Ammonia → 4-(1-methylpiperidin-4-yloxy)-2-(5-methylthiophen-2-yl)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene

HRID 1773885Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1773885
I[C:2]1[N:11]=[C:10]2[N:4]([CH2:5][CH2:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH:9]2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:3]=1.C[C:25]1[CH:26]=[C:27](B2OC(C)(C)C(C)(C)O2)[S:28][CH:29]=1.[F-].[Cs+].N.O1CCOC[CH2:43]1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:19][N:16]1[CH2:17][CH2:18][CH:13]([O:12][CH:9]2[C:8]3[CH:20]=[CH:21][CH:22]=[CH:23][C:7]=3[CH2:6][CH2:5][N:4]3[C:10]2=[N:11][C:2]([C:29]2[S:28][C:27]([CH3:43])=[CH:26][CH:25]=2)=[CH:3]3)[CH2:14][CH2:15]1

Komponenten

8

Edukt 5

HCID 222AmmoniaHCID 25953Cesium fluoride2×HCID 312751,4-DioxaneHCID 104435924,4,5,5-Tetramethyl-2-(4-methylthiophen-2-yl)-1,3,2-dioxaborolaneHCID 726957782-iodo-4-(1-methyl piperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene

Produkt 1

HCID 726944724-(1-methylpiperidin-4-yloxy)-2-(5-methylthiophen-2-yl)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)Katalysator2×HCID 962WaterLösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

To a solution of 2-iodo-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 2A) (50 mg, 0.12 mmoles) in 1,4-dioxane (2.5 mL) in a screw-capped vial under argon are added 4-methylthiophene-2-boronic acid pinacol ester (40 mg, 0.18 mmole), PdCl2(dppf)2 (6.7 mg, 12 μmole), CsF (36 mg, 0.24 mmoles). The reaction mixture is heated at 100° C. overnight. As the reaction is not completed, CsF (18 mg, 0.12 mmole) and PdCl2(dppf)2 (6.7 mg, 12 μmole) are added and the reaction mixture is heated at 100° C. overnight. Water is added, pH is made alkaline by adding concentrated ammonia solution and the aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) as eluent with a gradient from (98:2:0.2) to (96.5:3.5:0.35) followed by a purification on a preparative TLC over silica gel eluting with (9:1:0.1) to give 4-(1-methylpiperidin-4-yloxy)-2-(5-methylthiophen-2-yl)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene.

Aufarbeitung

  1. temperaturethe reaction mixture is heated at 100° C. overnight
  2. extractionthe aqueous phase is extracted three times with CH2Cl2
  3. dry with materialThe organic phase is dried over magnesium sulphate
  4. filtrationfiltered
  5. customthe solvent is removed under reduced pressure
  6. customThe residue is purified by silica gel chromatography
  7. customfollowed by a purification on a preparative TLC over silica gel eluting with (9:1:0.1)

Quellen und Nachweise

ORD-Eintrag
ord-b5154dcbfaa347c3887d36f464288975
Quelldatensatz
uspto-grants-2016_02
Patentnummer
US09255101B2

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