Réaction #42398

Équation de réaction

Methyl 3-{[butyl(methyl)amino]methyl}-5-(1,3-oxazol-2-yl)benzoate

diisopropylethylamine

HATU

(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[1-(3-ethynylphenyl)cyclopropyl]amino}butan-2-ol dihydrochloride

→

title compound

3-{[Butyl(methyl)amino]methyl}-N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethynylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-5-(1,3-oxazol-2-yl)benzamide dihydrochloride

Solvants

ethyl acetate

tetrahydrofuran methanol water

lithium hydroxide monohydrate

Conditions de réaction

Traitement

1. 1
   workup.ADDITIONis added (10 mg, 0.2 mmol)
2. 2
   ConcentrationThe solution is concentrated under reduced pressure
3. 3
   workup.DISSOLUTIONThe residue is redissolved in DMF (1 mL)
4. 4
   workup.STIRRINGThe reaction stirred at room temperature 2 h
5. 5
   Lavagewashed with water, saturated sodium bicarbonate, brine
6. 6
   Séchagedried (sodium sulfate)
7. 7
   Filtrationfiltered
8. 8
   Concentrationconcentrated under reduced pressure
9. 9
   AutrePurification by flash column chromatography (silica, 9-10% methanol/methylene chloride)

Mode opératoire

Methyl 3-{[butyl(methyl)amino]methyl}-5-(1,3-oxazol-2-yl)benzoate (30 mg, 0.1 mmol) is dissolved in 2:1:1 tetrahydrofuran/methanol/water (4 mL), and lithium hydroxide monohydrate is added (10 mg, 0.2 mmol), and the reaction stirred 16 h. The solution is concentrated under reduced pressure. The residue is redissolved in DMF (1 mL), and diisopropylethylamine (70 μL, 0.4 mmol), HATU (57 mg, 0.15 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[1-(3-ethynylphenyl)cyclopropyl]amino}butan-2-ol dihydrochloride (203 mg, 0.5 mmol) are added. The reaction stirred at room temperature 2 h. The reaction mixture is diluted with ethyl acetate, washed with water, saturated sodium bicarbonate, brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 9-10% methanol/methylene chloride) provides the title compound as the free base. The residue is dissolved in diethyl ether (3 mL) and 1N hydrochloric acid in diethyl ether (1 mL) is added. The mixture is concentrated under reduced pressure to yield the title compound. ESI MS m/z 627.3 [M+H]+.

Source