Hydrochloric Acid → (R)-4-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhexanoic acid

HRID 1055051Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1055051
[F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.Cl>C(#N)C>[F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:37]([CH3:38])([CH3:40])[CH3:39])[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1.[F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1

Komponenten

5

Edukt 2

HCID 313Hydrochloric Acid2×HCID 86714740(R)-ethyl 4-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhexanoate2×

Produkt 2

HCID 71511325(R)-4-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhexanoic acidHCID 71511347(R)-ethyl 4-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhexanoate

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6342AcetonitrileLösungsmittel

Reaktionsbedingungen

Temperatur
60 °C

Versuchsvorschrift

To a solution of (R)-ethyl 4-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhexanoate, 39a, (0.30 g, 0.53 mmol) was in acetonitrile (5 mL) was added HCl (0.70 mL of 4 M solution in dioxane, 2.80 mmol). The reaction mixture was heated at 60° C. for 3 hours and then heated to 80° C. for 6 hours to drive the reaction to completion. After cooling to room temperature, the mixture was then stirred overnight. LCMS showed remaining starting material. Fresh HCl (0.7 mL of 4 M solution in dioxane, 2.80 mmol) was added and the mixture was heated to 80° C. overnight. All volatiles were removed under reduced pressure and the residue was diluted with EtOAc and aqueous saturated NaHCO3 solution. The layers were separated and the organic phase was washed with brine, dried over MgSO4, filtered and evaporated to dryness. The crude residue was purified by silica gel chromatography (0-100% EtOAc/hexanes gradient) to afford 144 mg of (R)-ethyl 4-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhexanoate, 23, and 29 mg of (R)-4-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhexanoic acid, 20. Spectral data for 20: 1H NMR (400 MHz, DMSO) δ 12.23 (s, 1H), 11.93 (s, 1H), 8.48 (d, J=9.9 Hz, 1H), 8.33-8.07 (m, 3H), 7.18 (d, J=9.3 Hz, 1H), 4.39 (t, J=10.2 Hz, 1H), 2.38-2.07 (m, 2H), 1.99-1.92 (m, 1H), 1.80-1.64 (m, 1H), 1.00 (d, J=20.2 Hz, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=2.14 minutes (M+H) 390.06.

Aufarbeitung

  1. temperatureheated to 80° C. for 6 hours
  2. customthe reaction to completion
  3. temperatureAfter cooling to room temperature
  4. temperaturethe mixture was heated to 80° C. overnight
  5. customAll volatiles were removed under reduced pressure
  6. additionthe residue was diluted with EtOAc and aqueous saturated NaHCO3 solution
  7. customThe layers were separated
  8. washthe organic phase was washed with brine
  9. dry with materialdried over MgSO4
  10. filtrationfiltered
  11. customevaporated to dryness
  12. customThe crude residue was purified by silica gel chromatography (0-100% EtOAc/hexanes gradient)

Quellen und Nachweise

ORD-Eintrag
ord-b98652feaa084990ae77d44753d9c57b
Quelldatensatz
uspto-grants-2016_07
Patentnummer
US09394302B2

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