反应详情

To a mixture of 0.9503 g (3.0 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20), 0.6252 g (3.611 mmole) of 4-amino-2,5-difluorobenzoic acid, and 48 mL of dioxane, was added 1.96 g (6.01 mmole) of cesium carbonate and 0.0682 g (0.304 mmole) of palladium acetate. The mixture was deoxygenated with argon, 0.386 g (0.621 mmole) of 1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenyl phosphine was added and the reaction mixture was heated at 100 degrees for 3 hrs. The cooled mixture was concentrated under reduced pressure, dissolved in ethyl acetate, made slightly acidic by the addition of 1M hydrochloric acid, washed with water, brine, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.5533 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,5-difluoro-benzoic acid (I-232) as off-white solid.

1. additionwas added
2. temperaturethe reaction mixture was heated at 100 degrees for 3 hrs
3. concentrationThe cooled mixture was concentrated under reduced pressure
4. dissolutiondissolved in ethyl acetate
5. additionmade slightly acidic by the addition of 1M hydrochloric acid
6. washwashed with water, brine
7. filtrationfiltered
8. concentrationconcentrated under reduced pressure
9. customPurification by silica gel chromatography
10. washeluting with dichloromethane-methanol (gradient, 95:5-80:20)