Synthesis of a BACE1 Inhibitor

Key words

BACE1 inhibitor - Alzheimer’s disease - thioureas - 2-amino-1,3-oxazines - N-arylation - copper(I) iodide

Significance

The target molecule L, an inhibitor of the β-amyloid cleaving enzyme 1 (BACE1), is of interest for the treatment of Alzheimer’s disease. A synthesis of L was recently disclosed (US 2019 0106434 A1) that features the reaction of N-benzoyl thiourea G with TMSCl in DMSO at 10 °C to give 2-amino-1,3-oxazine I in 96% yield. Eight simpler examples of the cyclization reaction are described.

Comment

The key cyclization reaction G → H can be performed by reacting either TMSCl or HCl with DMSO to form sulfonium salts, which can activate the thiourea, enabling the elimination of dimethyl sulfide and sulfur to form a carbodiimide intermediate, which cyclizes to form the 2-amino-1,3-oxazine. The overall yield for the 18-step synthesis is 7.5%

Publication History

Article published online:
16 February 2021