JP2013503826A - 4’−エピダウノルビシンxHClの結晶化 - Google Patents
4’−エピダウノルビシンxHClの結晶化 Download PDFInfo
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- STQGQHZAVUOBTE-RPDDNNBZSA-N (7s,9s)-9-acetyl-7-[(2r,4s,5r,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 STQGQHZAVUOBTE-RPDDNNBZSA-N 0.000 title claims abstract description 128
- 238000002425 crystallisation Methods 0.000 title description 6
- 230000008025 crystallization Effects 0.000 title description 6
- 239000002904 solvent Substances 0.000 claims abstract description 163
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 131
- 239000000203 mixture Substances 0.000 claims abstract description 46
- 238000000034 method Methods 0.000 claims abstract description 34
- 150000001298 alcohols Chemical class 0.000 claims abstract description 19
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 239000011877 solvent mixture Substances 0.000 claims description 50
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 229940045799 anthracyclines and related substance Drugs 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical group O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims description 8
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 229960001904 epirubicin Drugs 0.000 claims description 8
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 8
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims 2
- 239000013078 crystal Substances 0.000 description 17
- 239000000243 solution Substances 0.000 description 11
- 125000000524 functional group Chemical group 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
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- 238000001556 precipitation Methods 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 5
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000002441 X-ray diffraction Methods 0.000 description 3
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 3
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- 239000002026 chloroform extract Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 229960004679 doxorubicin Drugs 0.000 description 3
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- UBOXGVDOUJQMTN-UHFFFAOYSA-N 1,1,2-trichloroethane Chemical compound ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 2
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 2
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 description 2
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 2
- 229960004176 aclarubicin Drugs 0.000 description 2
- 125000000746 allylic group Chemical group 0.000 description 2
- 239000012296 anti-solvent Substances 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- DIKBFYAXUHHXCS-UHFFFAOYSA-N bromoform Chemical compound BrC(Br)Br DIKBFYAXUHHXCS-UHFFFAOYSA-N 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- XREUEWVEMYWFFA-CSKJXFQVSA-N carminomycin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XREUEWVEMYWFFA-CSKJXFQVSA-N 0.000 description 2
- 229930188550 carminomycin Natural products 0.000 description 2
