Urea Nucleosides as Diagnostic and Therapeutic Agents

Title Urea Nucleosides as Therapeutic and Diagnostic Agents G. Kirschenheuter, US Patent 6,914,138 (July 5, 2005) 

Invention Significance Only a limited number of nucleosides exist that 

A suspension of 5-iodouridine (27 mmol) and 0.5 g of toluenesulfonic acid in 600 ml acetone were refluxed 4 hours and then passed through an addition funnel packed with 4 A molecular sieves. The reaction volume was then reduced to approximately 150 ml and passed through a 125 ml pad of flash silica gel eluting with 500 ml acetone. The solution was concentrated, then recrystallized using 225 ml ethyl alcohol, and the product isolated in 87% yield as a white crystalline solid. 

A mixture consisting of the Step 1 product (10 mmol), palladium(II) acetate (2.0 mmol), copper(I) iodide (6.0 mmol), triphenylphosphine (6.0 mmol) and 150 ml THF was mixed in a pressure apparatus that was then charged with 55 psi carbon monoxide and heated to 70°C. The mixture was then treated with a solution of vinyltributyl tin (15 mmol) in 200 ml THF over 6 hours, then stirred an additional 4 hours, filtered, and concentrated. The residue was dissolved in 50 ml CH2C12, then refiltered through Hyflo. The mixture was reconcentrated to approximately 25 ml, then added dropwise to 300 ml hexane and the crude product isolated in 85% yield by filtration. The residue was purified by flash chromatography using 0.5-5.0% methyl alcohol/CHCl3, and the product isolated as an yellow solid. 

Sarcosine ethyl ester hydrochloride (1.0 mmol) was suspended in 1ml DMF, treated with triethylamine (1.1 equiv.) and the Step 2product (1.0 mmol), then stirred overnight. The solution was quenched with 10 ml water, then extracted three times with 10 ml chloroform, dried over Na2S04, and concentrated. The residue was coevaporated four times with ethyl alcohol and the product isolated in 95% yield as a white foam. 

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