있어서, pH가 6.0 이하이거나 뒤에 pH 6.0 이하로 조정되는 수성 매질에 염을 용해시킨 후, 침전 용매와 혼합하여 재결정화시킴으로써 수용액으로부터 염을 분리시키는 방법.
- 제 10 항 내지 제 13 항 중 어느 한 항에 있어서, 1종 이상의 불순물을 함유하는 클라불란산의 출발 염을 제공하고, 상기 염을 재결정화 매질로부터 재결정화하여 상기 1종 이상의 불순물의 수준이 낮은 클라불란산의 생성물 염을 제조하는 방법을 포함하는 방법.
- 제 10 항 내지 제 14 항 중 어느 한 항에 있어서, 클라불란산의 출발 염을 재결정화 매질로부터 재결정화함으로써 상기 클라불란산의 출발 염으로부터 1종 이상의 불순물을 제거하는 방법을 포함하는 방법.
- 제 1 항 또는 제 2 항에 있어서, pH 6.0 이하의 액체 매질에서 클라불란산의 염을 제조하는 제조적 방법을 포함하는 방법.
- 제 16 항에 있어서, pH 6.0 이하의 액체 매질에서 클라불란산과 아민을 반응시켜 클라불란산의 아민 염을 제조하는 단계를 포함하는 방법.
- 제 18 항에 있어서, 클라불란산을 함유하는 유기 용매상, 및 아민 염을 추출하고 pH가 6.0 이하인 수성상으로 이루어진 2상계에서 수행하는 방법.
- 제 1 항 또는 제 2 항에 있어서, pH 6.0 이하의 액체 매질에서 클라불란산의아민 염과 금속염 전구체 화합물 사이의 반응에 의하여 클라불란산의 금속염이 생성물로 형성되는 제조적 방법을 포함하는 방법.
- 제 19 항에 있어서, 칼륨 클라불라네이트를 제조하는 방법.
- 제 19 항 또는 제 20 항에 있어서, pH가 6.0 이하이거나, 뒤에 이 pH로 조정되는, 수용성 유기 용매와 물의 혼합물 중의 아민 염 용액으로 수행하고, 금속염 전구체를 이 아민 염 용액에 첨가하는 방법.
- 제 1 항 내지 제 21 항 중 어느 한 항에 있어서, 발효액에서 형성된 미정제 클라불란산으로부터 칼륨 클라불라네이트를 제조하는 전체 방법의 일부분인 방법.
- 제 22 항에 있어서, (i) 클라불란산을 함유하는 수성액을 생성하는 미생물의 발효 단계, (ii) 클라불란산을 유기 용매 내로 추출하는 단계, (iii) 클라불란산을 클라불란산의 아민 염으로 전환하는 단계, (iv) 아민 염을 pH 6.0 이하, 특히 pH 5.5 이하에 노출시키는 단계, (v) 아민 염을 칼륨 클라불라네이트로 전환하는 단계를 포함하는 방법.
- 제 1 항 내지 제 18 항 중 어느 한 항에 따른 방법의 생성물인 클라불란산의 생성물 아민 염.
- 제 1 항 내지 제 3 항 또는 제 19 항 내지 제 23 항 중 어느 한 항에 따른 방법의 생성물인 칼륨 클라불라네이트.
- 제 8, 9, 14 또는 15 항 중 어느 한 항에 있어서, 상기 1종 이상의 불순물 중 하나가 N-숙시닐 티로신인 방법.
- N-숙시닐 티로신을 함유하거나, N-숙시닐 티로신으로 오염된 것으로 생각되는 클라불란산의 염을 N-숙시닐 티로신을 제거하는 조건에 두는 정제 방법.
- 제 27 항에 있어서, N-숙시닐 티로신을 파괴하는 시약을 함유하는 액체 매질에 염을 노출시키는 정제 방법.
