title: Practical synthesis of a p38 MAP kinase inhibitor.
abstract: p38 MAP kinase inhibitors have attracted considerable interest as potential agents for the treatment of inflammatory diseases. Herein, we describe a concise and efficient synthesis of inhibitor 1 that is based on a phthalazine scaffold. Highlights of our approach include a practical synthesis of a 1,6-disubstituted phthalazine building block 24 as well as the one-pot formation of boronic acid 27. Significant synthetic work to understand the reactivity principles of the intermediates helped in selection of the final synthetic route. Subsequent optimization of the individual steps of the final sequence led to a practical synthesis of 1.
authors.affiliation: Chemical Process Research and Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, USA. michala@amgen.com
authors.forename: Michał
authors.initials: M
authors.lastname: Achmatowicz
authors.forename: Oliver R
authors.initials: OR
authors.lastname: Thiel
authors.forename: Philip
authors.initials: P
authors.lastname: Wheeler
authors.forename: Charles
authors.initials: C
authors.lastname: Bernard
authors.forename: Jinkun
authors.initials: J
authors.lastname: Huang
authors.forename: Robert D
authors.initials: RD
authors.lastname: Larsen
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Faul
mesh_terms: D000577:Amides / Q000737:chemistry; D019817:Benzoic Acid / Q000737:chemistry; D009025:Morpholines / Q000737:chemistry; D010793:Phthalazines / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000577:Amides; D009025:Morpholines; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; C037574:morpholine; D019817:Benzoic Acid; C043388:phthalazine; D048051:p38 Mitogen-Activated Protein Kinases