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(3R,4R)-benzyl 3-(((2S,6R)-N-((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-2,6-dimethylmorpholine-4-carboxamido)methyl)-4-fluoropyrrolidine-1-carboxylate → (2S,6R)-N-((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-N-(((3S,4R)-4-fluoropyrrolidin-3-yl)methyl)-2,6-dimethylmorpholine-4-carboxamide

HRID 1037487
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 1037487
[CH2:1]([N:8]1[C:12]([C@H:13]([N:18]([CH2:29][C@H:30]2[C@@H:34]([F:35])[CH2:33][N:32](C(OCC3C=CC=CC=3)=O)[CH2:31]2)[C:19]([N:21]2[CH2:26][C@@H:25]([CH3:27])[O:24][C@@H:23]([CH3:28])[CH2:22]2)=[O:20])[C:14]([CH3:17])([CH3:16])[CH3:15])=[N:11][C:10]([C:46]2[CH:51]=[C:50]([F:52])[CH:49]=[CH:48][C:47]=2[F:53])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH2:1]([N:8]1[C:12]([C@H:13]([N:18]([CH2:29][C@H:30]2[C@@H:34]([F:35])[CH2:33][NH:32][CH2:31]2)[C:19]([N:21]2[CH2:22][C@@H:23]([CH3:28])[O:24][C@@H:25]([CH3:27])[CH2:26]2)=[O:20])[C:14]([CH3:15])([CH3:16])[CH3:17])=[N:11][C:10]([C:46]2[CH:51]=[C:50]([F:52])[CH:49]=[CH:48][C:47]=2[F:53])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
KomponentenVersuchsvorschriftAufarbeitungQuellen und NachweiseNotizen zur Reaktion

Komponenten

4

Edukt 1

HCID 58473031(3R,4R)-benzyl 3-(((2S,6R)-N-((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-2,6-dimethylmorpholine-4-carboxamido)methyl)-4-fluoropyrrolidine-1-carboxylate

Produkt 1

HCID 53482818(2S,6R)-N-((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-N-(((3S,4R)-4-fluoropyrrolidin-3-yl)methyl)-2,6-dimethylmorpholine-4-carboxamideAusbeute 94 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 23938
Palladium
Katalysator
HCID 702EthanolLösungsmittel

Versuchsvorschrift

To a solution of (3R,4R)-benzyl 3-(((2S,6R)—N—((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-2,6-dimethylmorpholine-4-carboxamido)methyl)-4-fluoropyrrolidine-1-carboxylate (91 mg, 0.124 mmol) in degassed ethanol (12 mL, 0.1 M solution) was added Pd/C (2.64 mg, 10 wt %) under anhydrous N2 atmosphere. After flushed with hydrogen gas, the reaction mixture equipped with a hydrogen gas balloon was stirred at room temperature for 45 min. The reaction mixture was filtered through Celite® pad that was washed with EtOAc. The volatile organic filtrate was removed in vacuo to give the crude product, which was purified by preparative reverse phase HPLC. The combined fractions of the product were neutralized with saturated NaHCO3 solution, which was then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The dried product was then dissolved in acetonitrile and water (1:1 ratio) and lyophilized for 48 h. The white powdery (2S,6R)—N—((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-N-(((3S,4R)-4-fluoropyrrolidin-3-yl)methyl)-2,6-dimethylmorpholine-4-carboxamide was obtained in 94% yield (70 mg) as a free amine 1H NMR (CD3Cl, 300 MHz): δ 7.83 (1H, m), 7.52 (2H, m), 7.34-7.27 (3H, m), 7.08 (1H, m), 7.04 (1H, m), 5.94 (2H, m), 5.41 (1H, s), 3.92-3.62 (3H, m), 3.60-3.45 (3H, m), 3.17-2.58 (3H, m), 2.57-2.37 (1H, m), 2.35-2.04 (2H, m), 1.85 (2H, m), 1.20 (6H, s), 0.9 (1H, m), 0.8 (9H, s). LC/MS (uplc): MH+ 599.5, 1.06 min.

Aufarbeitung

  1. customAfter flushed with hydrogen gas
  2. customthe reaction mixture equipped with a hydrogen gas balloon
  3. filtrationThe reaction mixture was filtered through Celite® pad that
  4. washwas washed with EtOAc
  5. customThe volatile organic filtrate was removed in vacuo
  6. customto give the crude product, which
  7. customwas purified by preparative reverse phase HPLC
  8. extractionwas then extracted with EtOAc
  9. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. dissolutionThe dried product was then dissolved in acetonitrile
  13. waitwater (1:1 ratio) and lyophilized for 48 h

Quellen und Nachweise

ORD-Eintrag
ord-9822c80915944f7fb2f553f9b57f9c64
Quelldatensatz
uspto-grants-2013_10
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08546434B2

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