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Cesium carbonate → 3,5-Dichloro-4-[4-(6-ethylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-benzonitrile

HRID 2366244
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Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 2366244
Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:18]([Cl:19])=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=3[Cl:20])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH2:21]([C:23]1[N:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:22].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+]>O1CCOCC1.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]>[Cl:20][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([Cl:19])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([NH:29][C:25]3[CH:24]=[C:23]([CH2:21][CH3:22])[N:28]=[CH:27][N:26]=3)=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=1)[C:15]#[N:16]
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Komponenten

7

Edukt 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 219116256-Ethylpyrimidin-4-amineHCID 866689964-(4-Bromothiazolo[5,4-c]pyridin-2-yl)-3,5-dichlorobenzonitrile

Produkt 1

HCID 569525123,5-Dichloro-4-[4-(6-ethylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-benzonitrile
Ausbeute 30,5 %

Reagenzien, Katalysatoren, Lösungsmittel 2

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

Reaktionsbedingungen

Temperatur
70 °C

Versuchsvorschrift

A mixture of 4-(4-bromothiazolo[5,4-c]pyridin-2-yl)-3,5-dichlorobenzonitrile (0.095 g, 0.25 mmol), 6-ethylpyrimidin-4-ylamine (29 mg, 0.23 mmol), Pd2(dba)3 (11 mg, 0.012 mmol), XantPhos (14 mg, 0.025 mmol) and cesium carbonate (0.201 g, 0.62 mmol) in dioxane (2.5 mL) was degassed with a stream of nitrogen. The reaction mixture was heated at 70° C. for 16 hours. After cooling to room temperature, the resultant mixture was diluted with water and filtered through Celite® washing with DCM. The aqueous phase was further extracted with DCM and the combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resultant residue was purified by silica gel flash C18 column chromatography eluting with 0-100% EtOAc in pentane followed by a 20-60% gradient MeOH in H2O+1M HCl (1.25 mL in each 25 mL of eluent). The product containing fractions were combined and concentrated under reduced pressure. The resultant solid was suspended in a mixture DCM/EtOAc/MeOH and washed with a saturated solution of NaHCO3, then dried and concentrated under reduced pressure. Further column chromatography purification on silica gel, eluting with 0-50% EtOAc in DCM, afforded the title compound as a pale yellow solid (30 mg, 28% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.70 (br s, 1H), 8.66 (d, J=1.2 Hz, 1H), 8.46 (d, J=5.6 Hz, 1H), 8.39 (s, 2H); 7.84 (d, J=5.6 Hz, 1H), 7.56 (s, 1H), 2.67 (q, J=7.6 Hz, 2H), 1.23 (t, J=7.6 Hz, 3H). LCMS (Method C): RT=3.81 min, m/z: 427 [M+H+].

Aufarbeitung

  1. customwas degassed with a stream of nitrogen
  2. temperatureAfter cooling to room temperature
  3. additionthe resultant mixture was diluted with water
  4. filtrationfiltered through Celite®
  5. washwashing with DCM
  6. extractionThe aqueous phase was further extracted with DCM
  7. dry with materialthe combined organic layers were dried (MgSO4)
  8. concentrationconcentrated under reduced pressure
  9. customThe resultant residue was purified by silica gel flash C18 column chromatography
  10. washeluting with 0-100% EtOAc in pentane
  11. additionThe product containing fractions
  12. concentrationconcentrated under reduced pressure
  13. washwashed with a saturated solution of NaHCO3
  14. customdried
  15. concentrationconcentrated under reduced pressure
  16. customFurther column chromatography purification on silica gel
  17. washeluting with 0-50% EtOAc in DCM

Quellen und Nachweise

ORD-Eintrag
ord-b9347fbc2d1f439fb0b87974dc39c21e
Quelldatensatz
uspto-grants-2014_04
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08697708B2

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