- Asymmetric synthesis of letermovir using a novel phase-Transfer-catalyzed aza-michael reaction
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The development of a concise asymmetric synthesis of the antiviral development candidate letermovir is reported, proceeding in 60% yield over a total of seven steps from commercially available materials. Key to the effectiveness of this process is a nove
- Humphrey, Guy R.,Dalby, Stephen M.,Andreani, Teresa,Xiang, Bangping,Luzung, Michael R.,Song, Zhiguo Jake,Shevlin, Michael,Christensen, Melodie,Belyk, Kevin M.,Tschaen, David M.
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- Asymmetric Hydrogen Bonding Catalysis for the Synthesis of Dihydroquinazoline-Containing Antiviral, Letermovir
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A weak Br?nsted acid-catalyzed asymmetric guanidine aza-conjugate addition reaction has been developed. C2-symmetric, dual hydrogen-bond donating bistriflamides are shown to be highly effective in activating α,β-unsaturated esters toward the intramolecular addition of a pendant guanidinyl nucleophile. Preliminary mechanistic investigation, including density functional theory calculations and kinetics studies, support a conjugate addition pathway as more favorable energetically than an alternative electrocyclization pathway. This methodology has been successfully applied to the synthesis of the 3,4-dihydroquinazoline-containing antiviral, Letermovir, and a series of analogues.
- Chung, Cheol K.,Liu, Zhijian,Lexa, Katrina W.,Andreani, Teresa,Xu, Yingju,Ji, Yining,Dirocco, Daniel A.,Humphrey, Guy R.,Ruck, Rebecca T.
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- Combining traditional 2D and modern physical organic-derived descriptors to predict enhanced enantioselectivity for the key aza-Michael conjugate addition in the synthesis of Prevymis (letermovir)
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Quantitative structure-activity relationships have an extensive history for optimizing drug candidates, yet they have only recently been applied in reaction development. In this report, the predictive power of multivariate parameterization has been explored toward the optimization of a catalyst promoting an aza-Michael conjugate addition for the asymmetric synthesis of letermovir. A hybrid approach combining 2D QSAR and modern 3D physical organic parameters performed better than either approach in isolation. Using these predictive models, a series of new catalysts were identified, which catalyzed the reaction to provide the desired product in improved enantioselectivity relative to the parent catalyst.
- Mets?nen, Toni T.,Lexa, Katrina W.,Santiago, Celine B.,Chung, Cheol K.,Xu, Yingju,Liu, Zhijian,Humphrey, Guy R.,Ruck, Rebecca T.,Sherer, Edward C.,Sigman, Matthew S.
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p. 6922 - 6927
(2018/09/11)
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- NOVEL PROCESSES FOR MAKING SUBSTITUTED QUINAZOLINE COMPOUNDS USING HYDROGEN BONDING CATALYSTS
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Disclosed herein is a novel process for preparing substituted quinazoline compounds of formula (I) using a hydrogen bonding catalyst.
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Page/Page column 11; 12; 13; 14; 15; 16 20; 21; 22
(2017/08/01)
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- METHOD FOR PRODUCING DIHYDROQUINAZOLINES
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The present invention relates to a method for producing dihydroquinazolines of formula (I), which are used to manufacture medicaments.
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