반응 #42395

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

(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-isopropylbenzyl)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-[(3-isopropylbenzyl)amino]propyl}-5-methylbenzamide dihydrochloride

용매

ethyl acetate

tetrahydrofuran methanol water

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후처리

1. 1
   workup.ADDITIONis added (17 mg, 0.4 mmol)
2. 2
   농축The solution is concentrated under reduced pressure
3. 3
   workup.DISSOLUTIONThe residue is redissolved in DMF (2 mL)
4. 4
   workup.ADDITIONare added
5. 5
   workup.STIRRINGThe reaction stirred at room temperature 16 h
6. 6
   세척washed with water, saturated sodium bicarbonate, brine
7. 7
   건조dried (sodium sulfate)
8. 8
   여과filtered
9. 9
   농축concentrated under reduced pressure
10. 10
    기타Purification by flash column chromatography (silica, 8% methanol/methylene chloride)

실험 절차

Analogous to the method in Example SP-188, methyl 3-{[butyl(methyl)amino]methyl}-5-methylbenzoate (50 mg, 0.2 mmol) is dissolved in 2:1:1 tetrahydrofuran/methanol/water (4 mL), and lithium hydroxide monohydrate is added (17 mg, 0.4 mmol), and the reaction stirred 16 h. The solution is concentrated under reduced pressure. The residue is redissolved in DMF (2 mL), and diisopropylethylamine (140 μL, 0.8 mmol), HATU (95 mg, 0.25 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-isopropylbenzyl)amino]butan-2-ol dihydrochloride prepared by the method in Example SP-170, Step 4 (85 mg, 0.2 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 566.3 [M+H]+.

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