2,8,9-Triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo(3.3.3)undecane → Isopropyl 4-((5-methoxy-6-((2-methyl-6-(methylsulfonyl)pyridin-3-yl)amino)pyrimidin-4-yl)oxy)piperidine-1-carboxylate

HRID 1811599

Reaktionsgleichung

Reaktionsgleichung von HRID 1811599
[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].[CH3:23][C:24]1[C:29]([NH2:30])=[CH:28][CH:27]=[C:26]([S:31]([CH3:34])(=[O:33])=[O:32])[N:25]=1.C(N1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2)C(C)C.CC([O-])(C)C.[Na+]>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:30][C:29]3[C:24]([CH3:23])=[N:25][C:26]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:28]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]

Komponenten

7

Edukt 4

HCID 45712432,8,9-Triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo(3.3.3)undecaneHCID 23676156Sodium t-butoxideHCID 51050526Isopropyl 4-[(6-chloro-5-methoxypyrimidin-4-yl)oxy]piperidine-1-carboxylateHCID 510505272-Methyl-6-(methylsulfonyl)pyridin-3-amine

Produkt 1

HCID 11691484Isopropyl 4-((5-methoxy-6-((2-methyl-6-(methylsulfonyl)pyridin-3-yl)amino)pyrimidin-4-yl)oxy)piperidine-1-carboxylateAusbeute 22 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 167845palladium(II) acetateKatalysatorHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
90 °C

Versuchsvorschrift

A mixture of 4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (14.7 g, 44.6 mmol), 2-methyl-6-(methylsulfonyl)pyridin-3-amine (8.20 g, 44.0 mmol), palladium acetate (0.50 g, 2.23 mmol), 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane (1.65 ml, 4.64 mmol), and sodium 2-methylpropan-2-olate (6.50 g, 67.6 mmol) in dioxane (300 mL) were stirred at 90° C. for 1 h and then at 60° C. overnight. The reaction mixture was cooled and filtered. The solid was washed with ethyl acetate. The filtrate was concentrated and the residue was purified by silica gel column chromatography using hexane/ethyl acetate (1:2). The fractions containing only the product were collected, and concentrated to give the title compound (4.6 g, 22%) that was crystallized from ethyl acetate/hexane as a white solid. The fractions containing the product contaminated with impurities were concentrated and the residue was further purified by recrystallization from ethanol to give the title compound (2.5 g, 12%) as a white solid. The two combined to give 7.1 g of the title compound in 34% yield. Exact mass calculated for C21H29N5O6S: 479.2. Found: LCMS m/z=480.4 (M+H+); 1H NMR (400 MHz, CDCl3) δ 1.27 (d, J=6.3 Hz, 6H), 1.80-1.85 (m, 2H), 2.02-2.07 (m, 2H), 2.66 (s, 3H), 3.19 (s, 3H), 3.38-3.45 (m, 2H), 3.78-3.83 (m, 2H), 4.01 (s, 3H), 4.91-4.97 (m, 1H), 5.38-5.42 (m, 1H), 7.30 (s, 1H), 7.97 (d, J=8.6 Hz, 1H), 8.20 (s, 1H), 9.01-9.04 (d, J=8.6 Hz, 1H).

Aufarbeitung

  1. customat 60° C.
  2. customovernight
  3. temperatureThe reaction mixture was cooled
  4. filtrationfiltered
  5. washThe solid was washed with ethyl acetate
  6. concentrationThe filtrate was concentrated
  7. customthe residue was purified by silica gel column chromatography
  8. additionThe fractions containing only the product
  9. customwere collected
  10. concentrationconcentrated

Quellen und Nachweise

ORD-Eintrag
ord-30812c56644542e6a9a9b55ae07d3a9e
Quelldatensatz
uspto-grants-2013_01
Patentnummer
US08362248B2

Verknüpfte Notizen

Wird geladen…