反应详情

To a mixture of 300 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid and 6 ml of DMF were added {5-[(aminooxy)methyl]pyrazin-2-yl}methyl acetate dihydrochloride, 0.16 ml of triethylamine, 119 mg of HOBt, and 200 mg of WSC, followed by stirring at room temperature for 3 hours. Ethyl acetate and water were added thereto to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. To the residue were added 4.5 ml of methanol and 2.4 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring at 0° C. for 2 hours, and then 1 M hydrochloric acid was added thereto for neutralization. Chloroform was added thereto for extraction, and the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: chloroform-methanol) and then recrystallized from ethyl acetate to obtain 73 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[5-(hydroxymethyl)pyrazin-2-yl]methoxy}-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless crystal.

1. customa liquid separation operation
2. washThe organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine
3. dry with materialdried over anhydrous magnesium sulfate
4. customevaporated under reduced pressure
5. additionTo the residue were added 4.5 ml of methanol and 2.4 ml of a 1 M aqueous sodium hydroxide solution
6. stirringby stirring at 0° C. for 2 hours
7. addition1 M hydrochloric acid was added
8. additionChloroform was added
9. extractionfor extraction
10. dry with materialthe organic layer was dried over anhydrous magnesium sulfate
11. concentrationconcentrated under reduced pressure
12. customThe residue was purified by silica gel chromatography (eluent: chloroform-methanol)
13. customrecrystallized from ethyl acetate