Cesium carbonate → 5-[5-Fluoro-2-(hydroxymethyl)-3-(8-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenyl]-8-thia-4,5-diazatricyclo-[7.4.0.02,7]trideca-1(9),2(7),3-trien-6-one

HRID 1024053Notes

Reaction equation

HRID 1024053 reaction equation
C([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][C:9]([F:21])=[CH:8][C:7]=1[N:22]1[C:34](=[O:35])[C:33]2[S:32][C:31]3[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=3[C:25]=2[CH:24]=[N:23]1)(=O)C.Cl[C:37]1[CH:38]=[C:39]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([N:53]3[CH2:58][CH2:57][N:56]([CH:59]4[CH2:62][O:61][CH2:60]4)[CH2:55][CH2:54]3)=[CH:49][N:48]=2)[C:40]2[N:41]([CH:43]=[CH:44][N:45]=2)[N:42]=1.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].O1CCOCC1>[F:21][C:9]1[CH:10]=[C:11]([C:37]2[CH:38]=[C:39]([NH:46][C:47]3[CH:52]=[CH:51][C:50]([N:53]4[CH2:58][CH2:57][N:56]([CH:59]5[CH2:62][O:61][CH2:60]5)[CH2:55][CH2:54]4)=[CH:49][N:48]=3)[C:40]3[N:41]([CH:43]=[CH:44][N:45]=3)[N:42]=2)[C:6]([CH2:5][OH:4])=[C:7]([N:22]2[C:34](=[O:35])[C:33]3[S:32][C:31]4[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=4[C:25]=3[CH:24]=[N:23]2)[CH:8]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 75806TricyclohexylphosphineHCID 58043634(4-Fluoro-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-5-yl}-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetateHCID 866841246-Chloro-N-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine

Product 1

HCID 715571335-[5-Fluoro-2-(hydroxymethyl)-3-(8-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenyl]-8-thia-4,5-diazatricyclo-[7.4.0.02,7]trideca-1(9),2(7),3-trien-6-oneYield 12%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
110 °C

Procedure

A sealed tube equipped with a magnetic stirrer was charged with (4-fluoro-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-5-yl}-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate (200 mg, 0.44 mmol), 6-chloro-N-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine 105a (155 mg, 0.44 mmol), tricyclohexylphosphine (112 mg, 0.4 mmol), Pd2(dba)3 (28 mg, 0.024 mmol), Cs2CO3 (261 mg, 0.8 mmol), and dioxane (25 mL). After three cycles of vacuum/argon flush, the reaction mixture was heated at 110° C. for 16 h. The mixture was evaporated in vacuo and the residue was extracted with ethyl acetate (10 mL×2). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 112 (26 mg, 12%). MS: [M+H]+ 680. 1H NMR (500 MHz, DMSO) δ 9.95 (s, 1H), 8.49 (s, 1H), 8.24 (s, 1H), 8.17 (s, 1H), 8.04 (s, 1H), 7.67 (s, 1H), 7.45-7.53 (m, 4H), 4.54-4.57 (m, 3H), 4.45-4.47 (m, 2H), 4.33 (d, J=12.5, 2H), 3.35-3.46 (m, 1H), 3.13-3.17 (m, 4H), 2.83-2.94 (m, 4H), 2.47-2.50 (m, 4H), 1.82-1.87 (m, 4H)

Workup

  1. customA sealed tube equipped with a magnetic stirrer
  2. customAfter three cycles of vacuum/argon flush
  3. customThe mixture was evaporated in vacuo
  4. extractionthe residue was extracted with ethyl acetate (10 mL×2)
  5. extractionThe combined ethyl acetate extract
  6. concentrationwas concentrated under reduced pressure
  7. customthe residue was purified with reverse-phase prep-HPLC

Sources & evidence

ORD record
ord-4193d4d0d822447aabda4f1abdbdbdc9
Source dataset
uspto-grants-2014_05
Patent number
US08722676B2

Reaction notes

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