Barbituric Acid → (2R,4S,4aS)-8-(3,3-difluoroazetidine-1-carbonyl)-11-fluoro-2,4-dimethyl-2,4,4a,6-tetrahydro-1H,1'H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5'-pyrimidine]-2', 4',6'(3'H)-trione

HRID 245555Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 245555
[F:1][C:2]1([F:28])[CH2:5][N:4]([C:6]([C:8]2[C:12]3[CH:13]=[C:14]([CH:26]=O)[C:15]([N:18]4[CH2:23][C@@H:22]([CH3:24])[O:21][C@H:20]([CH3:25])[CH2:19]4)=[C:16]([F:17])[C:11]=3[O:10][N:9]=2)=[O:7])[CH2:3]1.[NH:29]1[C:36](=[O:37])[CH2:35][C:33](=[O:34])[NH:32][C:30]1=[O:31]>C(O)C>[F:28][C:2]1([F:1])[CH2:3][N:4]([C:6]([C:8]2[C:12]3[CH:13]=[C:14]4[C:15](=[C:16]([F:17])[C:11]=3[O:10][N:9]=2)[N:18]2[CH2:23][C@@H:22]([CH3:24])[O:21][C@@H:20]([CH3:25])[C@@H:19]2[C:35]2([C:33](=[O:34])[NH:32][C:30](=[O:31])[NH:29][C:36]2=[O:37])[CH2:26]4)=[O:7])[CH2:5]1

Komponenten

4

Edukt 2

HCID 6211Barbituric AcidHCID 866580983-(3,3-difluoroazetidine-1-carbonyl)-6-((2R,6R)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-5-carbaldehyde2×

Produkt 1

HCID 58457175(2R,4S,4aS)-8-(3,3-difluoroazetidine-1-carbonyl)-11-fluoro-2,4-dimethyl-2,4,4a,6-tetrahydro-1H,1'H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5'-pyrimidine]-2', 4',6'(3'H)-trioneAusbeute 81,5 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 702EthanolLösungsmittel

Versuchsvorschrift

3-(3,3-difluoroazetidine-1-carbonyl)-6-((2R,6R)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-5-carbaldehyde (Intermediate 245, 2.08 g, 5.23 mmol) was dissolved in ˜100 ml of ethanol and heated with barbituric acid (0.704 g, 5.50 mmol) at 105° C. (external temperature) for 6 days. The reaction was absorbed onto celite then purified on by silica gel chromatography using a gradient of DCM to ethyl acetate. Fractions were combined and concentrated. This material was then purified by Supercritical Fluid Chromatography (separation of diastereomers), using a Chiralpak AD, 21×250 mm, 5μ column (elution with 40% isopropanol, 60% CO2 at 60 ml/min, 40° C., and 100 bar with detection at 220 nm), to give the title compound (2.16 g, 4.26 mmol, 81%) as the first eluting compound.

Aufarbeitung

  1. customThe reaction was absorbed onto celite
  2. customthen purified on by silica gel chromatography
  3. concentrationconcentrated
  4. customThis material was then purified by Supercritical Fluid Chromatography (separation of diastereomers)
  5. washa Chiralpak AD, 21×250 mm, 5μ column (elution with 40% isopropanol, 60% CO2 at 60 ml/min, 40° C., and 100 bar with detection at 220 nm)

Quellen und Nachweise

ORD-Eintrag
ord-ce688636365e46c7b79d6270e93da641
Quelldatensatz
uspto-grants-2014_02
Patentnummer
US08658641B2

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