Chemistry Department I Medicinal Chemistry Research, Laboratory Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aobaku, Yokohama, 227-0033, Japan.
Chem Asian J. 2013 Mar;8(3):630-8. doi: 10.1002/asia.201200904. Epub 2012 Dec 23.
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).
（20S）-10-（3-氨基丙氧基）-7-乙基喜树碱（T-2513，5）的一种稳定、实用的合成方法已经开发出来。该合成的关键步骤是在 C20 位进行高度非对映选择性的乙基化反应，使用 N-芳基磺酰基-（R）-1,2,3,4-四氢异喹啉-3-羧酸酯作为手性助剂，以 93%的收率和 87%的非对映选择性得到关键中间体乙基-（S）-2-酰氧基-2-（6-氰基-5-氧代-1,2,3,5-四氢吲哚嗪-7-基）丁酸酯（8k）。通过从丙酮中进行单一重结晶，可以得到光学纯的化合物 8k，并且通过 Friedlander 缩合进一步得到化合物 5。该合成不需要任何色谱纯化步骤，可以在 6.3%的总收率（16 步）下，以多克规模提供化合物 5。
