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, a...

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Published inOrganic letters Vol. 17; no. 21; pp. 5200 - 5203
Main Authors Halperin, Shira D, Kwon, Daniel, Holmes, Michael, Regalado, Erik L, Campeau, Louis-Charles, DiRocco, Daniel A, Britton, Robert
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 06.11.2015
Subjects
Biphenyl Compounds - chemical synthesis
Biphenyl Compounds - chemistry
Cathepsin K - antagonists & inhibitors
Esters
Halogenation
Leucine - analogs & derivatives
Leucine - chemistry
Molecular Structure
Sulfonamides - chemistry
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Summary: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.
Bibliography:ObjectType-Article-1
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ISSN:1523-7060
1523-7052
DOI:10.1021/acs.orglett.5b02532