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

HRID 513044

Reaktionsgleichung

Reaktionsgleichung von HRID 513044
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:65]1[CH:66]=[C:67]([CH:70]=[C:71]([C@H:73]2[CH2:77][C@H:76]([F:78])[CH2:75][NH:74]2)[CH:72]=1)[C:68]#[N:69]>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>[C:68]([C:67]1[CH:70]=[C:71]([C@H:73]2[CH2:77][C@H:76]([F:78])[CH2:75][N:74]2[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)[CH:72]=[C:65]([F:64])[CH:66]=1)#[N:69]

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 666849673-fluoro-5-((2R,4S)-4-fluoropyrrolidin-2-yl)benzonitrile

Produkt 1

HCID 60171437ethyl 5-((2R,4S)-2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate

Reagenzien, Katalysatoren, Lösungsmittel 2

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

Reaktionsbedingungen

Temperatur
140 °C

Versuchsvorschrift

A N2 purged flask was charged with ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (36 mg, 0.13 mmol), tris(dibenzylideneacetone)dipalladium(0) (2.5 mg, 2 μmol), xantphos (6 mg, 8 μmol), cesium carbonate (61 mg, 0.19 mmol), 1,4-dioxane (0.5 mL) and 3-fluoro-5-((2R,4S)-4-fluoropyrrolidin-2-yl)benzonitrile (I-15) (28 mg, 0.13 mmol). The contents were heated to 140° C. for 25 minutes under microwave irradiation. 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)-2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (X-7). 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1 H), 8.21 (d, J=7.6 Hz, 1 H), 7.39 (s, 1 H), 7.31-7.27 (m, 1 H), 7.26-7.21 (m, 1 H), 6.94 (d, J=2.4 Hz, 1 H), 6.24 (dd, J=2.8, 7.6 Hz, 1 H), 5.40 (d, J=52.4 Hz, 1 H), 5.07 (dd, J=7.2, 9.6 Hz, 1 H), 4.35-4.26 (m, 2 H), 4.23-4.08 (m, 1 H), 4.05-3.93 (m, 1 H), 2.97-2.85 (m, 1 H), 2.17-1.99 (m, 1 H), 1.35 (t, J=7.2 Hz, 3 H). MS m/z 397.1 (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-c327336f6d3c451497593c4e39bdec5f
Quelldatensatz
uspto-grants-2015_08
Patentnummer
US09102671B2

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