Cesium carbonate → 5-((2R,4S)-2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide

HRID 513048Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 513048
Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([N:13]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[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:80][C:81]1[CH:82]=[C:83]([CH:86]=[C:87]([C@H:89]2[CH2:93][C@H:92]([F:94])[CH2:91][NH:90]2)[CH:88]=1)[C:84]#[N:85]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[C:84]([C:83]1[CH:86]=[C:87]([C@H:89]2[CH2:93][C@H:92]([F:94])[CH2:91][N:90]2[C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([N:13]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)=[O:12])=[C:4]3[CH:3]=2)[CH:88]=[C:81]([F:80])[CH:82]=1)#[N:85]

Komponenten

7

Edukt 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 666849673-fluoro-5-((2R,4S)-4-fluoropyrrolidin-2-yl)benzonitrileHCID 682824605-bromo-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide

Produkt 1

HCID 682823175-((2R,4S)-2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 167845palladium(II) acetateKatalysatorHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
140 °C

Versuchsvorschrift

A N2 purged flask was charged with 5-bromo-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-26) (25 mg, 0.05 mmol), palladium acetate (1.0 mg, 5.1 μmol), xantphos (4.5 mg, 7.8 μmol), cesium carbonate (24 mg, 0.07 mmol), 1,4-dioxane (0.25 mL) and 3-fluoro-5-((2R,4S)-4-fluoropyrrolidin-2-yl)benzonitrile (I-15) (11 mg, 0.05 mmol). The contents were heated to 140° C. for 30 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 5-((2R,4S)-2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-53). 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=7.6 Hz, 1 H), 7.78 (s, 1 H), 7.38 (s, 1 H), 7.30-7.26 (m, 1 H), 7.25-7.23 (m, 1 H), 7.22-7.16 (m, 5 H), 6.92-6.87 (m, 4 H), 6.16 (dd, J=2.4, 7.6 Hz, 1 H), 5.40 (d, J=52.4 Hz, 1 H), 5.09 (dd, J=6.8, 9.2 Hz, 1 H), 4.74 (d, J=16.0 Hz, 2 H), 4.50 (d, J=15.6 Hz, 2 H), 4.22-3.94 (m, 2 H), 3.82 (s, 6 H), 2.96-2.84 (m, 1 H), 2.07 (dddd, J=4.0, 9.6, 13.6, 40.0 Hz, 1 H). MS m/z 608.1 (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-4084a10980194c73b6a3c72df6dff3bf
Quelldatensatz
uspto-grants-2015_08
Patentnummer
US09102671B2

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