- Development of a Scalable Synthesis for the Potent Kinase Inhibitor BMS-986236; 1-(5-(4-(3-Hydroxy-3-methylbutyl)-1 H-1,2,3-triazol-1-yl)-4-(isopropylamino)pyridin-2-yl)-1 H-pyrazolo[3,4- b]pyridine-5-carbonitrile
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A scalable route to 1-(5-(4-(3-hydroxy-3-methylbutyl)-1H-1,2,3-triazol-1-yl)-4-(isopropylamino)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (1, BMS-986236) was developed by incorporating an alternate azide intermediate following safety-driven processes. The newly developed process involved mitigating safety hazards and eliminating the column chromatography purification. The issue of trace metal contamination in the final API observed in the first-generation synthesis has been overcome.
- Arunachalam, Pirama Nayagam,Kuppusamy, Prakasam,Ganesan, Sivakumar,Krishnamoorthy, Suresh,Nimje, Roshan Y.,Jarugu, Lokesh Babu,Kanikahalli Chikkananjaiah, Nanjundaswamy,Anki Reddy, China,Anjanappa, Prakash,Botlagunta, Murali,Vanteru, Sridhar,Maddala, Nageswararao,Shankar, Muniyappa,Nair, Satheesh,Hynes, John,Santella, Joseph B.,Carter, Percy H.,Rampulla, Richard,Vetrichelvan, Muthalagu,Gupta, Anuradha,Gupta, Arun Kumar,Mathur, Arvind
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supporting information
p. 912 - 918
(2019/05/06)
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- Strategies for the selective functionalization of dichloropyridines at various sites
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Whereas 2,3-dichloropyridine and 2,5-dichloro-4-(lithiooxy)-pyridine undergo deprotonation exclusively at the 4- and 2-positions, respectively, optional site selectivity can be implemented with 2,5- and 3,4-dichloropyridine (which are attacked, depending on the choice of the reagents, at either the 4- or 6- and either the 2- and 5-positions, respectively). Upon treatment with lithium diisopropylamide, 2,4-dichloro-3-iodopyridine, 3,5-dichloro-4-bromopyridine and 2,6-dichloro-3-iodopyridine afford 5-, 2- and 4-lithiated intermediates, but the latter isomerize instantaneously to species in which lithium and iodine have swapped places, the driving force being the low basicity of C-Li bonds when flanked by two neighboring halogens.
- Marzi, Elena,Bigi, Anna,Schlosser, Manfred
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p. 1371 - 1376
(2007/10/03)
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