Potassium Phosphate, Tribasic → 4-Fluoro-2-(1-methyl-5-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-6,7,8,9-tetrahydropyridazino[4,5-b]indolizin-2(1H)-yl)benzaldehyde

HRID 1843266Notes

Reaction equation

HRID 1843266 reaction equation
Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N:11]2[C:23](=[O:24])[C:15]3[CH:16]=[C:17]4[N:22]([C:14]=3[CH:13]=[N:12]2)[CH2:21][CH2:20][CH2:19][CH2:18]4)[C:3]=1[CH:4]=[O:5].[CH3:25][N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][N:51]([CH:54]4[CH2:57][O:56][CH2:55]4)[CH2:50][C@@H:49]3[CH3:58])=[CH:44][N:43]=2)[C:27]1=[O:59].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[F:10][C:8]1[CH:7]=[C:6]([N:11]2[C:23](=[O:24])[C:15]3[CH:16]=[C:17]4[N:22]([C:14]=3[CH:13]=[N:12]2)[CH2:21][CH2:20][CH2:19][CH2:18]4)[C:3]([CH:4]=[O:5])=[C:2]([C:30]2[CH:29]=[C:28]([NH:41][C:42]3[CH:47]=[CH:46][C:45]([N:48]4[CH2:53][CH2:52][N:51]([CH:54]5[CH2:55][O:56][CH2:57]5)[CH2:50][CH:49]4[CH3:58])=[CH:44][N:43]=3)[C:27](=[O:59])[N:26]([CH3:25])[CH:31]=2)[CH:9]=1

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 517045Sodium AcetateHCID 866837011-methyl-3-((5-((2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-oneHCID 866837702-Bromo-4-fluoro-6-(1-oxo-6,7,8,9-tetrahydropyridazino[4,5-b]indolizin-2(1H)-yl)benzaldehyde

Product 1

HCID 866837714-Fluoro-2-(1-methyl-5-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-6,7,8,9-tetrahydropyridazino[4,5-b]indolizin-2(1H)-yl)benzaldehyde

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
100 °C

Procedure

A 100-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 127f (125.0 mg, 0.32 mmol), 1-methyl-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 113f (155.0 mg, 0.32 mmol), sodium acetate (53.0 mg, 0.64 mmol), K3PO4 (135.7.0 mg, 0.64 mmol), PdCl2(dppf) (50.0 mg, 0.06 mmol), acetonitrile (25 mL), and water (1 mL). The system was subjected to 3 cycles of vacuum/argon flush and heated at 100° C. for 3 hours. It was then evaporated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 30:1 methylene chloride/methanol to afforded 127g compound (108 mg, 51%) as a brown solid. MS: [M+H]+ 665.4.

Workup

  1. customA 100-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser
  2. customflush
  3. customIt was then evaporated under reduced pressure
  4. customthe residue was purified by silica-gel column chromatography
  5. washeluting with 30:1 methylene chloride/methanol

Sources & evidence

ORD record
ord-a73aa88cd05f4bc8954d717523fba463
Source dataset
uspto-grants-2015_02
Patent number
US08946213B2

Reaction notes

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