title: Practical synthesis of (20S)-10-(3-aminopropyloxy)-7-ethylcamptothecin, a water-soluble analogue of camptothecin.
abstract: A robust, practical synthesis of (20S)-10-(3-aminopropyloxy)-7-ethylcamptothecin (T-2513, 5), which is a water-soluble analogue of camptothecin, has been developed. The key step in this synthesis is a highly diastereoselective ethylation at the C20 position by using N-arylsulfonyl-(R)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ester as a chiral auxiliary, which affords the key intermediate ethyl-(S)-2-acyloxy-2-(6-cyano-5-oxo-1,2,3,5-tetrahydroindolizin-7-yl)butanoate (8k) in 93% yield and 87% de. Optically pure compound 8k was obtained by a single recrystallization from acetone and its further elaboration through Friedlander condensation afforded compound 5. This synthesis does not require any chromatographic purification steps and can provide compound 5 on a multi-gram scale in 6.3% overall yield (16 steps).
authors.affiliation: Chemistry Department I Medicinal Chemistry Research, Laboratory Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aobaku, Yokohama, 227-0033, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Watanabe
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Tsuboi
authors.forename: Sumihiro
authors.initials: S
authors.lastname: Nomura
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D012995:Solubility; D013237:Stereoisomerism; D014867:Water / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D014867:Water; C582557:(20S)-10-(3-aminopropyloxy)-7-ethylcamptothecin; D002166:Camptothecin