Synthesis of a 6-CF3-Substituted 2-Amino-dihydro-1,3-thiazine β-Secretase Inhibitor by N, N-Diethylaminosulfur Trifluoride-Mediated Chemoselective Cyclization

J Org Chem. 2019 Apr 19;84(8):4893-4897. doi: 10.1021/acs.joc.8b02179. Epub 2018 Oct 29.

Abstract

The synthesis of a 6-CF3-substituted 2-amino-dihydro-1,3-thiazine via N, N-diethylaminosulfur trifluoride (DAST)-mediated cyclization of N-hydroxypropyl thiourea 6 is described. This reaction gave 6-CF3-1,3-thiazine 7 with high chemical yield and chemoselectivity, suppressing the common byproduct of oxazine 8. This new protocol enabled access to 6-CF3-substituted 1,3-thiazine β-secretase inhibitor 2.

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Cyclization
  • Diethylamines / chemistry
  • Diethylamines / pharmacology*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Fluorine / chemistry
  • Fluorine / pharmacology*
  • Humans
  • Molecular Structure
  • Thiazines / chemical synthesis
  • Thiazines / chemistry
  • Thiazines / pharmacology*

Substances

  • Diethylamines
  • Enzyme Inhibitors
  • Thiazines
  • Fluorine
  • diethylaminosulfur trifluoride
  • Amyloid Precursor Protein Secretases