Asymmetric Fluorination Approach to an SYK Inhibitor
Asymmetric Fluorination Approach to the Scalable Synthesis of a SYK Inhibitor.
Org. Process Res. Dev. 2015;
18 September 2015 (online)
Key wordsSYK inhibitor - asymmetric fluorination - N-fluorobenzene-sulfonimide - palladium catalysis - Suzuki–Miyaura cross-coupling
Spleen tyrosine kinase (SYK) is implicated in diverse cellular responses such as proliferation, differentiation, and phagocytosis. The target molecule is a SYK inhibitor that is of interest for the treatment of rheumatoid arthritis, B-cell lymphoma, and asthma. The highly telescoped, large-scale synthesis depicted delivered eight kilograms of API.
The asymmetric fluorination of β-keto ester A using (S)-BINAP as the chiral ligand gave a modest 44% ee but this improved to 72% ee with the bulkier DTBM-SEGPHOS ligand. The best results were obtained by the combined use of a chiral auxiliary (l-menthol) and an enantio- and diastereoselective fluorination (C + D → E) mediated by Pd[(S)-binap](OTf)2.