Water → {4-Fluoro-2-[1-methyl-5-({5-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]-6-{7-oxo-3,6-diazatetracyclo[9.2.1.02,10.03,8]tetradeca-2(10),8-dien-6-yl}phenyl}methyl Acetate

HRID 1919150Notes

Reaction equation

HRID 1919150 reaction equation
[C:1]([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[N:25]([C:26]3[CH:27]4[CH2:36][CH:30]([C:31]=3[CH:32]=2)[CH2:29][CH2:28]4)[CH2:24][CH2:23]1)(=[O:3])[CH3:2].Br[C:38]1[CH:39]=[C:40]([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:41](=[O:45])[N:42]([CH3:44])[CH:43]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.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]>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:22]2[C:34](=[O:35])[C:33]3[N:25]([C:26]4[CH:27]5[CH2:36][CH:30]([C:31]=4[CH:32]=3)[CH2:29][CH2:28]5)[CH2:24][CH2:23]2)=[CH:8][C:9]([F:21])=[CH:10][C:11]=1[C:38]1[CH:39]=[C:40]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([N:53]3[CH2:58][CH2:57][N:56]([CH:59]4[CH2:60][O:61][CH2:62]4)[CH2:55][CH2:54]3)=[CH:49][N:48]=2)[C:41](=[O:45])[N:42]([CH3:44])[CH:43]=1)(=[O:3])[CH3:2]

Participants

7

Reactant 4

HCID 962WaterHCID 10340Sodium CarbonateHCID 580437945-Bromo-1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)pyridin-2(1H)-oneHCID 68096915(4-Fluoro-2-{7-oxo-3,6-diazatetracyclo[9.2.1.02,10.03,8]tetradeca-2(10),8-dien-6-yl}-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl Acetate

Product 1

HCID 68096442{4-Fluoro-2-[1-methyl-5-({5-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]-6-{7-oxo-3,6-diazatetracyclo[9.2.1.02,10.03,8]tetradeca-2(10),8-dien-6-yl}phenyl}methyl AcetateYield 70.6%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

A sealed tube was charged with 334h (300 mg, 0.6 mmol), 188e (254 mg, 0.6 mmol), Na2CO3 (129 mg, 1.2 mmol), PdCl2(dppf) (50 mg, 0.06 mmol) suspended in DMF (20 mL), and H2O (1 mL). The mixture was stirred at 80° C. for 5 hours. After reaction the mixture was partitioned between ethyl acetate and water. The organic phase was washed with water (2×), dried over sodium sulfate and concentrated. The residue was purified by reverse phase Combi-flash eluting with 0.3% NH4HCO3 in 1:5 water/CH3CN to give 334i as a brown solid (300 mg, 70%). MS: (M+H)+ 708.

Workup

  1. customAfter reaction the mixture
  2. customwas partitioned between ethyl acetate and water
  3. washThe organic phase was washed with water (2×)
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated
  6. customThe residue was purified by reverse phase Combi-flash
  7. washeluting with 0.3% NH4HCO3 in 1:5 water/CH3CN

Sources & evidence

ORD record
ord-2899fecc4bcf46039441fbe08814c1c6
Source dataset
uspto-grants-2013_12
Patent number
US08618107B2

Reaction notes

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