ORGN 79 |
Development of the synthesis of BMS-250749, a potent topoisomerase inhibitor
| Jianji Wang, Miguel Rosigana, Daniel Watson, Eric Dowdy, Meena Rao, Robert Discordia, Nachimuthu Soundarajan, and Wen-Sen Li. Process Research & Development, Bristol-Myers Squibb, One Squibb Drive, New Brunswick, NJ 08903 |
BMS-250749, a potent topoisomerase inhibitor, has shown antitumor activity and was advanced to human clinical trials for the treatment of cancer. Its molecular structure consists of 3,9-difluoroindolocarbazole linked to 4-fluoroglucose by a glycosidic bond. In an effort to develop an efficient, practical and cost-effective synthesis of this molecule, two new processes (Process A and B) were developed. In Process A, the desired product was synthesized via the Mitsunobu coupling of 3,9-difluoroindolocarbazole with Bz-protected 4-fluoroglucose followed by removal of the protecting groups. In Process B, the product was formed via the acid-catalyzed glycosidation of 4-fluoroglucose with 3,9-difluoroindoloindoline and subsequent oxidation utilizing I2 or NIS as the oxidant. Details of the preparation of the key fragments using new methodologies and the overall synthesis of the target molecule by both Process A and B will be described.  |
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