Cesium carbonate → Tert-butyl 4-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)piperidine-1-carboxylate

HRID 337275Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 337275
Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.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]>[C:27]([O:26][C:24]([N:21]1[CH2:20][CH2:19][CH:18]([C:15]2[CH:16]=[N:17][C:12]([NH:11][C:2]3[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[C:6]([Cl:8])[CH:7]=3)=[CH:13][CH:14]=2)[CH2:23][CH2:22]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]

Komponenten

7

Edukt 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 49839963tert-Butyl 4-(6-aminopyridin-3-yl)piperidine-1-carboxylateHCID 592164744-Bromo-6-chloro-2-methyl-2,3-dihydropyridazin-3-one

Produkt 1

HCID 66742247Tert-butyl 4-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)piperidine-1-carboxylateAusbeute 76,4 %

Reagenzien, Katalysatoren, Lösungsmittel 2

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

Reaktionsbedingungen

Temperatur
90 °C

Versuchsvorschrift

4-Bromo-6-chloro-2-methylpyridazin-3(2H)-one (3.59 g, 16.0 mmol, Eq: 1.00), tert-butyl 4-(6-aminopyridin-3-yl)piperidine-1-carboxylate (4.45 g, 16.0 mmol, Eq: 1.00), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (696 mg, 1.2 mmol, Eq: 0.075) and cesium carbonate (18.3 g, 56.2 mmol, Eq: 3.5) were suspended in dioxane (150 ml) under an argon atmosphere. Finally tris(dibenzylideneacetone)dipalladium(0) (551 mg, 602 μmol, Eq: 0.0375) was added. The reaction mixture was heated at 90° C. overnight. The reaction mixture was filtered over celite, and the celite cake was washed with dioxane several times. The combined filtrate and washes were concentrated in vacuo and the resultant solid was triturated with EtOAc, washed with ether and dried in a vacuum oven overnight at 50° C. to afford 4.57 g of the desired product as a white solid. The combined filtrate and washes were evaporated to dryness and dissolved in CH2Cl2 (4 ml) and the crude material was purified by flash chromatography (silica gel, 120 g Analogix column, 20% to 50% EtOAc in hexanes over 20 min) to afford and additional 582 mg. Total yield (5.15 g, 12.3 mmol, 76.4% yield). (M+H)+=420 m/e; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.50 (s, 9 H) 1.54-1.69 (m, 3 H) 1.83 (d, J=13.64 Hz, 2 H) 2.67 (tt, J=12.38, 3.66 Hz, 1 H) 2.83 (t, J=13.14 Hz, 2 H) 3.82 (s, 3 H) 6.89 (d, J=8.59 Hz, 1 H) 7.51 (dd, J=8.46, 2.40 Hz, 1 H) 8.25 (d, J=2.27 Hz, 1 H) 8.27 (br. s., 1 H) 8.30 (s, 1 H).

Aufarbeitung

  1. filtrationThe reaction mixture was filtered over celite
  2. washthe celite cake was washed with dioxane several times
  3. concentrationThe combined filtrate and washes were concentrated in vacuo
  4. customthe resultant solid was triturated with EtOAc
  5. washwashed with ether
  6. customdried in a vacuum oven overnight at 50° C.

Quellen und Nachweise

ORD-Eintrag
ord-948886f528014d198c30627c3244e7bf
Quelldatensatz
uspto-grants-2014_11
Patentnummer
US08889682B2

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