JP2016539107A - イリノテカンの合成方法 - Google Patents
イリノテカンの合成方法 Download PDFInfo
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- JP2016539107A JP2016539107A JP2016528014A JP2016528014A JP2016539107A JP 2016539107 A JP2016539107 A JP 2016539107A JP 2016528014 A JP2016528014 A JP 2016528014A JP 2016528014 A JP2016528014 A JP 2016528014A JP 2016539107 A JP2016539107 A JP 2016539107A
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- piperidino
- ethyl
- irinotecan
- camptothecin
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- 238000000034 method Methods 0.000 title claims abstract description 25
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 8
- 229960004768 irinotecan Drugs 0.000 title abstract description 22
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 title abstract description 22
- 229940127093 camptothecin Drugs 0.000 claims abstract description 24
- 150000001875 compounds Chemical group 0.000 claims abstract description 7
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- HAWSQZCWOQZXHI-FQEVSTJZSA-N 10-Hydroxycamptothecin Chemical compound C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-FQEVSTJZSA-N 0.000 claims description 14
- HAWSQZCWOQZXHI-UHFFFAOYSA-N CPT-OH Natural products C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-UHFFFAOYSA-N 0.000 claims description 14
- 239000007858 starting material Substances 0.000 claims description 13
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 10
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 7
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 7
- 150000007530 organic bases Chemical class 0.000 claims description 7
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 claims description 6
- 229910000359 iron(II) sulfate Inorganic materials 0.000 claims description 6
- 239000011790 ferrous sulphate Substances 0.000 claims description 5
- 235000003891 ferrous sulphate Nutrition 0.000 claims description 5
- 238000005886 esterification reaction Methods 0.000 claims description 3
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 abstract 2
- 238000006243 chemical reaction Methods 0.000 description 14
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 12
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 12
- 238000006200 ethylation reaction Methods 0.000 description 11
- FJHBVJOVLFPMQE-QFIPXVFZSA-N 7-Ethyl-10-Hydroxy-Camptothecin Chemical compound C1=C(O)C=C2C(CC)=C(CN3C(C4=C([C@@](C(=O)OC4)(O)CC)C=C33)=O)C3=NC2=C1 FJHBVJOVLFPMQE-QFIPXVFZSA-N 0.000 description 10
- -1 propionate aldehyde Chemical class 0.000 description 10
- 230000006203 ethylation Effects 0.000 description 8
- KUDUHLYXWIVQRQ-HKBQPEDESA-N [(19S)-19-ethyl-19-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2(11),3,5,7,9,15(20)-heptaen-7-yl] 4-piperidin-1-ylpiperidine-1-carboxylate Chemical compound O=C([C@]1(O)CC)OCC(C(N2CC3=CC4=C5)=O)=C1C=C2C3=NC4=CC=C5OC(=O)N(CC1)CCC1N1CCCCC1 KUDUHLYXWIVQRQ-HKBQPEDESA-N 0.000 description 7
