Toluene → (-)-(1R,3R)-1-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one

Participants

Reaction Steps

To a mixture of (+)-(1R,3R)-4-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (710 mg, 1.73 mmol) (from Example 27d supra) in anhydrous tetrahydrofuran (50 mL) at 0° C. was added in portions lithium aluminum hydride (196 mg, 5.19 mmol) (Aldrich). The slurry that resulted was allowed to slowly warm up to room temperature and after stirring for 5.5 hours was poured in portions to a vigorously stirred mixture of ethyl acetate and saturated aqueous potassium sodium tartrate solution. The organic layer was then collected, dried over sodium sulfate, filtered and concentrated to a solid residue that was dissolved in dichloromethane (50 mL). To this solution was added manganese dioxide (1.5 g, 17.30 mmol) (Aldrich) and the resulting slurry was stirred for 3.5 hours and then filtered. The solids were washed with tetrahydrofuran (approximately 30 mL) and the combined filtrate was concentrated to a residue that was dissolved in benzene (60 mL). That solution was treated with p-anisidine (180 mg, 1.49 mmol) (Aldrich) and p-toluenesulfonic acid mono-hydrate (25 mg) (Aldrich) and refluxed using a Dean Stark apparatus overnight. The mixture was then cooled, partitioned between ethyl acetate and water and the organic layer was collected, dried over sodium sulfate, filtered and concentrated. The residue was dissolved in anhydrous tetrahydrofuran (50 mL) and the solution that resulted was cooled at 0° C. To this solution was added lithium aluminum hydride (150 mg, 4.08 mmol) in small portions and the slurry that formed was allowed to slowly warm up to room temperature. After stirring overnight the slurry was poured in portions into a mixture of ethyl acetate and saturated aqueous potassium sodium tartrate solution. The organic layer was collected, dried over sodium sulfate, filtered and concentrated and the residue was purified by chromatography on a silica gel column with a 0–30% ethyl acetate in hexanes gradient. The intermediate obtained from that purification was then dissolved in dichloromethane (80 mL) and that solution was treated with triethylamine (490 μL, 0.35 g, 3.47 mmol) (Aldrich) and cooled at 0° C. This was followed by a dropwise addition of a 20% phosgene in toluene solution (570 μL, 1.16 mmol) (Fluka). The reaction mixture was stirred at 0° C. for 20 minutes and at room temperature for 1 hour and then partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on a silica gel column with a 0–30% ethyl acetate in hexanes gradient. The intermediate from this purification was dissolved in tetrahydrofuran (50 mL). This solution was then treated with 3-chloroperoxy-benzoic acid (75%, 320 mg, 1.43 mmol) (Aldrich) stirred overnight and partitioned between ethyl acetate and saturated aqueous potassium carbonate solution. The organic layer was collected, dried over sodium sulfate, filtered and concentrated to a solid residue. This residue was dissolved in aniline (3 mL) (Aldrich) and stirred at 75° C. for 16.5 hours. The mixture was then cooled, and purified by silica gel column chromatography with a 0–20% diethyl ether in toluene gradient to give (−)-(1R,3R)-1-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as an off-white solid. (Yield 152 mg, 68%).

Provenance & Evidence