反応 #42390

反応方程式

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

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

diisopropylethylamine

HATU

→

title compound

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

溶媒

ethyl acetate

tetrahydrofuran methanol water

lithium hydroxide monohydrate

反応条件

後処理

1. 1
   workup.ADDITIONis added (41 mg, 1 mmol)
2. 2
   濃縮The solution is concentrated under reduced pressure
3. 3
   workup.DISSOLUTIONThe residue is redissolved in DMF (5 mL)
4. 4
   workup.ADDITIONare added
5. 5
   workup.STIRRINGThe reaction stirred at room temperature 16 h
6. 6
   洗浄washed with water, saturated sodium bicarbonate, brine
7. 7
   乾燥dried (sodium sulfate)
8. 8
   ろ過filtered
9. 9
   濃縮concentrated under reduced pressure
10. 10
    その他Purification by flash column chromatography (silica, 8% methanol/methylene chloride)

実験手順

Methyl 3-{[butyl(methyl)amino]methyl}-5-methylbenzoate (122 mg, 0.49 mmol) is dissolved in 2:1:1 tetrahydrofuran/methanol/water (4 mL), and lithium hydroxide monohydrate is added (41 mg, 1 mmol), and the reaction stirred 16 h. The solution is concentrated under reduced pressure. The residue is redissolved in DMF (5 mL), and diisopropylethylamine (350 μL, 2 mmol), HATU (240 mg, 0.63 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[1-(3-ethynylphenyl)cyclopropyl]amino}butan-2-ol dihydrochloride prepared by the method in Example SP-272 (215 mg, 0.5 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 574.3 [M+H]+.

出典