Process Development of a Suzuki Reaction Used in the Manufacture of Lanabecestat
| Autor: | Sahar McKeever-Abbas, Robert L. Woodward, David Whittaker, Janette H. Cherryman, Alex Crampton, Edward G. B. Eden-Rump, Martin F. Jones, Matthew Charles Evans, Ian W. Ashworth, Rebecca E. Meadows, Phillip A. Inglesby, Andrew D. Campbell, Kathryn Skilling, Jemma Clark |
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| Rok vydání: | 2018 |
| Předmět: |
inorganic chemicals
Active ingredient Diethanolamine 010405 organic chemistry Organic Chemistry chemistry.chemical_element 010402 general chemistry 01 natural sciences Combinatorial chemistry Scavenger (chemistry) 0104 chemical sciences Catalysis law.invention chemistry.chemical_compound chemistry Suzuki reaction law Physical and Theoretical Chemistry Solubility Crystallization Palladium |
| Zdroj: | Organic Process Research & Development. 22:1801-1808 |
| ISSN: | 1520-586X 1083-6160 |
| DOI: | 10.1021/acs.oprd.8b00312 |
| Popis: | We developed a scalable Suzuki process for the synthesis of lanabecestat (+)-camsylate, an active pharmaceutical ingredient that was recently investigated in a Phase III clinical program for the treatment of early Alzheimer’s disease. The evolution of this process culminated with the use of a stable and crystalline diethanolamine boronic ester that rapidly hydrolyses under the reaction conditions. Herein, we report that the liberated diethanolamine plays an important role in the catalytic process, with supporting evidence for an equilibrium between an unbound and bound palladium complex. Additionally, the diethanolamine acts as an internal scavenger during the crystallization of lanabecestat by increasing the solubility of the palladium species, obviating the need for a discrete scavenging step. |
| Databáze: | OpenAIRE |
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