- 239000006227 byproduct Substances 0.000 description 7
- 239000007795 chemical reaction product Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- IEKWXGPJFJGZSM-DHUJRADRSA-N 8-ethyl irinotecan Chemical compound CCC1=CC2=NC(C=3N(C(C4=C([C@@](C(=O)OC4)(O)CC)C=3)=O)C3)=C3C(CC)=C2C=C1OC(=O)N(CC1)CCC1N1CCCCC1 IEKWXGPJFJGZSM-DHUJRADRSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- VBXXNCHZAMNCBX-UHFFFAOYSA-N 4-piperidin-1-ylpiperidine-1-carbonyl chloride;hydrochloride Chemical compound Cl.C1CN(C(=O)Cl)CCC1N1CCCCC1 VBXXNCHZAMNCBX-UHFFFAOYSA-N 0.000 description 3
- MYQKIWCVEPUPIL-QFIPXVFZSA-N 7-ethylcamptothecin Chemical compound C1=CC=C2C(CC)=C(CN3C(C4=C([C@@](C(=O)OC4)(O)CC)C=C33)=O)C3=NC2=C1 MYQKIWCVEPUPIL-QFIPXVFZSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000013067 intermediate product Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 235000019260 propionic acid Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- YNOQFRPIURNTSW-UHFFFAOYSA-N 1-piperidin-1-ylpiperidine-2-carboxylic acid Chemical group OC(=O)C1CCCCN1N1CCCCC1 YNOQFRPIURNTSW-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000003463 adsorbent Substances 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 150000002978 peroxides Chemical class 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000007154 radical cyclization reaction Methods 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- YSAMJAXLRIUOHA-SFVMKZFCSA-N (19S)-19-ethyl-19-hydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),4,6,8,15(20)-pentaene-14,18-dione Chemical compound N1C2=CC=CC=C2CC(CN2C3=O)C1C2=CC1=C3COC(=O)[C@]1(O)CC YSAMJAXLRIUOHA-SFVMKZFCSA-N 0.000 description 1
- 241000759909 Camptotheca Species 0.000 description 1
- 102000003915 DNA Topoisomerases Human genes 0.000 description 1
- 108090000323 DNA Topoisomerases Proteins 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
- JYJVVHFRSFVEJM-UHFFFAOYSA-N iodosobenzene Chemical compound O=IC1=CC=CC=C1 JYJVVHFRSFVEJM-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 1
- 229930002341 quinoline alkaloid Natural products 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明は、イリノテカンとも称される7-エチル-10-[4-(1-ピペリジノ)-1-ピペリジノ]カルボニルカンプトテシンの合成方法に向けられる。
カンプトテシンは、酵素トポイソメラーゼIを阻害する細胞毒性キノリンアルカロイドである。カンプトテシンは元々、カンレンボク(Camptotheca acuminate)(「Happy Tree」とも称される)の樹皮と幹より単離され、中国伝統医学においては、癌の治療に用いられている。カンプトテシンは、予備臨床試験において注目すべき抗癌活性を示しているが、低い溶解性や、少なからぬ副作用も示している。これらの不利益があることから、臨床的有益性を向上させるために様々な半合成誘導体が開発されてきた。その一方でこれら半合成誘導体のうち二つ、具体的にはトポテカンおよびイリノテカンが、化学療法における使用を許可されている(例えば、Ulukan, H. and Swaan P.W. (2002). Drugs 62, 2039-2057(非特許文献1)に概説されている)。
(a)10-[4-(1-ピペリジノ)-1-ピペリジノ]カルボニルオキシカンプトテシンを調製する工程、および
(b)工程(a)の化合物の7位を選択的にエチル化する工程であって、それにより7-エチル-10-[4-(1-ピペリジノ)-1-ピペリジノ]カルボニルオキシ-カンプトテシンの調製をもたらす、工程。
