- Large-scale Negishi coupling as applied to the synthesis of PDE472, an inhibitor of phosphodiesterase type 4D
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5-[2-Methoxy-5-(4-pyridinyl)phenyl]-2,1,3-benzoxadiazole (PDE472) is a selective inhibitor of the phosphodiesterase PDE4D isoenzyme, which is a recognised drug target for the treatment of asthma. Different synthetic routes to PDE472 were investigated, and the research synthesis was optimised to prepare a phase I batch on pilot-plant scale with the focus on the elimination or minimization of inherent process risks. An important refinement of the key Negishi aryl-aryl coupling involved preforming the arylpalladium complex, which was then added to the arylzinc intermediate. Residual palladium was removed from PDE472 via crystallization of the hemi-maleate salt, which afforded drug-substance containing 2 ppm Pd.
- Manley, Paul W.,Acemoglu, Murat,Marterer, Wolfgang,Pachinger, Werner
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p. 436 - 445
(2013/09/06)
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- Synthesis of 4-(8-benzo[1,2,5]oxadiazol-5-yl-[1,7]naphthyridine-6-yl)-benzoic acid: A potent and selective phosphodiesterase type 4D inhibitor
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The synthesis of a 6,8-disubstituted 1,7-naphthyridine 1 and its characterization as a potent and selective phosphodiesterase type 4D inhibitor (IC50=1.5nM) are described. The compound inhibited TNFα-release from human peripheral blood mononuclear cells and was orally active in a model of adjuvant-induced arthritis in rats.
- Hersperger, Rene,Dawson, Janet,Mueller, Thomas
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p. 233 - 235
(2007/10/03)
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