Synfacts 2021; 17(03): 0235
DOI: 10.1055/s-0040-1719374
Synthesis of Natural Products and Potential Drugs

Synthesis of a BACE1 Inhibitor

Philip Kocienski
Richardson J, *, Lindsay-Scott PJ, Larichev V, Pocock E. Eli Lilly and Company, Windlesham, UK
Efficient Method for the Synthesis of Amino-1,3-Oxazines from Thioureas.

Org. Process Res. Dev. 2020;
24: 2853-2863
DOI: 10.1021/acs.oprd.0c00369.


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.



The key cyclization reaction GH 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%



16. Februar 2021 (online)

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