Reaction #42359

Reaction equation

diisopropylethylamine

(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride

HATU

Methyl 3-{4-[2-(benzyloxy)ethyl]-1,3-oxazol-2-yl}benzoate

cyclohexene

lithium hydroxide

→

title compound

N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[4-(2-hydroxyethyl)-1,3-oxazol-2-yl]benzamide

Solvents

chloroform

ethanol

Conditions

Workup

1. 1
   TemperatureThe reaction is cooled
2. 2
   Filtrationfiltered through diatomaceous earth
3. 3
   Concentrationconcentrated under reduced pressure
4. 4
   workup.DISSOLUTIONThe residue is redissolved in 2:1:1 tetrahydrofuran/methanol/water (4 mL)
5. 5
   Concentrationconcentrated under reduced pressure
6. 6
   workup.DISSOLUTIONThe residue is dissolved in DMF (5 mL)
7. 7
   workup.ADDITIONare added
8. 8
   workup.STIRRINGThe reaction stirred at room temperature 16 h
9. 9
   Washwashed with water, 1N hydrochloric acid (aq), saturated sodium bicarbonate, brine
10. 10
    Dryingdried (sodium sulfate)
11. 11
    Filtrationfiltered
12. 12
    Concentrationconcentrated under reduced pressure
13. 13
    OtherPurification by flash column chromatography (silica, 8% methanol/chloroform)

Procedure

Methyl 3-{4-[2-(benzyloxy)ethyl]-1,3-oxazol-2-yl}benzoate (300 mg, 0.9 mmol), 20% palladium(II) hydroxide on carbon (65 mg), and cyclohexene (3 mL) in absolute ethanol (3 mL) are refluxed 1 h. The reaction is cooled, filtered through diatomaceous earth, and concentrated under reduced pressure. The residue is redissolved in 2:1:1 tetrahydrofuran/methanol/water (4 mL) is added lithium hydroxide (75 mg, 1.8 mmol). The reaction mixture is stirred at room temperature for 3 h, and concentrated under reduced pressure. The residue is dissolved in DMF (5 mL), and diisopropylethylamine (625 μL, 3.6 mmol), HATU (540 mg, 1.4 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride prepared by the method in Example SP-272 (407 mg, 1 mmol) are added. The reaction stirred at room temperature 16 h. The reaction mixture is diluted with chloroform, washed with water, 1N hydrochloric acid (aq), saturated sodium bicarbonate, brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/chloroform) provides the title compound. ESI MS m/z 550.3 [M+H]+.

Source