Trifluoroacetic acid → (2R,4S,5S)-5-Amino-6-[4-(2,6-difluorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-4-hydroxy-2-methylhexanoic acid cyclohexylamide hemifumarate

0.88 ml of trifluoroacetic acid (11.3 mmol) was added to a solution of 218 mg of {(1S,2S,4R)-4-(cyclohexylcarbamoyl)-1-[4-(2,6-difluorophenyl)-2,2-dimethyl-5-oxopiperazin-1-ylmethyl]-2-hydroxypentyl}carbamic acid t-butyl ester obtained in Example (95a) (0.38 mmol) in methylene chloride (1.7 ml) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. After concentration under reduced pressure, a saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol/triethylamine=100/10/1). 15 mg of fumaric acid (0.13 mmol) was added to a solution of 126 mg of (2R,4S,5S)-5-amino-6-[4-(2,6-difluorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-4-hydroxy-2-methylhexanoic acid cyclohexylamide obtained above (0.26 mmol) in methanol (3 ml), and the mixture was stirred at room temperature for five minutes. The reaction mixture was concentrated under reduced pressure, and methylene chloride (0.5 ml) was added to the residue. Diisopropyl ether (5 ml) was further added and the solid was collected by filtration to obtain 127 mg of the title compound (yield: 90%).

1. concentrationAfter concentration under reduced pressure
2. additiona saturated sodium bicarbonate aqueous solution was added to the reaction mixture
3. extractionfollowed by extraction with methylene chloride
4. dry with materialThen, the organic layer was dried over anhydrous magnesium sulfate
5. filtrationAfter filtration
6. customthe solvent was evaporated under reduced pressure
7. customthe residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol/triethylamine=100/10/1)
8. stirringthe mixture was stirred at room temperature for five minutes
9. concentrationThe reaction mixture was concentrated under reduced pressure, and methylene chloride (0.5 ml)
10. additionwas added to the residue
11. additionDiisopropyl ether (5 ml) was further added
12. filtrationthe solid was collected by filtration

ORD record

ord-3f5b1b637c374b24995dee2f45d20e9f

Source dataset

uspto-grants-2012_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08158790B2