Uses
Dolutegravir intermediate-1 (1-(2,2-diMethoxyethyl)-5-Methoxy-6-(Methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid) is used as an intermediate in the synthesis of GSK1265744 (I), a potent HIV integrase inhibitor.
Synthesis
N, N-Dimethylformamide dimethyl acetal was added to methyl 4-methoxy-3-oxobutanoate, and the mixture was kept for 2 h at 25-30°C. The resulting methyl2-(dimethylaminomethylidene)-4-methoxy-3-oxobutanoate was dissolved in methanol, 2-amino acetaldehyde dimethyl acetal was added, and the mixture was stirred at20-30°C for 2 h. The solvent was removed under reduced pressure, the residue was diluted with methanol, and dimethyl oxalate was added at 25-30°C. The mixture was cooled to 0-5°C, 30 wt % sodium methoxide in methanol was slowly added, and the mixture was slowly heated to 40°C, stirred for 14 h at that temperature, and concentrated under reduced pressure. The residue was diluted with dichloromethane and poured into cold (0-5°C)2 N aqueous HCl. The organic phase was separated, the aqueous layer was extracted with dichloromethane (2× ), and the combined organic layers were washed with demineralized water and concentrated under reduced pressure at 40-45 °C to obtain intermediate. The product was dissolved in methanol, the solution was cooled to 0-5°C, and lithium hydroxide monohydrate was added. The mixture was stirred at 0-5°C for 3 h, quenched with 2 N aqueous HCl, and extracted with ethyl acetate (3×). Finally, the product 1-(2,2-diMethoxyethyl)-5-Methoxy-6-(Methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid can be obtained through further purification.
