165896-48-0Relevant articles and documents
Ketone Reductase Biocatalysis in the Synthesis of Chiral Intermediates Toward Generic Active Pharmaceutical Ingredients
Forsyth, Sian M.,Moseley, Jonathan D.,Raynbird, Marina Y.,Sampson, Joanne B.,Smith, Dan A.,Wells, Andrew S.
supporting information, (2020/06/29)
A range of generic active pharmaceutical ingredients were examined for potential chiral alcohol motifs and derivatives within their structures that could be employed as key synthetic intermediates. For seven generic active pharmaceutical ingredients (APIs), eight precursor ketones were acquired and then subjected to reduction by >400 commercially available ketone reductases from different suppliers. Positive screening results were achieved for five ketones screened, with multiple ketone reductases available for each successful ketone. Selectivity was typically >99.5% ee in most cases, including for the opposite enantiomer. The three best examples were then optimized and quickly scaled up to 1 L scale in high conversion and isolated yield while retaining selectivity of >99.5% ee for the desired chiral alcohol enantiomer. This work illustrates that where a wide range of enzymes are available, productive enzymes to give either alcohol enantiomer can be readily identified for many ketones and rapidly scaled up to produce chiral alcohols. This approach is particularly applicable to generating chiral API intermediates.
The palladium-catalyzed aerobic kinetic resolution of secondary alcohols: Reaction development, scope, and applications
Ebner, David C.,Bagdanoff, Jeffrey T.,Ferreira, Eric M.,McFadden, Ryan M.,Caspi, Daniel D.,Trend, Raissa M.,Stoltz, Brian M.
supporting information; experimental part, p. 12978 - 12992 (2010/06/19)
The first palladium-catalyzed enantioselective oxidation of secondary alcohols has been developed, utilizing the readily available diamine (-)-sparteine as a chiral ligand and molecular oxygen as the stoichiometric oxidant. Mechanistic insights regarding the role of the base and hydrogen-bond donors have resulted in several improvements to the original system. Namely, addition of cesium carbonate and tert-butyl alcohol greatly enhances reaction rates, promoting rapid resolutions. The use of chloroform as solvent allows the use of ambient air as the terminal oxidant at 23°C, resulting in enhanced catalyst selectivity. These improved reaction conditions have permitted the successful kinetic resolution of benzylic, allylic, and cyclopropyl secondary alcohols to high enantiomeric excess with good-toexcellent selectivity factors. This catalyst system has also been applied to the desymmetrization of meso-diols, providing high yields of enantioenriched hydroxyketones.
The resolution of important pharmaceutical building blocks by palladium-catalyzed aerobic oxidation of secondary alcohols
Caspi, Daniel D.,Ebner, David C.,Bagdanoff, Jeffrey T.,Stoltz, Brian M.
, p. 185 - 189 (2007/10/03)
The palladium-catalyzed aerobic oxidative kinetic resolution of key pharmaceutical building blocks is described. Substrates investigated are relevant to the enantioselective preparation of Prozac, Singulair, and the promising hNK-1 receptor antagonist from Merck. The latter provides the most selective aerobic oxidative kinetic resolution yet described.
