Development of a Direct Photocatalytic C-H Fluorination for the Preparative Synthesis of Odanacatib.
Late-stage C-H fluorination is an appealing reaction for medicinal chemistry. However, the application of this strategy to process research appears less attractive due to the formation and necessary purification of mixtures of organofluorines. Here we demonstrate that γ-fluoroleucine methyl ester, an intermediate critical to the large-scale synthesis of odanacatib, can be accessed directly from leucine methyl ester using a combination of the decatungstate photocatalyst and N-fluorobenzenesulfonimide in flow. This efficient C-H fluorination reaction compares favorably with several generations of classical γ-fluoroleucine process syntheses.
Department of Chemistry, Simon Fraser University , Burnaby, British Columbia, Canada.
Shira D
SD
Halperin
Department of Chemistry, Simon Fraser University , Burnaby, British Columbia, Canada.
Daniel
D
Kwon
Department of Chemistry, Simon Fraser University , Burnaby, British Columbia, Canada.
Michael
M
Holmes
Department of Process Chemistry, Merck Research Laboratories , Rahway, New Jersey, United States.
Erik L
EL
Regalado
Department of Process Chemistry, Merck Research Laboratories , Rahway, New Jersey, United States.
Louis-Charles
LC
Campeau
Department of Process Chemistry, Merck Research Laboratories , Rahway, New Jersey, United States.
Daniel A
DA
DiRocco
Department of Chemistry, Simon Fraser University , Burnaby, British Columbia, Canada.
Robert
R
Britton
D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D056657:Cathepsin K / Q000037:antagonists & inhibitors; D004952:Esters; D054879:Halogenation; D007930:Leucine / Q000031:analogs & derivatives / Q000737:chemistry; D015394:Molecular Structure; D013449:Sulfonamides / Q000737:chemistry; D000096926:Benzenesulfonamides
D001713:Biphenyl Compounds; D056657:Cathepsin K; D004952:Esters; D007930:Leucine; D013449:Sulfonamides; C030365:leucine methyl ester; C523711:N-fluorobenzenesulfonimide; D000096926:Benzenesulfonamides; C527128:odanacatib