2-oxopentanal

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-propyl-2-pyrazinone-4-N-oxide is first synthesized by condensing equimolar amounts of methyl dimethoxyacetate and methyl butyrate in the presence of 1 equivalent of sodium methoxide in dry benzene at reflux for about 3-4 hours (See scheme II). The cooled solution is subsequently poured into cold 50% acetic acid, separated and the aqueous portion is extracted with ether (3X). Organic extracts are washed with saturated sodium bicarbonate, dried and concentrated to yield 2-ethyl-4,4-dimethoxyacetoacetate (7). Compound 7 is subsequently decarboxylated by reflux in a mixture of methanol and 2N KOH solution for 1 hour to produce propylglyoxal dimethylacetal 8, which is isolated by partition of the reaction mixture between water and ether and concentration of the organic mixture. Compound 8 is hydrolyzed in a 3% H2SO4 solution by refluxing for 1 hour. The hydrolyzed in a 3% H2S04 solution by refluxing reaction mixture is subsequently allowed to cool to 5 C and is carefully neutralized with NaHCO3. The aqueous solution of propylglyoxal is then added to a solution of aminoacetamidine dihyrobromide (1 eq., prepared by the method of Mengelberg, Chem. Ber., 89, 1185 (1956)) in methanol at -35° to -40° C. A solution of sodium hydroxide (12.5N) representing about 3.5-4 equivalents is added slowly so that the temperature of the reaction mixture is maintained below about -35° C. 30 minutes after completing the addition of sodium hydroxide, the reaction is allowed to warm to room temperature, stirred for several hours, acidified with HCl to pH 6 and concentrated in vacuo. The resulting residue is then partitioned between water and ethyl acetate (3X), the organic layer is decolorized with charcoal, dried and concentrated to produce 2-amino-5-propylpyrazine 9 which is recrystallized from n-hexane. Compound 9 is diazotised in 50% acetic acid by the slow addition of NaNO2 in 50% acetic acid at 0°-5° C. followed by holding the reaction at room temperature for 1-3 hours. Cautious neutralization of this solution with 4 NaOH is followed by ethyl acetate extraction and isolation of a crude residue which is coevaporated with benzene to an anhydrous state, dissolved in pyridine and benzoylated (excess benzoyl chloride in pyridine) to yield, after workup and chromatography, 2-benzyloxy-5-propylpyrazine 10. Compound 10 is subsequently oxidized with m-chloroperbenzoic acid in dichloroethane as described in Example 1, hereinabove, to give 2-benzyloxy-4-oxo-5-propylpyrazine 11. Compound 11 is debenzoylated in sodium methoxide/methanol using conventional workup procedures to produce 1,2-dihydro-5-propyl-2-pyrazinone-4-N-oxide 12. Compound 12 is then silylated as described in example 1, above and coupled to 2-deoxy-3,5-di-0-p-chlorobenzoyl-alpha-D-ribofuranosyl chloride, also as described above. The anomeric blocked 2'-deoxyriboside of 5-propyl-2-pyrazinone-4-N-oxide is then separated, recrystallized and deprotected in a fashion analogous to the 5-ethyl derivative as described above to produce 1-(2-Deoxy-B-D-ribofuranosyl)-5-propyl-2-pyrazinone-4-N-oxide 13. which is isolated by partition of the reaction mixture between water and ether and concentration of the organic mixture by refluxing for 1 hour The hydrolyzed in a 3% H2S04 solution by refluxing reaction mixture to cool to 5 C prepared by the method of Mengelberg, Chem at -35° to -40° C is added slowly so that the temperature of the reaction mixture is maintained below about -35° C 30 minutes concentrated in vacuo The resulting residue is then partitioned between water and ethyl acetate (3X) dried concentrated