Comprehensive Synthetic Route Redesign of AZD5991: A High-Complexity Atropisomeric Macrocycle We describe our approach to the total synthesis of AZD5991 (1) from a process development perspective through the complete redesign of our synthetic strategy from the ground up. The size and complexity of small-molecule therapeutic targets have continued to increase over recent decades. One such example, 1, is arguably the most complex active pharmaceutical ingredient (API) in AstraZeneca’s small molecule development portfolio to date and poses formidable synthetic challenges. The previous racemic synthesis of 1 was sufficient to supply early clinical activities; however, the route was not deemed commercially viable and had significant environmental challenges. The identification of a long-term sustainable route was therefore critical to enable the robust manufacture of drug substance for later clinical activities and launch. We report exploration of asymmetric approaches toward the atropisomeric core, new routes toward each of the four heterocyclic building blocks, including a divergent pyrazole functionalization, and final assembly in a scalable and controlled macrocyclization process. These improvements resulted in a 49% reduction in step count and 95% reduction in projected waste generation.

For #ChemSky #SynthesisSaturday here’s a very cool #OPRD on a process scalemacrocycle from GSK and my pal Ollie Ring
I’ve seen this story in talk form and there’s some excellent chemistry in here

A Chiral Pool Strategy for the Synthesis of a SMARCA2 Degrading PROTAC A scalable synthesis of the SMARCA2 degrading PROTAC 1 was developed. The linker fragment was derived from (S)-citronellol by oxidative cleavage and diastereoselective aryl Grignard addition to a deri...

It’s not every day you open up OPRD and see some degrader scale-up chemistry, so here you go. #SynthesisSaturday

Drug Discovery Axiom 5: make more compound than you think you need.

Something always comes up, no matter the project’s stage. 50% more is a good rule of thumb. Resynthesis takes time; time costs money.

#SynthesisSaturday