- Development of a scalable palladium-catalyzed α-arylation process for the synthesis of a CGRP antagonist
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The Pd-catalyzed α-arylation of cycloheptapyridyl ketone is a key complexity-building step in the synthesis of BMS-846372, a CGRP antagonist. A first-generation process utilized Pd(OAc)2/PtBu 3·HBF4 catalyst system with a strong base NaO tBu. Although this process was demonstrated on multi-kilo scale, the harsh conditions led to non-selective metal catalyzed processes, which generated several operational, quality, and throughput issues. By acquiring detailed knowledge around several important process parameters, we were able to design an efficient and scalable second-generation α-arylation process using a Pd(OAc)2/RuPhos catalyst system with the weaker base, K 3PO4 in tert-amyl alcohol. This new weak base process was high yielding, efficient, and superior in several respects compared to the strong base process. The strategy behind the reaction and isolation development and the process considerations important to scaling a catalytic reaction from laboratory to manufacturing scale will be discussed.
- Desai, Lopa V.,Hay, Michael B.,Leahy, David K.,Wei, Carolyn,Fanfair, Dayne,Rosner, Thorsten,Hsiao, Yi
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p. 5677 - 5684
(2013/07/11)
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- An extremely active catalyst for the Negishi cross-coupling reaction
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A new catalyst system for the Pd-catalyzed cross-coupling of organozinc reagents with aryl halides (Negishi coupling) has been developed. This system permits efficient preparation of hindered biaryls (triand tetra-ortho- substituted), functions effectively at low levels of catalyst, and tolerates a wide range of functional groups and heterocyclic substrates. A systematic study of ligand structure was performed and was correlated with catalyst activity.
- Milne, Jacqueline E.,Buchwald, Stephen L.
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p. 13028 - 13032
(2007/10/03)
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