A practical chromatography-free synthesis of a 5,6-dihydroimidazolo[1,5-f]pteridine derivative as a polo-like kinase-1 inhibitor

• Published in: Tetrahedron 2018-09, Vol.74 (39), p.5779-5790
• Main Authors: Ishimoto, Kazuhisa, Nakaoka, Keiichiro, Yabe, Osamu, Nishiguchi, Atsuko, Ikemoto, Tomomi
• Format: Article
• Language: English
• Subjects: 5,6-dihydroimidazolo[1,5-f]pteridine; Amination; Chromatography-free synthesis; Piperazine ring formation; Polo-like kinase-1 inhibitor; trans 1,4-cyclohexyldiamine
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2018.08.020

A practical chromatography-free synthesis of a potent polo-like kinase-1 inhibitor possessing a unique 5,6-dihydroimidazolo[1,5-f]pteridine structure has been developed. We showed that key cyanoimidazole ring formation could be conducted at benign temperature and obtained a chiral 5,6-dihydroimidazolo[1,5-f]pteridine derivative in good yield without epimerization. An aniline derivative containing a trans 1,4-cyclohexyl diamine structure was prepared by a synthesis that makes use of defined stereocenters of commercially available trans-cyclohexane-1,4-diamine via selective piperazine ring formation from a primary diamine. A coupling reaction of the 3-chloro-5,6-dihydroimidazolo[1,5-f]pteridine derivative and the aniline derivative in the endgame was closely investigated, and good yields were achieved both by palladium-catalyzed amination and acid-promoted coupling under benign reaction conditions. As a result of these investigations, the polo-like kinase-1 inhibitor was successfully obtained in a practical way without concern for generation/separation of stereoisomers. [Display omitted]