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Cesium carbonate → 4-amino-6-[[(1S)-1-[7-(3,6-dihydro-2H-pyran-4-yl)-6-fluoro-1-methyl-benzimidazol-2-yl]ethyl]amino]pyrimidine-5-carbonitrile

HRID 243506
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 243506
[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19](Br)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH2:34][CH2:35][O:36][CH2:37][CH:38]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19]([C:33]4[CH2:38][CH2:37][O:36][CH2:35][CH:34]=4)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
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Komponenten

7

Edukt 3

HCID 10796Cesium carbonateHCID 112180533,6-Dihydro-2H-pyran-4-boronic acid pinacol esterHCID 681575724-Amino-6-[(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile

Produkt 1

HCID 681582864-amino-6-[[(1S)-1-[7-(3,6-dihydro-2H-pyran-4-yl)-6-fluoro-1-methyl-benzimidazol-2-yl]ethyl]amino]pyrimidine-5-carbonitrileAusbeute 15,6 %

Reagenzien, Katalysatoren, Lösungsmittel

3
HCID 178418397HCID 178418397, VerbindungKatalysatorHCID 962WaterLösungsmittelHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
140 °C

Versuchsvorschrift

A mixture of 4-amino-6-[(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile (122 mg, 0.31 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (85 mg, 0.41 mmol), tetrakis(triphenylphosphine)palladium (36 mg, 10 mol %) and caesium carbonate (204 mg, 0.63 mol) in dioxane (3 mL) and H2O (1.5 mL) was purged with argon gas then heated at 140° C., for 30 min, by microwave irradiation. After cooling to RT, the reaction mixture was diluted with MeOH and loaded into an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in DCM) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a gradient 5-75%, 0.1% NH4OH in acetonitrile/water) to afford 432 as a white solid (19 mg, 15%). LCMS (Method K): RT 2.79 min [M+H]+ 394.16. 1H NMR (DMSO-d6, 400 MHz): δ 8.07 (1H, s), 7.69 (1H, m), 7.55 (1H, dd, J=8.76, 4.82 Hz), 7.30 (2H, br s), 7.04 (1H, dd, J=10.42, 8.75 Hz), 5.87 (1H br s), 5.70 (1H, m), 4.24 (2H, s), 3.86 (2H, m), 3.73 (3H, s), 2.45-2.23 (2H, m), 1.58 (3H, d, J=6.72 Hz)

Aufarbeitung

  1. customwas purged with argon gas
  2. temperatureAfter cooling to RT
  3. additionthe reaction mixture was diluted with MeOH
  4. washThe cartridge was washed with MeOH
  5. concentrationconcentrated in vacuo
  6. customthe resulting residue purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in DCM)

Quellen und Nachweise

ORD-Eintrag
ord-eab5b26fbc12433696851c0426fad923
Quelldatensatz
uspto-grants-2014_02
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08653089B2

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