O-Methyl Dolutegravir

Dolutegravir intermediate is a new synthetic intermediate of Dolutegravir. Dolutegravir is an integrase inhibitor used to treat human immunodeficiency virus (HIV)-1 infection.

(4R,12AS)-N-(2,4-Difluorobenzyl)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1'',2'':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide is an intermediate in the preparation of dolutegravir, an integrase inhibitor for HIV-1 infection therapy.

(3S,11aR)-3-methyl-6-(methyloxy)-5,7-dioxo-2,3,5,7,11,11a- hexahydro[1,3]oxazolo [3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (100 gm) and carbonyl dimidazole (78.89 gm) was suspended in acetonitrile (1000 mL). The mixture was heated to 75°C and stirred for 1 hour. The resulting solution was cooled to a temperature of 20°C and treated with 2,4- difluorobenzyl amine solution (55.2 gm was dissolved in 200 mL of acetonitrile). The reaction mixture was maintained for 2 hours, concentrated, and the compound was extracted with ethyl acetate (1000 mL). Isopropyl alcohol (500 mL) was added at 40°C, stirred the reaction mass for 30 minutes at a temperature of 50°C, and cooled the reaction mass to 25°C. The reaction mixture was maintained for 8 hours at the same temperature. The product O-Methyl Dolutegravir was collected by filtration and dried under vacuum (85 gm).