- Synthetic studies on camptothecins. Part 3
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A concise and efficient asymmetric process for the total synthesis of (20S)-7-ethyl-10-hydroxycamptothecin (=SN-38; 1f), an active metabolic form of the prodrug irinotecan, is described. This approach features the enantioselective cyanosilylation of indolizinone 4 into the corresponding cyanohydrin 5, mediated by a bifunctional thiourea-based cinchona alkaloid under mild conditions, and I2-catalyzed Friedlnder condensation of the tricyclic lactone 6 and 2-amino-5-hydroxy propiophenone (=1-(2-amino-5- hydroxyphenyl)propan-1-one). Copyright
- Kuang, Yun-Yan,Niu, Jing-Ze,Chen, Fen-Er
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- Enantioselective synthesis of 20(S)-camptothecin using Sharpless catalytic asymmetric dihydroxylation
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The homochiral key intermediate 2 of 20(S)-camptothecin was prepared enantioselectively by using catalytic asymmetric dihydroxylation as the key reaction.
- Jew,Ok,Kim,Kim,Kim,Hah,Cho
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- Enantioselective synthesis of 20(S)-camptothecin using an enzyme- catalyzed resolution
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The important key intermediate of a 20(S)-camptothecin synthesis was prepared enantioselectively using an enzyme-catalyzed resolution. A commercially available papain was found to exhibit the highest enantioselectivity with moderate activity, and the (S)-enantiomer of 99% ee was obtained as the remaining substrate.
- Imura, Akihiro,Itoh, Motohiro,Miyadera, Akihiko
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- Rigid Analogs of Camptothecin as DNA Topoisomerase I Inhibitors
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Substituted 8-ethyl-2-(2-oxo-1,2-dihydroindol-3-ylidene)-8-hydroxy-2,3,5,8-tetrahydro-6-oxa-3a-azacyclopentanaphthalene-1,4,7-triones were synthesized and evaluated as topoisomerase I inhibitors in an in vitro cleavable complex assay.The activity of these compounds may be attributed to their rigid, planar geometry, and an attempt was made to correlate the SAR in this series to known attributes of camptothecin.
- Lackey, Karen,Besterman, Jeffrey M.,Fletcher, Wade,Leitner, Peter,Morton, Bradley,Sternbach, Daniel D.
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- Camptothecin derivative and preparation method and application thereof
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The invention relates to a compound with a structure shown in a formula (I), a stereoisomer of the compound and a pharmaceutically acceptable salt form of the compound, and further relates to a preparation method of the compound, a pharmaceutical composition containing therapeutically effective dose of the compound, and application of the pharmaceutical composition in the preparation for the prevention and/or treatment of cancer. The compound is a camptothecin derivative with a novel structure with 10 site and 11 site of a stem nucleus introduced with methylene dioxy groups and 7-site introduced with different substituted groups. The raw materials of the preparation method can be obtained easily, a synthetic method is simple, a purification method is simple and fast, the compound has excellent cytotoxic activity in vitro and excellent antitumor effect in vivo, and the compound has broad medicinal prospects.(Please see the specification for the formula).
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Paragraph 0223-0227; 0250-0253
(2020/01/03)
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- An improved synthesis of (20S)-camptothecin and its analogue via an asymmetric α-hydroxylation with a chiral organocatalyst
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An efficient and stereocontrolled synthesis of (20S)-camptothecin and an analogue has been developed. The key feature of this synthesis is the organocatalyzed asymmetric α-hydroxylation of the lactone precursor 4 to construct its stereocenter, providing tricyclic hydroxylactone 2 in 90% yield and with 88% enantioselectivity. The precursor 4 was efficiently synthesized from the known pyridine 5 in three steps.
- Wang, Xinlong,Xu, Lingjun,Xiong, Fangjun,Wu, Yan,Chen, Fener
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p. 843 - 848
(2017/06/13)
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- COMPOUND OF CAMPTOTHECIN AND PREPARATION AND USE THEREOF
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The present disclosure relates to a compound of formula I, a pharmaceutical composition thereof and the use thereof as an anti-tumor drug.
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Paragraph 0097
(2015/05/05)
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- COMPOUND OF CAMPTOTHECIN AND PREPARATION AND USE THEREOF
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The present disclosure relates to a compound of formula I, a pharmaceutical composition thereof and the use thereof as an anti-tumor drug.
