Benzyl 4-{2-[(di-tert-butoxyphosphoryl)oxy]ethyl}-3-oxopiperazine-1-carboxylate → Di-tert-butyl 2-(2-oxopiperazin-1-yl)ethyl phosphate

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Reaction Steps

Benzyl 4-{2-[(di-tert-butoxyphosphoryl)oxy]ethyl}-3-oxopiperazine-1-carboxylate (1.20 g, 2.55 mmol) and 10% palladium on carbon (100 mg) in methanol (25 ml) were stirred at room temperature under an atmosphere of hydrogen for 2 hours and then filtered through Celite. The filtrate was evaporated to give di-tert-butyl 2-(2-oxopiperazin-1-yl)ethyl phosphate as a colourless oil which was dissolved in dimethylacetamide(4.0 ml) containing 2-(4-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-1-yl)-N-(2,3-difluorophenyl)acetamide hydrochloride (326 mg, 0.64 mmol) and potassium iodide (213 mg, 1.28 mmol) and the mixture was then heated at 90° C. for 3 hours. The mixture was cooled to room temperature, poured into dilute aqueous sodium hydrogen carbonate solution and then extracted with a solution of 10% isopropanol in dichloromethane. The organic layer was dried over magnesium sulphate and then evaporated to leave an orange oil. The crude product was purified by silica gel chromatography eluting with 5% methanol in dichloromethane containing 0-4% 7N ammonia in methanol to give di-tert-butyl 2-{4-[3-({4-[(1-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-4-yl)amino]quinazolin-7-yl}oxy)propyl]-2-oxopiperazin-1-yl}ethyl phosphate (211 mg, 43% yield) as a pale yellow solid: MS (+ve ESI): 773 (M+H)+.

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