反应详情

To a mixture of 0.075 g (0.155 mmole) 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)-3-trifluoromethyl-benzoic acid (I-204) and 8 mL of dimethylformamide was added 0.0313 g (0.232 mmole) of 1-hydroxybenzotriazole, 0.0880 g (0.232 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.080 g (0.617 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.027 g (0.236 mmole) of 4-amino-1-methylpiperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0392 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)-N-(1-methyl-piperidin-4-yl)-3-trifluoromethyl-benzamide (I-205) as a white solid.

1. stirringThe reaction mixture was stirred for 2 hours
2. concentrationconcentrated under reduced pressure
3. dissolutionThe residue was dissolved in 80 mL of ethyl acetate
4. washwashed three times with 10 mL of 1M sodium hydroxide
5. dry with materialtwice with 15 mL of brine, dried
6. filtrationfiltered
7. concentrationconcentrated under reduced pressure
8. customPurification by silica gel chromatography
9. washeluting with dichloromethane-methanol (gradient, 95:5-80:20)