Practical synthesis of a p38 MAP kinase inhibitor.
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.
Achmatowicz
Michał
M
Chemical Process Research and Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, USA. michala@amgen.com
Thiel
Oliver R
OR
Wheeler
Philip
P
Bernard
Charles
C
Huang
Jinkun
J
Larsen
Robert D
RD
Faul
Margaret M
MM
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*
D000577:Amides; D009025:Morpholines; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; C037574:morpholine; D019817:Benzoic Acid; C043388:phthalazine; D048051:p38 Mitogen-Activated Protein Kinases