No abstract

A highly effective and operationally simple method for the regioselective deuteration of anilines is presented. A variety of electron-rich and electron-deficient anilines are efficiently deuterated at the ortho and/or para position with respect to the nitrogen in the presence of 1 equiv of conc HCl in D 2O. Under the present conditions, aromatic methoxy groups do not facilitate deuteration, enabling a chemo- and regioselective deuteration of p-anisidine.

[reaction: see text] Polycyclic thiophenes and furans were synthesized using a one-pot ortho alkylation/direct heteroarylation reaction sequence. Under the optimized reaction conditions, aryl iodides were coupled with 3-(bromoalkyl)thiophenes or -furans, affording six- and seven-membered annulated ring products via formation of two C-C bonds from two aryl C-H bonds.

Over the years, structure-based design programs and specifically docking small molecules to proteins have become prominent in drug discovery. However, many of these computational tools have been developed to primarily dock enzyme inhibitors (and ligands to other protein classes) relying heavily on hydrogen bonds and electrostatic and hydrophobic interactions. In reality, many drug targets either feature metal ions, can be targeted covalently, or are simply not even proteins (e.g., nucleic acids). Herein, we describe several new features that we have implemented into FITTED to broaden its applicability to a wide range of covalent enzyme inhibitors and to metalloenzymes, where metal coordination is essential for drug binding. This updated version of our docking program was tested for its ability to predict the correct binding mode of drug-sized molecules in a large variety of proteins. We also report new datasets that were essential to demonstrate areas of success and those where additional efforts are required. This resource could be used by other program developers to assess their own software.

This manuscript describes the chemical process development and multi-kilogram synthesis of rovafovir etalafenamide (GS-9131), a phosphonamidate prodrug nucleotide reverse transcriptase inhibitor under investigation for the treatment of HIV-1 infection. Rovafovir etalafenamide is assembled in a four-step sequence beginning from the nucleoside core and an elaborated phosphonamidate alcohol. The assembly starts with a decarboxylative elimination of a β-hydroxyacid to yield the corresponding cyclic enol ether, which is subsequently coupled to a functionalized phosphonamidate alcohol in an iodoetherification reaction. Oxidative syn elimination then installs the required fluoroalkene, after which a final deprotection reaction yields the active pharmaceutical ingredient (API). Understanding the genesis, fate, and purge of the des-fluoro analog of the API, a mitochondrial toxin, proved to be a central driver in the development of the manufacturing route and impurity control strategy. Initial control strategies revolved around the use of silica gel chromatography or simulated moving bed chromatography to purge the des-fluoro impurity to an acceptable level, but ultimately a chromatography-free approach to mitigate the formation of this impurity was devised that expanded manufacturing flexibility. Design of experiments was used to improve the iodoetherification fragment coupling reaction and to reduce the level of the des-fluoro impurity formed in this step. Furthermore, several new crystalline intermediate forms were discovered and implemented as isolation points to bolster the overall impurity control strategy for standard, diastereomeric, and potentially mutagenic impurities as well as for the des-fluoro impurity. These processes were executed on multikilogram scale to produce API for clinical studies.