本発明は、7-エチル-10-[4-(1-ピペリジノ)-1-ピペリジノ]カルボニルカンプトテシン(即ち、イリノテカン)を、副産物の混入を実質的に伴うことなく90%超の高い全収率で生成できるという、予想外の知見に関する。この合成経路は、10-ヒドロキシカンプトテシンを出発物質として、および7位での選択的なエチル化を実施するために10-[4-(1-ピペリジノ)-1-ピペリジノ]カルボニルオキシカンプトテシン(即ち、7-デス-エチル-イリノテカン)を中間生成物として使用することを特徴とし、これにより、それぞれ不要な副産物である11-エチル-イリノテカンおよび7-エチル-10-ヒドロキシカンプトテシンの生成が妨げられている。
(a)10-[4-(1-ピペリジノ)-1-ピペリジノ]カルボニルオキシカンプトテシンを調製する工程、および
(b)工程(a)の化合物の7位を選択的にエチル化する工程であって、それにより7-エチル-10-[4-(1-ピペリジノ)-1-ピペリジノ]カルボニルオキシ-カンプトテシンの調製をもたらす、工程。
20gの10-ヒドロキシカンプトテシンを100mlのアセトニトリルに溶解した後、30gの無水K2CO3を加える。次に、17.6gの1-クロロカルボニル-4-ピペリジノ-ピペリジン塩酸塩溶液を300mlのアセトニトリルに撹拌しながら加える。撹拌を60℃にて約6時間続ける。
20gの10-ヒドロキシカンプトテシンを300mlのアセトニトリルに溶解する。20mLのトリエチルアミンと共に17.6gの1-クロロカルボニル-4-ピペリジノピペリジン塩酸塩を加える。撹拌を60℃にて約2時間続ける。
20gのイリノテカンを硫酸水溶液(400mlの40%H2SO4)で希釈する。FeSO4×7H2O(10.5g)を20℃で加え、この溶液を-10℃まで冷却した後、プロピオン酸アルデヒド(10ml)を加える。得られるH2O2およびプロピオン酸アルデヒドの溶液を0℃まで冷却し(75mlの蒸留水を0℃まで冷却し、3.3mlの32%H2O2および5mLのプロピオン酸アルデヒドを加える)、滑らかに流れる様式で150分間インキュベーションする。11-エチル-イリノテカンは、HPLCによる反応生成物の分析の際にも検出されない。
不要な反応生成物の数および種類に関して、図3に示した本発明の方法を、本技術分野において確立されている(それぞれ図1および図2に示されている)2つのイリノテカン合成方法と比較した場合、本発明の方法が優れた結果を提供することは直ぐに明白になる。知見は下記の表に要約されている。
Claims (9)
- 工程(a)において、10-ヒドロキシカンプトテシンが出発物質として使用される、請求項1記載の方法。
- 無水アルカリ金属炭酸塩または有機強塩基の存在下、アセトニトリル中で工程(a)を実施する、請求項2記載の方法。
- 無水アルカリ金属炭酸塩が、Na2CO3、K2CO3、Rb2CO3、およびCs2CO3からなる群より選択される、請求項3記載の方法。
- 有機強塩基がトリエチルアミンである、請求項3記載の方法。
- 20℃〜80℃の範囲内の温度で、好ましくは60℃で工程(a)を実施する、請求項1〜5のいずれか一項に記載の方法。
- 硫酸第一鉄、過酸化水素、およびプロピオン酸アルデヒド(propionic aldehyde)の存在下で工程(b)を実施する、請求項1〜6のいずれか一項に記載の方法。
- 工程(b)の前にC9位におけるエステル化反応を行う、請求項1〜7のいずれか一項に記載の方法。
- 請求項1〜8のいずれか一項に定義される7-エチル-10-[4-(1-ピペリジノ)-1-ピペリジノ]カルボニルオキシ-カンプトテシンを合成する方法における中間体としての、10-[4-(1-ピペリジノ)-1-ピペリジノ]カルボニルオキシカンプトテシンの使用。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP13195464.6 | 2013-12-03 | ||
EP13195464.6A EP2881396A1 (en) | 2013-12-03 | 2013-12-03 | Method for the synthesis of irinotecan |
PCT/EP2014/075369 WO2015082240A1 (en) | 2013-12-03 | 2014-11-24 | Method for the synthesis of irinotecan |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2016539107A true JP2016539107A (ja) | 2016-12-15 |
JP6200084B2 JP6200084B2 (ja) | 2017-09-20 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016528014A Expired - Fee Related JP6200084B2 (ja) | 2013-12-03 | 2014-11-24 | イリノテカンの合成方法 |
Country Status (23)
Country | Link |
---|---|
US (1) | US9765083B2 (ja) |
EP (2) | EP2881396A1 (ja) |
JP (1) | JP6200084B2 (ja) |
KR (1) | KR101813423B1 (ja) |
CN (1) | CN105636963B (ja) |
AU (1) | AU2014359552B2 (ja) |
BR (1) | BR112016012717A2 (ja) |
CA (1) | CA2924256C (ja) |
DK (1) | DK3030567T3 (ja) |
ES (1) | ES2606771T3 (ja) |
HK (1) | HK1220969A1 (ja) |
HU (1) | HUE032281T2 (ja) |
IL (1) | IL244487B (ja) |
MX (1) | MX2016005065A (ja) |
NZ (1) | NZ717802A (ja) |
PL (1) | PL3030567T3 (ja) |
PT (1) | PT3030567T (ja) |
RS (1) | RS55483B1 (ja) |
RU (1) | RU2648989C2 (ja) |
SI (1) | SI3030567T1 (ja) |
UA (1) | UA114155C2 (ja) |
WO (1) | WO2015082240A1 (ja) |