- XREUEWVEMYWFFA-UHFFFAOYSA-N carminomycin I Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XREUEWVEMYWFFA-UHFFFAOYSA-N 0.000 description 2
- 229950001725 carubicin Drugs 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 229960000975 daunorubicin Drugs 0.000 description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
- 238000005858 glycosidation reaction Methods 0.000 description 2
- 229930182470 glycoside Natural products 0.000 description 2
- 150000002338 glycosides Chemical class 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229960000908 idarubicin Drugs 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 229960001221 pirarubicin Drugs 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 150000005846 sugar alcohols Polymers 0.000 description 2
- 238000002411 thermogravimetry Methods 0.000 description 2
- 229960000641 zorubicin Drugs 0.000 description 2
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 2
- MWWSFMDVAYGXBV-FGBSZODSSA-N (7s,9s)-7-[(2r,4s,5r,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydron;chloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-FGBSZODSSA-N 0.000 description 1
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 229910018072 Al 2 O 3 Inorganic materials 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229950005228 bromoform Drugs 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 description 1
- 238000011143 downstream manufacturing Methods 0.000 description 1
- 229960003265 epirubicin hydrochloride Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
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- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
【選択図】なし
Description
a)C1およびC2のハロゲン化溶媒ならびにこれらの混合物からなる群から選択される溶媒A、
b)C1〜C5の直鎖状および分枝状のアルコールならびにこれらの混合物からなる群から選択される溶媒B、ならびに
c)C1〜C5の直鎖状および分枝状のアルコールならびにこれらの混合物からなる群から選択される溶媒Cであって、溶媒Cは、溶媒Bよりも低い溶解度を4’−エピダウノルビシン塩酸塩に与えるように選択される、溶媒C
を含む溶媒系の中で4’−エピダウノルビシン塩酸塩を結晶化させることを含む、4’−エピダウノルビシン塩酸塩を結晶化させるためのプロセスによって解決される。
10gの4’−エピダウノルビシン塩酸塩を、クロロホルムおよびブタノール(体積比=2:1)の混合物に溶解させた。この混合物に、60℃で、10倍の体積の1−プロパノールおよび1−ブタノール(体積比=3:7)の混合物を加えた。得られた溶媒系の中の4’−エピダウノルビシン塩酸塩の最終濃度は8g/lであった。
10gの4’−エピダウノルビシン塩酸塩を、クロロホルムおよびブタノール(体積比=2:1)の混合物に溶解させた。この混合物を、60℃で、10倍の体積の1−プロパノールおよび1−ブタノール(体積比=3:7)の混合物にゆっくり加えた。得られた溶媒系の中の4’−エピダウノルビシン塩酸塩の最終濃度は20g/lであった。
10gの4’−エピダウノルビシン塩酸塩を、ジクロロメタンおよび1−プロパノール(体積比=1:1)の混合物に溶解させた。この混合物に、10倍の体積の1−プロパノールおよびイソプロパノール(体積比=2.5:8)の混合物を、60℃でゆっくり加えた。得られた溶媒系の中の4’−エピダウノルビシン塩酸塩の最終濃度は8gであった。
10gの4’−エピダウノルビシン塩酸塩を、ジクロロメタンおよび1−プロパノール(体積比=1:1)の混合物に溶解させた。この混合物に、60℃で、10倍の体積の1−プロパノールおよびイソプロパノール(体積比=2.5:8)の混合物をゆっくり加えた。得られた溶媒系の中の4’−エピダウノルビシン塩酸塩の最終濃度は20gであった。
米国特許第4,345,068号明細書の実施例2に従って、4’−エピダウノルビシン塩酸塩を製造し、(メタノール性塩化水素を、4’−エピダウノルビシン塩酸塩のクロロホルム抽出液に加えることにより)精製した。結果として、4’−エピダウノルビシン塩酸塩が得られ、非晶性粉末として沈殿した。
米国特許第4,345,068号明細書の実施例5に従って、4’−エピダウノルビシン塩酸塩を製造し、(メタノール性塩化水素を、4’−エピダウノルビシン塩酸塩のクロロホルム抽出液に加えることにより)精製した。結果として、4’−エピダウノルビシン塩酸塩が得られ、非晶性粉末として沈殿した。
