反应详情

DIPEA (5.3 mL) was added to a DMF (16 mL) solution of 1-{[(2S)-2-carboxy-1-(methylamino)-1-oxopropan-2-yl](methyl)carbamoyl}-4-iodobenzene (Intermediate 14, 4.0 g) and O-(tetrahydropyran-2-yl)hydroxylamine (1.6 g), and HATU (5.9 g) was added under water cooling. The mixture was stirred for 2 hours under ice cooling, and then stirred for 1 hour at room temperature. Water and ethyl acetate were sequentially added, and the organic layer was isolated. The extract was washed sequentially with water and brine, and dried over anhydrous sodium sulfate. OH type silica gel (4.0 g) was added, and the mixture was filtered for 10 minutes at room temperature. Then, the silica gel was filtered out, and the solvent was distilled off under reduced pressure. A mixed solvent (IPE:ethyl acetate=10:1) was added to the resulting residue, and the supernatant was removed. This procedure was repeated twice, and then a solvent mixture of ethyl acetate (6.0 mL) and IPA (6.0 mL) was added to the resulting residue. The solids were collected by filtration to obtain (2S)-2-[(4-iodobenzoyl)(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (Intermediate 15, white solid) (1.3 g, 26%). Moreover, the residue obtained from the filtrate was purified by OH type silica gel column chromatography (ethyl acetate/hexane=50/50→gradient elution with chloroform/acetone=100/0→85/15) to obtain (2S)-2-[(4-iodobenzoyl)(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (Intermediate 15, white solid) (1.7 g, 34%).

1. additionwas added under water cooling
2. stirringstirred for 1 hour at room temperature
3. customthe organic layer was isolated
4. washThe extract was washed sequentially with water and brine
5. dry with materialdried over anhydrous sodium sulfate
6. additionOH type silica gel (4.0 g) was added
7. filtrationthe mixture was filtered for 10 minutes at room temperature
8. filtrationThen, the silica gel was filtered out
9. distillationthe solvent was distilled off under reduced pressure
10. additionA mixed solvent (IPE:ethyl acetate=10:1) was added to the resulting residue
11. customthe supernatant was removed
12. additiona solvent mixture of ethyl acetate (6.0 mL) and IPA (6.0 mL)
13. additionwas added to the resulting residue
14. filtrationThe solids were collected by filtration