The Large-Scale Synthesis of (S)-N-Boc-bis(4-fluorophenyl)alanine

Abstract

The synthesis of (S)-N-Boc-bis(4-fluorophenyl)alanine, an intermediate in the synthesis of denagliptin, is described from the synthesis of a 12 g proof of principle sample to a >900 kg cGMP manufacturing campaign. The chiral centre was established by the asymmetric hydrogenation of the sterically crowded precursor, ethyl 2-acetamido-3,3-bis(4-fluorophenyl)acrylate. The ability to isolate the various intermediates in a physical form that would readily allow filtration, washing, and ultimately purification underpinned the successful manufacturing campaign.

Ligand‐Free Palladium‐Catalyzed Oxidative Carbonylative Homocoupling of Arylboron Reagents at Ambient Pressure

“…Fluoro‐substituted potassium aryltrifluoroborates underwent facile carbonylative homocoupling to provide fluorinated biaryl ketones ( 2i and 4c ), which are potentially important intermediates in the synthesis of drugs and organic materials. Indeed, 4c is a key intermediate in the preparation of denagliptin employed for the treatment of type II diabetes . The chloro substituent, a reactive group in Pd‐catalyzed cross‐coupling reactions, could be tolerated by this protocol (compound 2j ).…”

An efficient and recyclable thermoregulated phosphine–palladium catalyst for the carbonylative Suzuki coupling of aryl halides with arylboronic acids in water

“…for the treatment of Type Ⅱ diabetes [35], was produced in 84% yield ( In addition, under the reaction conditions used for aryl bromides, 1,2-diphenylethanone was obtained in 72% yield in the carbonylative coupling of…”

Directed C(sp3)–H arylation of tryptophan: transformation of the directing group into an activated amide

“…We assumed that β-phenylated tryptophan will be suitable for this purpose. While the synthesis of β,β-diaryl α-amino acids bearing two identical aromatic groups was widely elaborated in earlier studies,9 the synthesis of these amino acids containing different aromatic groups is a more challenging endeavor. The construction of β,β-diaryl α-amino acids with different aryl substituents, ensuring full control over two vicinal stereocenters, has stimulated numerous synthetic studies in the field of asymmetric alkylation/conjugate addition,10 asymmetric hydrogenation11 and directed C–H activation 12.…”