Cesium carbonate → 1-[5-(3-Methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarbonitrile

HRID 410669Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 410669
[CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:29]1[S:33][C:32]([C:34]2([C:40]#[N:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[N:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>CCOC(C)=O.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]>[CH3:1][C:2]1[CH:7]=[C:6]([C:29]2[S:33][C:32]([C:34]3([C:40]#[N:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[N:31][CH:30]=2)[CH:5]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][N:19]=2)[CH:3]=1

Komponenten

7

Edukt 4

HCID 10796Cesium carbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 58456089N-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2-amine2×HCID 674297131-(5-Bromothiazol-2-yl)cyclohexanecarbonitrile

Produkt 1

HCID 584561351-[5-(3-Methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarbonitrileAusbeute 82,6 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 9811564Bis(dibenzylideneacetone)palladiumKatalysatorHCID 8857Ethyl AcetateLösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (INTERMEDIATE 3, 134 mg, 0.35 mmol), the compound from Step 2 (96 mg, 0.35 mmol), cesium carbonate (346 mg, 1.06 mmol), X-Phos (16.9 mg, 0.035 mmol) and Pd2(dba)3 (16.2 mg, 0.018 mmol) were placed in a flask and evacuated/purged with N2 for three times. Dioxane (1.5 mL) and water (0.15 mL) were degassed by undersurface N2 bubbling and added to the reaction vessel. The resulting reaction mixture was stirred at 100° C. for 5 hrs and then diluted with EtOAc (5 mL), washed with brine (5 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (gradient elution 7% to 60% EtOAc in Hexanes) to give the title compound (128 mg, 0.289 mmol, 82% yield) as an off white foam. MS ESI: [M+H]+ m/z 444.1. 1H NMR (500 MHz, CD3-OD) δ 8.72 (d, J=5.0, 1H), 8.06 (bs, 1H), 8.00 (s, 1H), 7.48 (bs, 1H), 7.16 (bs, 1H), 7.14 (d, J=4.9, 1H), 2.41-2.37 (m, 5H), 2.06-2.00 (m, 2H), 1.94-1.89 (m, 2H), 1.85-1.73 (m, 3H), 1.40 (m, 1H). rhSYK activity=++.

Aufarbeitung

  1. customevacuated/purged with N2 for three times
  2. customDioxane (1.5 mL) and water (0.15 mL) were degassed by undersurface N2 bubbling
  3. additionadded to the reaction vessel
  4. customThe resulting reaction mixture
  5. washwashed with brine (5 mL)
  6. dry with materialdried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe residue was purified by column chromatography on silica (gradient elution 7% to 60% EtOAc in Hexanes)

Quellen und Nachweise

ORD-Eintrag
ord-c5883e7a6a5f493e9afa6541b86f69b7
Quelldatensatz
uspto-grants-2014_06
Patentnummer
US08759366B2

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