Synfacts 2018; 14(09): 0885
DOI: 10.1055/s-0037-1610562
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of a Bruton’s Tyrosine Kinase Inhibitor

Contributor(s):
Philip Kocienski
Razler TM. * et al. Bristol-Myers Squibb Company, New Brunswick, USA
Adventures in Atropisomerism: Total Synthesis of a Complex Active Pharmaceutical Ingredient with Two Chirality Axes.

Org. Lett. 2018;
20: 3736-3740
Further Information

Publication History

Publication Date:
20 August 2018 (online)

 

Significance

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.


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Comment

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.


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