Toluene → HCID 11237883, compound

Participants

Reaction Steps

A solution of 1-N-Boc-4-amino piperidine (300 mg, 1.49 mmol) (Astatech) and triethylamine (840 μL, 606 mg, 5.99 mmol) (Aldrich) in anhydrous dichloromethane (10 mL) was treated at 0° C. with a 20% solution of phosgene in toluene (1.47 mL, 2.99 mmol) (Fluka). After stirring for 30 minutes the mixture was partitioned between 0.5 M aqueous hydrochloric acid and dichloromethane. The organic layer was then collected, washed with brine, dried over sodium sulfate and concentrated. The residue was dissolved in diethyl ether (approx. 6 mL) and the resulting solution was filtered and concentrated. The residue was then dissolved in a small volume of anhydrous tetrahydrofuran (approx. 3 mL) and transferred via cannula to a −78° C. solution of [(2,4-dichloropyrimidin-5-yl)methyl](4-methoxyphenyl)amine (300 mg, 1.06 mmol) (from Example 1d supra) and n-butyllithium (2.5 M solution in hexanes, 0.51 mL, 1.27 mmol) in anhydrous tetrahydrofuran (20 mL). The reaction mixture was allowed to slowly warm to room temperature and stirred for 4 hours before it was partitioned between ethyl acetate and brine. The organic layer was then collected, dried over sodium sulfate, filtered, concentrated and the residue was purified by chromatography on a silica gel column with 0–60% ethyl acetate in hexanes. The product from this purification was then dissolved in aniline (2 mL) (Aldrich) and the resulting solution was heated at 80° C. for a period of 12 hours. The reaction mixture was then cooled, and purified by silica gel column chromatography using a 0–70% ethyl acetate in hexanes gradient to afford the product. After a precipitation out of THF with excess of pentane, 4-[3-(4-methoxy-phenyl)-2-oxo-7-phenylamino-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was isolated as an off white solid. (Yield 74 mg, 13%).

Provenance & Evidence