Cesium carbonate → ethyl 5-((2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate

HRID 513041

Reaktionsgleichung

Reaktionsgleichung von HRID 513041
Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[CH:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[F:64][C@@H:65]1[CH2:69][NH:68][C@@H:67]([C:70]2[CH:75]=[CH:74][CH:73]=[C:72]([F:76])[CH:71]=2)[CH2:66]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:64][C@@H:65]1[CH2:69][N:68]([C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]3[CH:3]=2)[C@@H:67]([C:70]2[CH:75]=[CH:74][CH:73]=[C:72]([F:76])[CH:71]=2)[CH2:66]1

Komponenten

7

Edukt 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 53249841Ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylateHCID 66684522(2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidine

Produkt 1

HCID 60165028ethyl 5-((2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 9811564Bis(dibenzylideneacetone)palladiumKatalysatorHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
120 °C

Versuchsvorschrift

A N2 purged flask was charged with ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (27 mg, 0.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (2 mg, 2 μmol), xantphos (5 mg, 8 μmol), cesium carbonate (46 mg, 0.14 mmol), 1,4-dioxane (0.5 mL) and (2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidine (I-6) (18 mg, 0.1 mmol). The contents were heated to 120° C. for 12 hours. Upon cooling to room temperature the reaction was partitioned with EtOAc and water. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered and reduced to dryness. The crude product was purified by column chromatography on silica gel with EtOAc/hexanes gradient as eluant to yield ethyl 5-((2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (X-1). 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1 H), 8.16 (d, J=7.6 Hz, 1 H), 7.31 (td, J=5.6, 7.6 Hz, 1 H), 7.05 (d, J=7.6 Hz, 1 H), 6.98 (d, J=2.8 Hz, 1 H), 6.96-6.91 (m, 2 H), 6.24 (dd, J=2.8, 8.0 Hz, 1 H), 5.39 (d, J=52.8 Hz, 1 H), 5.04 (dd, J=7.2, 9.2 Hz, 1H), 4.34-4.26 (m, 2 H), 4.17-3.90 (m, 2 H), 2.93-2.81 (m, 1 H), 2.11 (dddd, J=3.6, 9.2, 13.2, 40.8 Hz, 1 H). MS m/z 372.1 (M+1)+.

Aufarbeitung

  1. temperatureUpon cooling to room temperature the reaction
  2. customwas partitioned with EtOAc and water
  3. washThe organic layer was washed with water, brine
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered
  6. customThe crude product was purified by column chromatography on silica gel with EtOAc/hexanes gradient as eluant

Quellen und Nachweise

ORD-Eintrag
ord-cd37d316d9d8428d95597e21b332dd68
Quelldatensatz
uspto-grants-2015_08
Patentnummer
US09102671B2

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