title: Synthesis of Verubecestat, a BACE1 Inhibitor for the Treatment of Alzheimer's Disease.
abstract: Verubecestat is an inhibitor of β-secretase being evaluated for the treatment of Alzheimer's disease. The first-generation route relies on an amide coupling with a functionalized aniline, the preparation of which introduces synthetic inefficiencies. The second-generation route replaces this with a copper-catalyzed C-N coupling, allowing for more direct access to the target. Other features of the new route include a diastereoselective Mannich-type addition into an Ellman sulfinyl ketimine and a late-stage guanidinylation.
authors.forename: David A
authors.initials: DA
authors.lastname: Thaisrivongs
authors.forename: Steven P
authors.initials: SP
authors.lastname: Miller
authors.forename: Carmela
authors.initials: C
authors.lastname: Molinaro
authors.forename: Qinghao
authors.initials: Q
authors.lastname: Chen
authors.forename: Zhiguo J
authors.initials: ZJ
authors.lastname: Song
authors.forename: Lushi
authors.initials: L
authors.lastname: Tan
authors.affiliation: WuXi AppTec (Shanghai) Pharmaceutical Co., Ltd., 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Chen
authors.forename: Wenyong
authors.initials: W
authors.lastname: Chen
authors.forename: Azzeddine
authors.initials: A
authors.lastname: Lekhal
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Pulicare
authors.forename: Yanke
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002384:Catalysis; D060326:Chemistry Techniques, Synthetic; D003300:Copper / Q000737:chemistry; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D015394:Molecular Structure; D013829:Thiadiazines / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D003499:Cyclic S-Oxides; D013829:Thiadiazines; D003300:Copper; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C000613570:verubecestat