- Hindered dialkyl ether synthesis with electrogenerated carbocations
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Hindered ethers are of high value for various applications; however, they remain an underexplored area of chemical space because they are difficult to synthesize via conventional reactions1,2. Such motifs are highly coveted in medicinal chemistry, because extensive substitution about the ether bond prevents unwanted metabolic processes that can lead to rapid degradation in vivo. Here we report a simple route towards the synthesis of hindered ethers, in which electrochemical oxidation is used to liberate high-energy carbocations from simple carboxylic acids. These reactive carbocation intermediates, which are generated with low electrochemical potentials, capture an alcohol donor under non-acidic conditions; this enables the formation of a range of ethers (more than 80 have been prepared here) that would otherwise be difficult to access. The carbocations can also be intercepted by simple nucleophiles, leading to the formation of hindered alcohols and even alkyl fluorides. This method was evaluated for its ability to circumvent the synthetic bottlenecks encountered in the preparation of 12 chemical scaffolds, leading to higher yields of the required products, in addition to substantial reductions in the number of steps and the amount of labour required to prepare them. The use of molecular probes and the results of kinetic studies support the proposed mechanism and the role of additives under the conditions examined. The reaction manifold that we report here demonstrates the power of electrochemistry to access highly reactive intermediates under mild conditions and, in turn, the substantial improvements in efficiency that can be achieved with these otherwise-inaccessible intermediates.
- Xiang, Jinbao,Shang, Ming,Kawamata, Yu,Lundberg, Helena,Reisberg, Solomon H.,Chen, Miao,Mykhailiuk, Pavel,Beutner, Gregory,Collins, Michael R.,Davies, Alyn,Del Bel, Matthew,Gallego, Gary M.,Spangler, Jillian E.,Starr, Jeremy,Yang, Shouliang,Blackmond, Donna G.,Baran, Phil S.
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p. 398 - 402
(2019/11/05)
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- ISOXAZOLYL-CARBONYLOXY AZABICYCLO[3.2.1]OCTANYL COMPOUNDS AS FXR ACTIVATORS
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The disclosure relates to activators of FXR useful in the treatment of autoimmune disorders, liver disease, intestinal disease, kidney disease, cancer, and other diseases in which FXR plays a role, having the Formula (I): wherein L1, L2, A, B, R1, R2, R3, and R4 are described herein.
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- HETEROCYCLES USEFUL AS IDO AND TDO INHIBITORS
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Provided are compounds of Formula (I) shown below using for treatment of diseases or disorders mediated by IDO and/or TDO, pharmaceutical compositions and methods of preparation thereof.
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Paragraph 146
(2016/10/31)
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- PYRAZOLES AND METHODS OF MAKING AND USING THE SAME
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The invention is based on the discovery that compounds of formula I possess unexpectedly high affinity for Alk 5 and/or Alk 4, and can be useful as antagonists thereof for preventing and/or treating numerous diseases, including fibrotic disorders. In one embodiment, the invention features a compound of formula I (I).
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- BENZAMIDINE DERIVATIVES SUBSTITUTED BY CYCLIC AMINO ACID AND CYCLIC HYDROXY ACID DERIVATIVES AND THEIR USE AS ANTI-COAGULANTS
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This invention is directed to benzamidine derivatives substituted by cyclic amino acid and cyclic hydroxy acid derivatives which are useful as anti-coagulants. This invention is also directed to pharmaceutical compositions containing the compounds of the invention, and methods of using the compounds to treat disease-states characterized by thrombotic activity.
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- Synthesis of 4-Substituted Bicyclooct-1-yl Fluorides
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The main details of the synthesis of a series of 4-substituted (X) bicyclooct-1-yl fluorides (1), which were required for substituent effect studies, are presented.The synthesis of most of these compounds 1, X = NO2, CN, CONH2, COCH3, CHO, OCH3, O
- Adcock, William,Abeywickrema, Anil N.
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p. 2951 - 2957
(2007/10/02)
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