2-(Di-tert-butylphosphino)biphenyl → 4-[6-(6-Bromo-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester

HRID 1811562

Reaktionsgleichung

Reaktionsgleichung von HRID 1811562
[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([O:20][CH3:21])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[Br:23][C:24]1[N:29]=[C:28]([CH3:30])[C:27]([NH2:31])=[CH:26][CH:25]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[Li]N([Si](C)(C)C)[Si](C)(C)C>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([O:20][CH3:21])=[C:18]([NH:31][C:27]3[C:28]([CH3:30])=[N:29][C:24]([Br:23])=[CH:25][CH:26]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]

Komponenten

7

Edukt 4

HCID 27342152-(Di-tert-butylphosphino)biphenylHCID 144180456-Bromo-2-methylpyridin-3-amineHCID 51050526Isopropyl 4-[(6-chloro-5-methoxypyrimidin-4-yl)oxy]piperidine-1-carboxylateHCID 178418261HCID 178418261, Verbindung

Produkt 1

HCID 586716014-[6-(6-Bromo-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl esterAusbeute 44 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 167845palladium(II) acetateKatalysator2×HCID 312751,4-DioxaneLösungsmittel

Versuchsvorschrift

A mixture of 4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (3.3 g, 10.0 mmol), 6-bromo-2-methyl-pyridin-3-ylamine (1.88 g, 10.0 mmol), palladium acetate (118 mg, 0.53 mmol), 2-(di-t-butylphosphino) biphenyl (157 mg, 0.53 mmol) and LiN(TMS)2 (1M in THF, 15 mL, 15 mmol) in 75 mL of dioxane was stirred under reflux. After 4.5 h, more palladium acetate (111 mg, 0.50 mmol) was added and mixture was stirred under reflux for another hour and then at room temperature for 3 days. The mixture was concentrated and residue was extracted with brine and AcOEt. Organic phases were dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (hexane/AcOEt 2:1→1:1) to give 4-[6-(6-bromo-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester as a solid (2.09 g, 44%). 1HNMR (CDCl3, 400 MHz) a 1.27-1.28 (d, 6H), 1.84-1.87 (m, 2H), 2.02-2.08 (m, 2H), 2.58 (s, 3H), 3.40-3.47 (m, 2H), 3.73 (s, 3H), 3.77-3.82 (m, 2H), 4.93-4.97 (m, 1H), 5.41-5.43 (m, 1H), 7.44-7.46 (m, 1H), 7.91-7.93 (m, 1H), 8.24 (s, 1H), 8.70 (s br, 1H). Exact mass calculated for C20H26BrN5O4 479.12. found 482.0 (MH+).

Aufarbeitung

  1. temperatureunder reflux
  2. stirringmixture was stirred
  3. temperatureunder reflux for another hour
  4. waitat room temperature for 3 days
  5. concentrationThe mixture was concentrated
  6. extractionresidue was extracted with brine and AcOEt
  7. dry with materialOrganic phases were dried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe residue was purified by column chromatography (hexane/AcOEt 2:1→1:1)

Quellen und Nachweise

ORD-Eintrag
ord-dad365111948425bb8ac377e3c966d47
Quelldatensatz
uspto-grants-2013_01
Patentnummer
US08362248B2

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