Cesium carbonate → 2-(5-Fluoro-2-(hydroxymethyl)-3-(8-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one

HRID 1024024Notes

Reaction equation

HRID 1024024 reaction equation
Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[CH:14][N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C([O:28][CH2:29][C:30]1[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][C:33]([F:45])=[CH:32][C:31]=1[N:46]1[CH2:58][CH2:57][N:49]2[C:50]3[CH2:51][CH2:52][CH2:53][CH2:54][C:55]=3[CH:56]=[C:48]2[C:47]1=[O:59])(=O)C.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>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].O.O1CCOCC1>[F:45][C:33]1[CH:34]=[C:35]([C:2]2[CH:3]=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][N:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[C:30]([CH2:29][OH:28])=[C:31]([N:46]2[CH2:58][CH2:57][N:49]3[C:50]4[CH2:51][CH2:52][CH2:53][CH2:54][C:55]=4[CH:56]=[C:48]3[C:47]2=[O:59])[CH:32]=1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 75806TricyclohexylphosphineHCID 580442052-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzyl AcetateHCID 866841236-Chloro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine

Product 1

HCID 715593222-(5-Fluoro-2-(hydroxymethyl)-3-(8-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-oneYield 20.1%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
130 °C

Procedure

A sealed tube was charged with 104b (340 mg, 0.8 mmol), 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 101l (400 mg, 0.8 mmol), Pd2(dba)3 (72 mg, 0.1 eq., 0.08 mmol), PCy3 (68 mg, 0.3 eq., 0.24 mmol), cesium carbonate (520 mg, 2 eq., 1.6 mmol), dioxane (15 mL), and water (1 mL). After three cycles of vacuum/argon flash, the mixture was heated at 130° C. for 14 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/-methanol (20:1) to afford 104 (100 mg, 16%). LCMS: [M+H]+ 622. 1H NMR (500 MHz, DMSO) δ 9.95 (s, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 8.00 (d, J=2.0, 1H), 7.67 (s, 1H), 7.43-7.46 (m, 3H), 7.34-7.36 (m, 1H), 6.52 (s, 1H), 4.67 (t, J=5.0, 1H), 4.34-4.41 (m, 2H), 4.13-4.18 (m, 3H), 3.87-3.88 (m, 1H), 3.10-3.12 (m, 4H), 2.57-2.61 (m, 2H), 2.43-2.47 (m, 6H), 2.21 (s, 3H), 1.77-1.79 (m, 2H), 1.68-1.69 (m, 2H)

Workup

  1. temperatureIt was then cooled to room temperature
  2. filtrationfiltered
  3. concentrationThe filtrate was concentrated under reduced pressure
  4. customthe resulting residue was purified by silica-gel column chromatography
  5. washeluting with dichloromethane/-methanol (20:1)

Sources & evidence

ORD record
ord-942288e5b1d14e1aa17ac99919ab4440
Source dataset
uspto-grants-2014_05
Patent number
US08722676B2

Reaction notes

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