Réaction #42394

Équation de réaction

methyl 3-{[butyl(methyl)amino]methyl}-5-methylbenzoate

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

diisopropylethylamine

HATU

lithium hydroxide monohydrate

→

title compound

3-{[Butyl(methyl)amino]methyl}-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-phenylcyclopropyl)amino]propyl}-5-methylbenzamide dihydrochloride

Solvants

ethyl acetate

tetrahydrofuran methanol water

Conditions de réaction

Traitement

1. 1
   workup.ADDITIONis added (57 mg, 1.4 mmol)
2. 2
   ConcentrationThe solution is concentrated under reduced pressure
3. 3
   workup.DISSOLUTIONThe residue is redissolved in DMF (3 mL)
4. 4
   workup.ADDITIONare added
5. 5
   workup.STIRRINGThe reaction stirred at room temperature 16 h
6. 6
   Lavagewashed with water, saturated sodium bicarbonate, brine
7. 7
   Séchagedried (sodium sulfate)
8. 8
   Filtrationfiltered
9. 9
   Concentrationconcentrated under reduced pressure
10. 10
    AutrePurification by flash column chromatography (silica, 8% methanol/methylene chloride)

Mode opératoire

Analogous to the method in Example SP-188, methyl 3-{[butyl(methyl)amino]methyl}-5-methylbenzoate (170 mg, 0.68 mmol) is dissolved in 2:1:1 tetrahydrofuran/methanol/water (4 mL), and lithium hydroxide monohydrate is added (57 mg, 1.4 mmol), and the reaction stirred 2 h. The solution is concentrated under reduced pressure. The residue is redissolved in DMF (3 mL), and diisopropylethylamine (472 μL, 2.7 mmol), HATU (322 mg, 0.85 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(1-phenylcyclopropyl)amino]butan-2-ol dihydrochloride prepared by the method in Example S-XYZ (275 mg, 0.68 mmol) are added. The reaction stirred at room temperature 16 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, 8% 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 550.3 [M+H]+.

Source