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EP2881396A1 (en) | 2013-12-03 | 2015-06-10 | Synbias Pharma AG | Method for the synthesis of irinotecan |
CN111362960A (zh) * | 2018-12-25 | 2020-07-03 | 华北制药集团新药研究开发有限责任公司 | 一种伊立替康-y的制备方法 |
CN115073483B (zh) * | 2022-07-27 | 2022-10-25 | 泽升科技(广州)有限公司 | 一种伊立替康的对映体的制备方法 |
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JPS6185319A (ja) * | 1984-10-03 | 1986-04-30 | Yakult Honsha Co Ltd | 抗腫瘍剤 |
WO2005019223A1 (en) * | 2003-08-26 | 2005-03-03 | Pliva-Lachema A.S. | Method of manufacturing of 7-ethyl-10-[4-(1-piperidino)-1- piperidino]- carbonyloxycamptothecin |
US20070208050A1 (en) * | 2006-02-24 | 2007-09-06 | Palle Venkata Raghavendra Acha | Process for preparing irinotecan |
EP2341046A2 (en) * | 2009-11-18 | 2011-07-06 | Cadila Healthcare Limited | Process for the preparation of 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy-camptothecin hydrochloride trihydrate |
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EP2881396A1 (en) | 2013-12-03 | 2015-06-10 | Synbias Pharma AG | Method for the synthesis of irinotecan |
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2013
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JPS6185319A (ja) * | 1984-10-03 | 1986-04-30 | Yakult Honsha Co Ltd | 抗腫瘍剤 |
WO2005019223A1 (en) * | 2003-08-26 | 2005-03-03 | Pliva-Lachema A.S. | Method of manufacturing of 7-ethyl-10-[4-(1-piperidino)-1- piperidino]- carbonyloxycamptothecin |
US20070208050A1 (en) * | 2006-02-24 | 2007-09-06 | Palle Venkata Raghavendra Acha | Process for preparing irinotecan |
EP2341046A2 (en) * | 2009-11-18 | 2011-07-06 | Cadila Healthcare Limited | Process for the preparation of 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy-camptothecin hydrochloride trihydrate |
CN102718772A (zh) * | 2012-04-17 | 2012-10-10 | 肖文辉 | 一类羟喜树碱衍生物和其制剂的制备及临床应用 |
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PT3030567T (pt) | 2016-12-15 |
US9765083B2 (en) | 2017-09-19 |
UA114155C2 (xx) | 2017-04-25 |
BR112016012717A2 (pt) | 2020-08-11 |
WO2015082240A1 (en) | 2015-06-11 |
KR101813423B1 (ko) | 2017-12-28 |
JP6200084B2 (ja) | 2017-09-20 |
RS55483B1 (sr) | 2017-04-28 |
IL244487A0 (en) | 2016-04-21 |
ES2606771T3 (es) | 2017-03-27 |
CN105636963B (zh) | 2018-07-03 |
RU2648989C2 (ru) | 2018-03-29 |
HK1220969A1 (zh) | 2017-05-19 |
EP3030567B1 (en) | 2016-09-14 |
EP2881396A1 (en) | 2015-06-10 |
IL244487B (en) | 2019-07-31 |
ZA201601775B (en) | 2017-07-26 |
AU2014359552B2 (en) | 2017-03-30 |
NZ717802A (en) | 2017-06-30 |
HUE032281T2 (en) | 2017-09-28 |
MX2016005065A (es) | 2016-07-19 |
CN105636963A (zh) | 2016-06-01 |
US20160264590A1 (en) | 2016-09-15 |
CA2924256C (en) | 2018-09-18 |
PL3030567T3 (pl) | 2017-06-30 |
KR20160091907A (ko) | 2016-08-03 |
DK3030567T3 (en) | 2016-12-19 |
SI3030567T1 (sl) | 2017-01-31 |
EP3030567A1 (en) | 2016-06-15 |
CA2924256A1 (en) | 2015-06-11 |
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