Boivinら(「Substitutions of allylic esters: preparation of 3−aminoglycals and their acid−catalyzed glycosidation. Use in the partial synthesis of glycosides of the anthracycline group」、Carbohydrate Research、1980年、第79巻、第2号、193−204頁)に従って、4’−エピダウノルビシン塩酸塩を製造し、(エタノール/エーテルを使用することにより)精製した。結果として、4’−エピダウノルビシン塩酸塩が得られ、非晶性粉末として沈殿した。
Claims (19)
- a)C1およびC2のハロゲン化溶媒ならびにこれらの混合物からなる群から選択される溶媒A、
b)C1〜C5の直鎖状および分枝状のアルコールならびにこれらの混合物からなる群から選択される溶媒B、ならびに
c)C1〜C5の直鎖状および分枝状のアルコールならびにこれらの混合物からなる群から選択される溶媒Cであって、溶媒Cは、溶媒Bよりも低い溶解度を4’−エピダウノルビシン塩酸塩に与えるように選択される、溶媒C
を含む溶媒系の中で4’−エピダウノルビシン塩酸塩を結晶化させることを含む、結晶性4’−エピダウノルビシン塩酸塩を製造するためのプロセス。 - 前記溶媒系は、0.1〜20体積%の溶媒A、7〜50体積%の溶媒Bおよび45〜92体積%の溶媒Cを含む、請求項1に記載のプロセス。
- 前記溶媒系は、1〜6体積%の溶媒A、10〜40体積%の溶媒Bおよび54〜89体積%の溶媒Cを含む、請求項2に記載のプロセス。
- a)4’−エピダウノルビシン塩酸塩を、(i)溶媒Aおよび(ii)溶媒BまたはCを含む溶媒混合物Iに溶解させることと、
b)a)で得られた溶液を、溶媒BおよびCを含む溶媒混合物IIと接触させることと、
を含む、請求項1に記載のプロセス。 - 溶媒混合物Iは、(i)溶媒Aおよび(ii)溶媒BまたはCを、体積比1:2〜4:1、好ましくは0.75:1〜3:1、最も好ましくは1:1〜2:1で含む、請求項4に記載のプロセス。
- 溶媒混合物Iを溶媒混合物IIに接触させると、前記溶媒系は、0.1〜20体積%、好ましくは0.1〜15体積%、より好ましくは0.1〜12体積%、最も好ましくは0.1〜10体積%、の溶媒Aを含む、請求項4に記載のプロセス。
- 前記溶媒系の中の4’−エピダウノルビシン塩酸塩の濃度は、7g/l〜30g/l、好ましくは7.5g/l〜25g/l、最も好ましくは8g/l〜20g/lである、請求項1に記載のプロセス。
- 4’−エピダウノルビシン塩酸塩を溶媒混合物Iに溶解させることは、40〜80℃、好ましくは50〜70℃、最も好ましくは55〜65℃の範囲の温度で実施される、請求項4に記載のプロセス。
- 4’−エピダウノルビシン塩酸塩の前記溶液を溶媒混合物IIに接触させた後、得られた混合物は、5〜35℃、好ましくは15〜30℃、最も好ましくは20〜30℃の範囲の温度に冷却される、請求項8に記載のプロセス。
- 溶媒Aは、クロロホルムおよびジクロロメタンからなる群から選択される、請求項1から請求項9のいずれか1項に記載のプロセス。
- 溶媒Bは、メタノール、エタノールおよび1−プロパノールからなる群から選択される、請求項1から請求項10のいずれか1項に記載のプロセス。
- 溶媒Cは、1−ブタノール、イソプロパノール、イソブタノールおよび1−ペンタノールからなる群から選択される、請求項1から請求項11のいずれか1項に記載のプロセス。
- 前記溶媒系は、溶媒A、BおよびC以外の溶媒を欠く、請求項1から請求項12のいずれか1項に記載のプロセス。
- 結晶性4’−エピダウノルビシン塩酸塩。
- 請求項1から請求項13のいずれか1項に記載のプロセスによって得られることを特徴とする、請求項14または請求項15に記載の結晶性4’−エピダウノルビシン塩酸塩。
- 少なくとも10%の単斜晶相含量を有することを特徴とする、請求項14から請求項16のいずれか1項に記載の結晶性4’−エピダウノルビシン塩酸塩。
- アントラサイクリンの製造における中間体としての、請求項14から請求項17のいずれか1項に記載の結晶性4’−エピダウノルビシン塩酸塩の使用。
- 前記アントラサイクリンはエピルビシンである、請求項18に記載の使用。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2017514821A (ja) * | 2014-04-30 | 2017-06-08 | メダック・ゲゼルシャフト・フューア・クリニッシェ・スペツィアルプレパラーテ・ミット・ベシュレンクテル・ハフツングmedac, Gesellschaft fuer klinische Spezialpraeparate mbH | エピダウノルビシンの精製 |
KR20180009737A (ko) | 2015-03-30 | 2018-01-29 | 메이지 세이카 파루마 가부시키가이샤 | 에피루비신 제조방법 및 그의 신규한 제조 중간체 |
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Publication number | Priority date | Publication date | Assignee | Title |
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EP2301943B1 (en) | 2009-09-08 | 2014-01-08 | Heraeus Precious Metals GmbH & Co. KG | Crystallization of epidaunorubicin x HCI |
DE102011103751A1 (de) * | 2011-05-31 | 2012-12-06 | Heraeus Precious Metals Gmbh & Co. Kg | Kristallisierung von Epirubicinhydrochlorid |
KR101428340B1 (ko) * | 2012-12-31 | 2014-08-07 | 현대자동차주식회사 | 이온성 용매를 이용한 락타이드 제조법 |
WO2015149001A1 (en) | 2014-03-27 | 2015-10-01 | The Brigham And Women's Hospital, Inc. | Metabolically-activated drug conjugates to overcome resistance in cancer therapy |
CN109384822B (zh) * | 2017-08-11 | 2021-08-03 | 鲁南制药集团股份有限公司 | 一种盐酸表柔比星晶型及其制备方法 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6442498A (en) * | 1987-08-07 | 1989-02-14 | Biogal Gyogyszergyar | Improvement for collecting daunorubicin hydrochloride from fermentation liquid |
