Reference

A novel synthesis of guanine PDE inhibitors via tricyclic imidazopyrimidines

A novel synthesis of guanine PDE inhibitors via tricyclic imidazopyrimidines. Gala, Dinesh; DiBenedetto, Donald J.; Kugelman, Max; Mitchell, Michael B. (Schering-Plough Research Institute, Union, NJ 07083, USA). Tetrahedron Letters, 44(13), 2721-2723 (English) 2003 Elsevier Science Ltd. CODEN: TELEAY. ISSN: 0040-4039. DOCUMENT TYPE: Journal CA Section: 28 (Heterocyclic Compounds (More Than One Hetero Atom)) A new method for the prepn. of developmental tetracyclic guanine PDE inhibitors via a common tricyclic pyrimidine intermediate is described. Nitration of 6-amino-3-methyl-2-(methylthio)-4(3H)-Pyrimidinone gave 6-amino-3-methyl-2-(methylthio)-5-nitro-4(3H)-Pyrimidinone in 80% yield. Reaction of the latter with (1R,2R)-2-aminocyclopentanol gave rel-6-amino-2-[[(1R,2R)-2-hydroxycyclopentyl]amino]-3-methyl-5-nitro-4( 3H)-pyrimidinone. Cyclization of the latter gave (5aR,8aS)-rel-4-amino-1,5a,6,7,8,8a-hexahydro-1-methyl-3-nitro-2H-cy clopent[4,5]imidazo[1,2-a]pyrimidin-2-one (I) as the key intermediate for rel-N-[(5aR,8aS)-4-amino-1,5a,6,7,8,8a-hexahydro-1-methyl-2-oxo-2H- cyclopent[4,5]imidazo[1,2-a]pyrimidin-3-yl]-4-(trifluoromethyl)benzamid e (65% yield from I) and rel-N-[(5aR,8aS)-4-amino-1,5a,6,7,8,8a-hexahydro-1-methyl-2-oxo-2H- cyclopent[4,5]imidazo[1,2-a]pyrimidin-3-yl]heptanamide (81% yield from I). These compds. are intermediates for guanine PDE inhibitors (6aR,9aS)-rel-5,6a,7,8,9,9a-hexahydro-5-methyl-2-[[4-(trifluoromethyl)p henyl]methyl]cyclopent[4,5]imidazo[2,1-b]purin-4(1H)-one (Sch 51866) and (6aR,9aS)-rel-2-hexyl-5,6a,7,8,9,9a-hexahydro-5-methylcyclopent[4,5]i midazo[2,1-b]purin-4(1H)-one (Sch 59498).