A solution of (±)-trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamine (270 mg, 1.25 mmol) (from Example 9b supra) and triethylamine (1.15 mL, 840 mg, 8.30 mmol) (Aldrich) in dichloromethane (5 mL) was treated at 0° C. with a 20% solution of phosgene in toluene (2 mL, 4.15 mmol) (Fluka). After stirring for 30 minutes the mixture was filtered and the filtrate was concentrated to a small volume. Benzene (5 mL) was added and the mixture was filtered again. The filtrate was concentrated, the residue was dissolved in a small volume of anhydrous tetrahydrofuran (approx. 3 mL) and then transferred via a cannula to a −78° C. solution of (2,4-dichloro-pyrimidin-5-yl-methyl)-(4-methoxyphenyl)-amine (180 mg, 0.63 mmol) (from Example 1d supra) and n-butyllithium (2.5 M solution in hexanes, 250 μL, 0.63 mmol) (Aldrich) in anhydrous tetrahydrofuran (15 mL). The reaction mixture was allowed to slowly warm up to room temperature, stirred for 5.5 hours and then partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate, filtered, concentrated and the residue was purified by chromatography on a silica gel column with a 0–40% ethyl acetate in hexanes gradient. The intermediate obtained from this purification was dissolved in aniline (2 mL) (Aldrich), a catalytic amount of 4-(dimethylamino)pyridine (Aldrich) was added and the resulting solution was stirred for 7 hours at 80° C. The mixture was then cooled and purified by silica gel column chromatography using a 0–40% ethyl acetate in hexanes gradient. The product from this purification was dissolved in acetonitrile (3 mL), 5% aqueous hydrofluoric acid (50 μL) was added and the mixture was stirred for 21 hours. The reaction mixture was then concentrated to a small volume and purified by silica gel column chromatography using a 0–100% tetrahydrofuran in hexanes gradient to afford the product. After a precipitation out of dichloromethane with excess of pentane, the product, (±)-1-(trans-3-hydroxy-cyclopentyl)-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, was isolated as a white solid. (Yield 23 mg, 8%).
