Thomas E. La Cruz

Practical olefin hydroamination with nitroarenes

Stitching C-N bonds from nitro groups Numerous compounds in pharmaceutical research have carbon-nitrogen bonds, and chemists are always looking for ways to make them more efficiently. Gui et al. present a method that links the carbon in an olefin to the nitrogen in a nitroaromatic compound (see the Perspective by Kürti). Nitroaromatics are readily available, and the method tolerates a wide range of other chemical groups present on either reacting partner. Science, this issue p. 886; see also p. 863 A method to form carbon-nitrogen bonds via nitro group reduction could streamline synthetic routes in medicinal chemistry. [Also see Perspective by Kürti] The synthesis and functionalization of amines are fundamentally important in a vast range of chemical contexts. We present an amine synthesis that repurposes two simple feedstock building blocks: olefins and nitro(hetero)arenes. Using readily available reactants in an operationally simple procedure, the protocol smoothly yields secondary amines in a formal olefin hydroamination. Because of the presumed radical nature of the process, hindered amines can easily be accessed in a highly chemoselective transformation. A screen of more than 100 substrate combinations showcases tolerance of numerous unprotected functional groups such as alcohols, amines, and even boronic acids. This process is orthogonal to other aryl amine syntheses, such as the Buchwald-Hartwig, Ullmann, and classical amine-carbonyl reductive aminations, as it tolerates aryl halides and carbonyl compounds.

Multicomponent synthesis of 1-aryl 1,2,4-triazoles.

A multicomponent (single reactor) process for the synthesis of 1-aryl 1,2,4-triazoles was explored and developed. This transformation prepared the 1,2,4-triazole directly from anilines, amino pyridines, and pyrimidines. The reaction scope was explored with 21 different substrates, and the position of the nitrogen atoms in the newly formed ring was established by (15)N labeling and NMR spectroscopy.

Enantioselective Synthesis of a γ-Secretase Modulator via Vinylogous Dynamic Kinetic Resolution

Two efficient asymmetric routes to γ-secretase modulator BMS-932481, under investigation for Alzheimers disease, have been developed. The key step for the first route involves a challenging enantioselective hydrogenation of an unfunctionalized trisubstituted alkene to establish the benzylic stereocenter, representing a very rare case of achieving high selectivity on a complex substrate. The second route demonstrates the first example of a vinylogous dynamic kinetic resolution (VDKR) ketone reduction, where the carbonyl and the racemizable stereocenter are not contiguous, but are conjugated through a pyrimidine ring. Not only did this transformation require both catalyst and substrate control to correctly establish the two stereocenters, but it also necessitated that the nonadjacent benzylic center of the ketone substrate be more acidic than that of the alcohol product to make the process dynamic. DFT computations aided the design of this novel VDKR pathway by reliably predicting the relative acidities of the intermediates involved.

A photochemical kinetic model for solid dosage forms

ABSTRACT Photochemical kinetic models to describe the solution phase degradation of pharmaceutical compounds have been extensively reported, but formalisms applicable to the solid phase under polychromatic light have not received as much attention. The objective of this study was to develop a mathematical model to describe the solid state photodegradation of pharmaceutical powder materials under different area/volumetric scales and light exposure conditions. The model considered the previous formalism presented for photodegradation kinetics in solution phase with important elements applied to static powder material being irradiated with a polychromatic light source. The model also included the influence of optical phenomena (i.e. reflectance, scattering factors, etc.) by applying Beer‐Lambert law to light attenuation, including effects of powder density. Drug substance and drug product intermediates (blends and tablet cores) were exposed to different light sources and intensities. The model reasonably predicted the photodegradation levels of powder beds of drug substance and drug product intermediates under white and yellow lights with intensities around 5–11 kLux. Importantly, the model estimates demonstrated that the reciprocity law for photoreactions was held. Further model evaluation showed that, due to light attenuation, the powder bed is in virtual darkness at cake depths greater than 500 &mgr;m. At 100 &mgr;m, the photodegradation of the investigated compound is expected to be close to 100% in 10 days under white fluorescent halophosphate light at 9.5 kLux. For tablets, defining the volume over exposed surface area ratio is more challenging. Nevertheless, the model can consider a bracket between worst and best cases to provide a reasonable photodegradation estimate. This tool can be significantly leveraged to simulate different light exposure scenarios while assessing photostability risk in order to define appropriate control strategy in manufacturing.