Toluene → (R)-3-(4-methoxy-phenyl)-7-phenylamino-1-(tetrahydrofuran-3-yl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one

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Reaction Steps

To a solution of (R)-2-methylsulfanyl-4-(tetrahydrofuran-3-ylamino)-pyrimidine-5-carboxylic acid ethyl ester (1.0 g, 3.55 mmol) (from Example 11a supra) at 0° C. in anhydrous tetrahydrofuran (60 mL) was added in portions solid lithium aluminum hydride (400 mg, 10.65 mmol) (Aldrich). The resulting slurry was allowed to slowly warm up to room temperature. After overnight stirring the slurry was poured slowly into a vigorously stirred mixture of ethyl acetate and saturated aqueous potassium sodium tartrate solution. The organic layer was separated, dried over sodium sulfate, filtered and concentrated to give the crude reduction product. This crude intermediate was dissolved in dichloromethane (30 mL) and treated with manganese dioxide (2.9 g, 34.27 mmol) (Aldrich). After stirring for 2 hours the solids were filtered, washed with tetrahydrofuran (approx. 30 mL), the combined filtrate was concentrated and the residue was dissolved in toluene (40 mL). The solution was then treated with p-anisidine (470 mg, 3.77 mmol) (Aldrich), a catalytic amount of p-toluenesulfonic acid mono-hydrate (Aldrich) was added and the mixture was heated at reflux using a Dean-Stark apparatus for 3 hours. The mixture was then cooled and partitioned between ethyl acetate and saturated aqueous potassium carbonate. The ethyl acetate layer was collected, dried over sodium sulfate, filtered, and concentrated to a residue that was then dissolved in tetrahydrofuran (40 mL). The resulting solution was treated at 0° C. with lithium aluminum hydride (390 mg, 10.28 mmol) (Aldrich). The slurry was allowed to slowly warm to room temperature and after stirring for 13.5 hours was poured slowly into a vigorously stirred mixture of ethyl acetate and saturated aqueous potassium sodium tartrate solution. The organic layer was separated, dried over sodium sulfate, filtered, concentrated and the resulting residue was purified by silica gel column chromatography using a 0–70% ethyl acetate in hexanes gradient. The intermediate isolated from this purification was dissolved in tetrahydrofuran (50 mL). Triethylamine (1 mL) (Aldrich) was added and the solution was cooled to 0° C. Followed a dropwise addition of 20% phosgene in toluene solution (1.3 mL, 2.71 mmol) (Fluka) and stirring at 0° C. for 1.5 hours. The mixture was then partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate, filtered and concentrated to a residue that was purified by chromatography on a silica gel column with a 0–40% ethyl acetate in hexanes gradient. The intermediate isolated from this purification was dissolved in tetrahydrofuran (50 mL) and the resulting solution was cooled at 0° C. and treated with 3-chloroperoxybenzoic acid (75%, 1.13 g, 4.93 mmol) (Aldrich). The reaction mixture was allowed to slowly warm up to room temperature and after stirring overnight was partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate, filtered and concentrated. The residue was dissolved in aniline (10 mL) (Aldrich), a catalytic amount of aniline hydrochloride (Aldrich) was added and the resulting solution was stirred for 4.5 hours at 95° C. The mixture was then cooled and purified by silica gel column chromatography using a 0–100% ethyl acetate in hexanes gradient to afford the product. Trituration with pentane yielded (R)-3-(4-methoxy-phenyl)-7-phenylamino-1-(tetrahydrofuran-3-yl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as an off-white solid. (Yield 740 mg, 50%).

Provenance & Evidence