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

HRID 14081

Reaktionsgleichung

Reaktionsgleichung von HRID 14081
C([O:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19]([O:21]C)=O)[O:14][CH:15]=1)C1C=CC=CC=1.C1CCCCC=1.[OH-].[Li+].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:69][C@@H:70]([CH2:84][C:85]1[CH:90]=[C:89]([F:91])[CH:88]=[C:87]([F:92])[CH:86]=1)[C@H:71]([OH:83])[CH2:72][NH:73][CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[C:77]([CH2:81][CH3:82])[CH:76]=1>C(O)C.C(Cl)(Cl)Cl.[OH-].[Pd+2].[OH-]>[F:91][C:89]1[CH:90]=[C:85]([CH:86]=[C:87]([F:92])[CH:88]=1)[CH2:84][C@H:70]([NH:69][C:19](=[O:21])[C:18]1[CH:23]=[CH:24][CH:25]=[C:16]([C:13]2[O:14][CH:15]=[C:11]([CH2:10][CH2:9][OH:8])[N:12]=2)[CH:17]=1)[C@H:71]([OH:83])[CH2:72][NH:73][CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[C:77]([CH2:81][CH3:82])[CH:76]=1

Komponenten

10

Edukt 6

HCID 3939Lithium HydroxideHCID 8079CyclohexeneHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 21086153Methyl 3-{4-[2-(benzyloxy)ethyl]-1,3-oxazol-2-yl}benzoateHCID 57487281(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride

Produkt 1

HCID 58802533N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[4-(2-hydroxyethyl)-1,3-oxazol-2-yl]benzamide

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 9942167Palladium hydroxideKatalysatorHCID 702EthanolLösungsmittelHCID 6212ChloroformLösungsmittel

Versuchsvorschrift

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]+.

Aufarbeitung

  1. temperatureThe reaction is cooled
  2. filtrationfiltered through diatomaceous earth
  3. concentrationconcentrated under reduced pressure
  4. dissolutionThe residue is redissolved in 2:1:1 tetrahydrofuran/methanol/water (4 mL)
  5. concentrationconcentrated under reduced pressure
  6. dissolutionThe residue is dissolved in DMF (5 mL)
  7. additionare added
  8. stirringThe reaction stirred at room temperature 16 h
  9. washwashed with water, 1N hydrochloric acid (aq), saturated sodium bicarbonate, brine
  10. dry with materialdried (sodium sulfate)
  11. filtrationfiltered
  12. concentrationconcentrated under reduced pressure
  13. customPurification by flash column chromatography (silica, 8% methanol/chloroform)

Quellen und Nachweise

ORD-Eintrag
ord-9754d01035a24eabb1da70c4c49754ac
Quelldatensatz
uspto-grants-2010_06
Patentnummer
US07727997B2

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