Synthesis of β-Secretase Inhibitor NB-360

Key words

NB-360 - β-secretase 1 inhibitor - Alzheimer's disease - aziridine ring opening - 1,4-oxazine ring formation

Significance

β-Secretase 1 (BACE1) is an aspartic acid protease located primarily in neurons. It is the major β-secretase involved in the generation of ­amyloid-β peptides (Aβ) and their subsequent aggregation to form plaques associated with the onset of Alzheimer’s disease. NB-360 is the latest in a long line of similar amidine-based BACE1 inhibitors that have hitherto failed in phase II/III clinical trials.

Comment

The two quaternary centers in NB-360 shielded the amidine and ether oxygen from undesired chemical and metabolic transformations. The key step in the most practical route to the 1,4-oxazine K entailed the nucleophilic opening of the chiral N-sulfonylaziridine F with the chiral alkoxide derived from E in the presence of potassium tert-butoxide in DMF at 35 °C.

Publication History

Article published online:
17 June 2021