Potassium Carbonate → 6-tert-Butyl-8-fluoro-2-(2-(hydroxymethyl)-3-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)phthalazin-1(2H)-one

HRID 407609Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 407609
[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19](Cl)[C:18]=1[CH2:24][OH:25])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([N:49]3[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]3)=[CH:45][N:44]=2)[C:28]1=[O:56].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])([O-])=O.[K+].[K+]>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]>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:31]3[CH:30]=[C:29]([NH:42][C:43]4[CH:48]=[CH:47][C:46]([N:49]5[CH2:50][CH2:51][N:52]([CH3:55])[CH2:53][CH2:54]5)=[CH:45][N:44]=4)[C:28](=[O:56])[N:27]([CH3:26])[CH:32]=3)[C:18]=1[CH2:24][OH:25])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]

Komponenten

6

Edukt 4

HCID 11430Potassium CarbonateHCID 75806TricyclohexylphosphineHCID 580437641-methyl-3-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-oneHCID 594737806-(tert-butyl)-2-(3-chloro-2-(hydroxymethyl)phenyl)-8-fluorophthalazin-1(2H)-one

Produkt 1

HCID 469082206-tert-Butyl-8-fluoro-2-(2-(hydroxymethyl)-3-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)phthalazin-1(2H)-oneAusbeute 47,5 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6505921(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladiumKatalysator

Reaktionsbedingungen

Temperatur
90 °C

Versuchsvorschrift

To a 10 mL flask were added 6-tert-butyl-2-(3-chloro-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one 101j (100 mg, 0.27 mmol), 1-methyl-3-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (141 mg, 0.33 mmol), PCy3 (6 mg), Pd(dba)2 (6 mg) and K2CO3 (112 mg, 0.8 mmol) in order. The flask was evacuated and backfilled with nitrogen. This sequence was repeated three times. Then, 20 percent aqueous 1,4-dioxane was added to the reaction mixture. The resulting mixture was heated to 90° C. for gentle reflux and stirred for 1.5 hr under Nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through a diatomaceous earth filtration agent pad (CELITE®) and concentrated to afford a residue which was purified by prep-TLC (10% MeOH in CH2Cl2) to afford 101 (80 mg, 46%) as a yellow solid. MS: [M+H]+624. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J=2.0 Hz, 1H), 8.50 (d, J=1.6 Hz, 1H), 8.36 (s, 1H), 7.87 (d, J=3.2 Hz, 2H), 7.73 (d, J=12.8 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 7.41 (d, J=3.2 Hz, 1H), 7.39 (d, J=3.6 Hz, 1H), 7.35 (dd, J=2.8, 9.2 Hz, 1H), 7.28 (d, J=2. Hz, 1H), 7.20 (d, J=9.2 Hz, 1H), 4.58 (t, J=4.8 Hz, 1H), 4.36 (s, 2H), 3.58 (s, 3H), 3.04 (m, 4H), 2.44 (m, 4H), 2.21 (s, 3H), 1.38 (s, 9H).

Aufarbeitung

  1. customThe flask was evacuated
  2. additionThen, 20 percent aqueous 1,4-dioxane was added to the reaction mixture
  3. temperaturefor gentle reflux
  4. temperatureThe reaction mixture was cooled to room temperature
  5. filtrationfiltered through a diatomaceous earth filtration agent pad (CELITE®)
  6. concentrationconcentrated
  7. customto afford a residue which
  8. customwas purified by prep-TLC (10% MeOH in CH2Cl2)

Quellen und Nachweise

ORD-Eintrag
ord-551132e81edd4c6e8d4f1a4f83e876d2
Quelldatensatz
uspto-grants-2014_06
Patentnummer
US08754077B2

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