Welcome to Phase II
Dear Drug Hunter, It’s gotten harder and harder to keep up with everything that’s going on in the industry. From new company launches to drug approvals, endless publications to regulatory updates, the volume of information drug discovery leaders need to make good decisions seems endless. Our mission is to save you time by curating industry…
2021 Pantheon Award for Scientific Advancement
Afternote: We’re pleased to see Dan Erlanson made it as a finalist in the awards and Amgen’s sotorasib won “Product of the Year.” Well deserved! Thanks to our readers for voting. Which drug hunters are making the greatest scientific contributions to drug discovery R&D? Our non-profit partner, California Life Sciences, is currently taking nominations for scientists…
Merck/Codexis Magic: Biocatalytic Synthesis of Islatravir
By Michael Lambrecht We all knew process scientists were good, but the Merck and Codexis teams just took it to another level! Unnatural nucleosides like Merck’s reverse transcriptase inhibitor islatravir (1, Figure 1) are well-known to be challenging to synthesize by traditional methods, as evidenced by several published chemical syntheses of this molecule requiring a…
A Non-Nitrogen Containing Morpholine Isostere
Scientists from GlaxoSmithKline’s Stevenage site have an excellent article in J. Med. Chem. showing that cyclopropyl pyran (CPP) groups can serve as viable isosteres to N-pyrimidyl morpholines thanks in part to favorable cyclopropane σ -> aryl π interactions. N-aryl morpholines are privileged motifs in drug discovery, and suitable hydrogen-bond accepting isosteres are scarce. This is…
Adventures in Atropisomerism: A Case Study from BMS
BMS-986142 is a reversible BTK inhibitor with two axial stereocenters. BMS synthetic chemists were able to make >200 kilos of this compound as a single isomer using this route. Wow. Atropisomers are a nightmare in drug discovery. Axial stereocenters are not easy to set predictably, separation of isomers is a pain, and the products are…
A Trick to Fluorinate Grignards
Knochel’s group has shown that you can fluorinate Grignard reagents without decomposition via single-electron transfer reactivity (SET) by a simple solvent switch from THF to DCM. A common way to prepare aryl fluorides is through lithium-halogen exchange, followed by trapping with N-fluorosulfonimide (NFSI). This isn’t always viable, as the alkyllithium reagents used in the exchange…