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 407609Notes

Reaction equation

HRID 407609 reaction equation
[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]

Participants

6

Reactant 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

Product 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)-oneYield 47.5%

Reagents, catalysts & solvents 1

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

Conditions

Temperature
90 °C

Procedure

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).

Workup

  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)

Sources & evidence

ORD record
ord-551132e81edd4c6e8d4f1a4f83e876d2
Source dataset
uspto-grants-2014_06
Patent number
US08754077B2

Reaction notes

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