Synthesis of a Bruton’s Tyrosine Kinase Inhibitor
Adventures in Atropisomerism: Total Synthesis of a Complex Active Pharmaceutical Ingredient with Two Chirality Axes.
Org. Lett. 2018;
20. August 2018 (online)
Key wordsBruton’s tyrosine kinase inhibitor - atropisomerism - chirality axes - dynamic diastereoselection - asymmetric Suzuki–Miyaura reaction
The target molecule N is a Bruton’s tyrosine kinase (BTK) inhibitor that is of interest for the treatment of rheumatoid arthritis. A major challenge in the synthesis depicted is the construction of the two axes of chirality marked α and β. Rotation about these chiral axes gives four possible atropisomeric diastereoisomers. While the higher-energy C–C chirality axis α is relatively stable (rotational barrier 28 kcal/mol), the lower-energy C–N bond β (rotational barrier 26 kcal/mol) has a rotational half-life of hours to days, with a risk of epimerization.
The chiral axis α was constructed using an asymmetric Suzuki–Miyaura reaction at 5 °C to afford biaryl K (dr = 16:1). After crystallization from n-BuOH, K was obtained with dr = 65:1. The chiral axis β was created by crystallization-induced diastereoselection at 25 °C. Compound N was obtained in 90% yield and dr > 99:1. Thus the higher barrier diastereoisomer K acted as a chiral template to construct the stereochemical configuration of lower barrier bond β. This route delivered >200 kg of the target compound N in 28.3% overall yield.