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Paragraph 0145; 0146
(2015/06/24)
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- METHOD OF SYNTHESIZING CAMPTOTHECIN-RELATING COMPOUNDS
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The present invention is to prepare efficiently 2'-amino-5'-hydroxypropiophenone corresponding to the AB-ring part of camptothecin (CPT) skeleton and a tricyclic ketone corresponding to the CDE-ring part in order to provide efficiently CPT by the total synthesis, which is a starting material for irinotecan hydrochloride and various kinds of camptothecin derivatives, and to provide stably CPT and its derivatives.
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- Condensed-hexacyclic compounds and a process therefor
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Disclosed are a process for the preparation of a compound represented by the formula (1), which comprises treating a compound represented by the formula (2) with methanesulfonic acid and then subjecting the thus-treated compound to recrystallization; and Compound (1) so obtained. This Compound (1) is free of hygroscopicity, excellent in filterability and solubility and easy in handling. Furthermore, according to the preparation process of the present invention, an unnecessary isomer can be converted into the target one and separation of the target isomer can be conducted easily.
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- Practical asymmetric synthesis of (S)-4,ethyl-7,8-dihydro-4-hydroxy-1H- pyrano[3,4-f]indolizine-3,6,10(4H)-trione, a key intermediate for the synthesis of Irinotecan and other camptothecin analogs
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A practical asymmetric synthesis of (S) 4-ethyl-7,8-dihydro-4-hydroxy- 1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (1), a versatile intermediate for the synthesis of camptothecin analogs, was developed. Commercially available citrazinic acid is converted in four steps into the 2-chloro-6- methoxypyridine 5. An ortho-directed metalation followed by reaction with a formamide produces an aldehyde with the required 2,3,4,6-substituted pyridine (6) with high regioselectivity. After refunctionalization of the aldehyde, the chloropyridine is converted into an ester by a facile palladium-mediated carbonylation reaction. Wittig reaction and racemic osmylation produce the diol 16 which is resolved by an efficient lipase resolution to an ee > 99%, and a one-pot recycle of the unwanted diol enantiomer was developed. A series of high-yielding oxidation and deprotection steps convert (S)-16 into the pyridone 25, which is then converted into 1 with an ee > 99.6%.
- Henegar,Ashford,Baughman,Sih,Gu
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p. 6588 - 6597
(2007/10/03)
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- Antitumour Agents. Part 2. Asymmetric Synthesis of (S)-Camptothecin
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The total synthesis of (S)-camptothecin by a novel diastereoselective ethylation process is described.
- Ejima, Akio,Terasawa, Hirofumi,Sugimori, Masamichi,Tagawa, Hiroaki
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- ASYMMETRIC SYNTHESIS OF (S)-CAMPTOTHECIN
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The title compound was synthesized via a novel diastereoselective ethylation process from indolizine derivative 5a bearing N-tosyl-(R)-proline.
- Ejima, Akio,Terasawa, Hirofumi,Sugimori, Masamichi,Tagawa, Hiroaki
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p. 2639 - 2640
(2007/10/02)
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- Certain pyrano (3,4-f)-indolizine derivatives
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A pyranoindolizine derivative represented by the following general formula (I): STR1 wherein R means a hydrogen atom or hydroxyl group and Q denotes >C=O or STR2 with a proviso that Q is other than >C=O when R is a hydrogen atom. Its preparation process is also described.
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- Plant antitumor agents. 28. Resolution of a key tricyclic synthon, 5'(RS)-1,5-dioxo-5'-ethyl-5'-hydroxy-2'H,5'H,6'H,H-6'-oxopyrano[3',4' f]Δ6,8-tetrahydroindolizine: Total synthesis and antitumor activity of 20(S)- and 20(R)-camptothecin
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The resolution of the tricyclic ketone (3a + 3b) by the separation of diastereomeric adducts 4a and 4c of the precursor ketal 5 is described. The regenerated enantiomers 3a and 3b of 100% optical purity represent the key intermediates from which 20(R)-camptothecin (1a) and 20(S)-camptothecin (1b), respectively, have been prepared. The 20R analogue 1a was 10-100 times less active than the natural 20(S)-camptothecin (1b) in 9KB and 9PS cytotoxicity assays and almost inactive in in vivo L-1210 leukemia tests as compared to the highly potent and active natural compound 1b.
- Wani,Nicholas,Wall
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p. 2317 - 2319
(2007/10/02)
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