反应详情

Added, under an argon atmosphere and at a temperature close to 20° C., to a solution of 180 mg of 7-chloro-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid in 2.2 cm3 of anhydrous dimethylformamide are 0.25 cm3 of triethylamine and 263 mg of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)butan-2-ol hydrochloride (2:1), then 90 mg of 1-hydroxy-7-azabenzotriazole and 127 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The solution is kept stirring, under argon, for 15 h at a temperature close to 20° C. The reaction medium is then added to 10 cm3 of water and 20 cm3 of ethyl acetate. After decanting, the organic phase is washed with 10 cm3 of a saturated aqueous solution of ammonium chloride, five lots of 10 cm3 of water, then 10 cm3 of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa). The residual solution (around 2 cm3) is purified by flash chromatography over silica (column: 15 g; spherical silica of BP-SUP type, particle size: 20-40 μm; eluent: 50% heptane/50% ethyl acetate). After concentrating the fractions under reduced pressure, 274 mg of N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-7-chloro-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide are obtained in the form of a beige foam.

1. additionAdded, under an argon atmosphere and at a temperature
2. customclose to 20° C
3. customAfter decanting
4. washthe organic phase is washed with 10 cm3 of a saturated aqueous solution of ammonium chloride, five lots of 10 cm3 of water
5. dry with material10 cm3 of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate
6. filtrationfiltered
7. concentrationconcentrated under reduced pressure (5 kPa)
8. customThe residual solution (around 2 cm3) is purified by flash chromatography over silica (column: 15 g; spherical silica of BP-SUP type, particle size: 20-40 μm; eluent: 50% heptane/50% ethyl acetate)
9. concentrationAfter concentrating the fractions under reduced pressure, 274 mg of N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-7-chloro-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide
10. customare obtained in the form of a beige foam