Desymmetrization of pibrentasvir for efficient prodrug synthesis.

A novel and practical desymmetrization tactic is described to access a new class of pibrentasvir prodrugs. The homotopic benzimidazoles of pibrentasvir (PIB) are differentiated via a one-pot di-Boc/mono-de-Boc selective N-Boc protection and formaldehyde adduct formation sequence, both enabled by crystallization-induced selectivity. The first step represents the only known application of the Horeau principle of statistical amplification for C 2-symmetric polyheterocycle regioselective functionalization. The resulting versatile intermediate is employed in the high-yielding preparation of several pibrentasvir prodrug candidates.

Origin of Nanodroplet Formation Upon Dissolution of an Amorphous Solid Dispersion: A Mechanistic Isotope Scrambling Study.

It has been observed that certain amorphous solid dispersions (ASDs), upon dissolution, generate drug-rich amorphous nanodroplets. These nanodroplets, present as a dispersed phase, can potentially enhance oral bioavailability of poorly soluble drugs by serving as a drug reservoir that efficiently feeds the continuous aqueous solution phase following absorption of drug. The purpose of this study is to probe the formation mechanism of the nanodroplets. The model system studied was nifedipine (NFD) formulated as an ASD with hydroxypropyl methylcellulose E5 Premium LV or polyvinylpyrrolidone/vinyl acetate. Dissolution of ASDs prepared with proteated nifedipine (H-NFD) was carried out in a medium saturated with deuterated nifedipine (D-NFD) at the amorphous solubility. Upon dissolution, the H/D composition of NFD aqueous solution was determined using nuclear magnetic resonance spectroscopy. The results suggested that isotopic scrambling (equilibrium in the distribution of deuterated and proteated form of the drug) had occurred. Thus, as the H-NFD was brought into the aqueous solution via ASD dissolution, the drug concentration in solution exceeded the amorphous solubility. Subsequent precipitation of the drug, a process which does not differentiate H-NFD from D-NFD, generated NFD nanodroplets and resulted in redistribution of the isotopes. Thus, nanodroplets of NFD are formed due to dissolution of these homogenous ASDs followed by precipitation of the drug from aqueous solutions.

Synthesis of novel and uniquely shaped 3-azabicyclo[4.2.0]octan-4-one derivatives by sequential Ugi/[2+2] ene-enone photocycloadditions.

[structure: see text]. We report a new methodology for the construction of novel and uniquely shaped 3-azabicyclo[4.2.0]octan-4-one derivatives by combining the Ugi multicomponent reaction with [2+2] enone-olefin photochemical transformations. The overall sequence is capable of creating up to five stereocenters; however, in most cases, only two diastereomers are observed.