WO1999029708A1 (fr) * | 1997-12-05 | 1999-06-17 | Mercian Corporation | Anthracycline cristalline antibiotique et son procede de production |
JP2009524600A (ja) * | 2006-01-04 | 2009-07-02 | ドゥ−コープ テクノロジーズ リミテッド | 固液組成物 |
WO2009112851A1 (en) * | 2008-03-13 | 2009-09-17 | Enbio Limited | Surface modification of nitinol |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1506200A (en) | 1975-04-30 | 1978-04-05 | Farmaceutici Italia | Glycosides |
US4345068A (en) * | 1979-11-22 | 1982-08-17 | Farmitalia Carlo Erba S.P.A. | Process for the preparation of 4'-epidaunorubicin, 3',4'-diepidaunorubicin, their doxorubicin analogs, and intermediates used in said process |
IT1155446B (it) | 1982-12-23 | 1987-01-28 | Erba Farmitalia | Procedimento per la purificazione di glucosidi antraciclinonici mediante adsobimento selettivo su resine |
IT1275953B1 (it) | 1995-03-22 | 1997-10-24 | Sicor Spa | Procedimento per la preparazione di antibiotici della classe delle antracicline |
DK0848009T3 (da) | 1996-12-16 | 2000-11-20 | Pharmachemie Bv | Fremgangsmåde til fremstilling af epirubicin eller syreadditionssalte deraf ud fra daunorubicin |
DK1034181T3 (da) * | 1997-11-28 | 2006-03-20 | Dainippon Sumitomo Pharma Co | Krystallinsk amrubicinhydrochlorid |
AU750738B2 (en) * | 1998-10-16 | 2002-07-25 | Microbiopharm Japan Co., Ltd. | Crystallization of doxorubicin hydrochloride |
US7485707B2 (en) * | 2003-07-02 | 2009-02-03 | Solux Corporation | Thermally stable crystalline epirubicin hydrochloride and method of making the same |
US8802830B2 (en) * | 2005-12-20 | 2014-08-12 | Solux Corporation | Synthesis of epirubicin from 13-dihydrodaunorubicine |
EP1990405B1 (en) | 2007-05-08 | 2017-07-26 | Provivo Oy | Genetically modified strains producing anthracycline metabolites useful as cancer drugs |
EP2301943B1 (en) | 2009-09-08 | 2014-01-08 | Heraeus Precious Metals GmbH & Co. KG | Crystallization of epidaunorubicin x HCI |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6442498A (en) * | 1987-08-07 | 1989-02-14 | Biogal Gyogyszergyar | Improvement for collecting daunorubicin hydrochloride from fermentation liquid |
WO1999029708A1 (fr) * | 1997-12-05 | 1999-06-17 | Mercian Corporation | Anthracycline cristalline antibiotique et son procede de production |
JP2009524600A (ja) * | 2006-01-04 | 2009-07-02 | ドゥ−コープ テクノロジーズ リミテッド | 固液組成物 |
WO2009112851A1 (en) * | 2008-03-13 | 2009-09-17 | Enbio Limited | Surface modification of nitinol |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2017514821A (ja) * | 2014-04-30 | 2017-06-08 | メダック・ゲゼルシャフト・フューア・クリニッシェ・スペツィアルプレパラーテ・ミット・ベシュレンクテル・ハフツングmedac, Gesellschaft fuer klinische Spezialpraeparate mbH | エピダウノルビシンの精製 |
KR20180009737A (ko) | 2015-03-30 | 2018-01-29 | 메이지 세이카 파루마 가부시키가이샤 | 에피루비신 제조방법 및 그의 신규한 제조 중간체 |
US10301343B2 (en) | 2015-03-30 | 2019-05-28 | Meiji Seika Pharma Co., Ltd. | Method of producing epirubicin and novel production intermediate thereof |
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