- 제 27 항에 있어서, 고체 기질 내에 혼입되거나 그 위에 흡착된, N-숙시닐 티로신을 파괴하는 시약에 염을 노출시키는 정제 방법.
- N-숙시닐 티로신을 함유하거나, N-숙시닐 티로신으로 오염된 것으로 생각되는 클라불란산의 염을 액체 매질 중에 현탁시키거나 용해시키고, N-숙시닐 티로신을 흡수하여 염으로부터 N-숙시닐 티로신을 제거하는 물질에 노출시키는 정제 방법.
- N-숙시닐 티로신의 형성 및(또는) 클라불란산의 생성물 염 중 그 함유량을 최소화하도록 선택된 조건 하에서 클라불란산의 염을 제조하는 제조적 방법.
- 제 31 항에 있어서, N-숙시닐 티로신을 제거하는 시약을 함유하는 액체 매질 중에서, 또는 N-숙시닐 티로신을 제거하는 화학적 또는 물리적 조건에서 클라불란산의 염을 제조하는 방법.
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GB0011519.6 | 2000-05-13 | ||
GB0011519A GB0011519D0 (en) | 2000-05-13 | 2000-05-13 | Process |
GB0011521A GB0011521D0 (en) | 2000-05-13 | 2000-05-13 | Process |
GB0011521.2 | 2000-05-13 | ||
PCT/GB2001/002025 WO2001087891A1 (en) | 2000-05-13 | 2001-05-09 | Process for the purification of a salt of clavulanic acid |
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KR20030014222A true KR20030014222A (ko) | 2003-02-15 |
KR100827898B1 KR100827898B1 (ko) | 2008-05-07 |
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US (1) | US7767823B2 (ko) |
EP (1) | EP1284978B2 (ko) |
JP (1) | JP4954421B2 (ko) |
KR (1) | KR100827898B1 (ko) |
CN (1) | CN1222528C (ko) |
AT (1) | ATE273982T1 (ko) |
AU (1) | AU776184B2 (ko) |
BR (1) | BRPI0110774B8 (ko) |
CA (1) | CA2408853C (ko) |
CZ (1) | CZ304775B6 (ko) |
DE (1) | DE60105016T3 (ko) |
DK (1) | DK1284978T4 (ko) |
ES (1) | ES2225524T5 (ko) |
HK (1) | HK1055111A1 (ko) |
HU (1) | HU228593B1 (ko) |
IL (2) | IL152643A0 (ko) |
MX (1) | MXPA02011192A (ko) |
NO (1) | NO328528B1 (ko) |
NZ (1) | NZ522414A (ko) |
PL (1) | PL206316B1 (ko) |
PT (1) | PT1284978E (ko) |
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CA2408853C (en) | 2000-05-13 | 2012-01-10 | Smithkline Beecham P.L.C. | Process |
CN105384758B (zh) * | 2015-12-01 | 2018-05-01 | 国药集团威奇达药业有限公司 | 克拉维酸胺盐的制备方法 |
US10624899B2 (en) | 2016-07-14 | 2020-04-21 | Achaogen, Inc. | Combination products for the treatment of bacterial infections and methods of producing or dosing of same |
CN109305978A (zh) * | 2017-07-26 | 2019-02-05 | 山东睿鹰先锋制药有限公司 | 一种制备克拉维酸盐的新方法 |
CN109535184B (zh) * | 2017-09-21 | 2020-11-20 | 联邦制药(内蒙古)有限公司 | 一种克拉维酸叔辛胺制备克拉维酸钾的方法 |
CN108558909B (zh) * | 2018-05-17 | 2019-09-17 | 国药集团威奇达药业有限公司 | 综合回收克拉维酸叔丁胺盐结晶母液中有效成分的方法 |
CN114072493A (zh) | 2019-07-05 | 2022-02-18 | 葛兰素史密斯克莱知识产权(第2 号)有限公司 | 棒状链霉菌 |
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