Cesium carbonate → N-(3-(6-Methoxy-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)pyridine-3-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-carboxamide

HRID 557537Notes

Reaction equation

HRID 557537 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([CH3:28])=[C:12]([NH:16][C:17]([C:19]3[S:23][C:22]4[CH2:24][CH2:25][CH2:26][CH2:27][C:21]=4[CH:20]=3)=[O:18])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].Cl[C:30]1[N:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)=[CH:32][CH:31]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[CH3:9][O:8][C:7]1[N:6]=[CH:5][C:4]([C:10]2[C:11]([CH3:28])=[C:12]([NH:16][C:17]([C:19]3[S:23][C:22]4[CH2:24][CH2:25][CH2:26][CH2:27][C:21]=4[CH:20]=3)=[O:18])[CH:13]=[CH:14][CH:15]=2)=[CH:3][C:2]=1[NH:1][C:30]1[CH:31]=[CH:32][C:33]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)=[CH:34][N:35]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 59740583N-(3-(5-Amino-6-methoxypyridin-3-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamideHCID 753557481-(6-Chloropyridin-3-yl)-4-methylpiperazine

Product 1

HCID 59740597N-(3-(6-Methoxy-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)pyridine-3-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-carboxamideYield 50%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
95 °C

Procedure

In a 48-mL seal tube equipped with a magnetic stirring bar was placed N-(3-(5-Amino-6-methoxypyridin-3-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide (17) (0.20 g, 0.5 mmol), 1-(6-chloro-pyridin-3-yl)-4-methyl-piperazine (0.11 g, 0.5 mmol), Pd2(dba)3 (0.046 g, 0.050 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.040 g, 0.070 mmol), and Cs2CO3 (0.33 g, 1.0 mmol) in dioxane (10 mL). After the mixture was degassed for 15 min., it was heated at 95° C. for 16 h. Then, the reaction mixture was cooled to room temperature and poured into H2O (10 mL). To this was added dichloromethane (10 mL) and the layers were separated. The aqueous phase was extracted with dichloromethane (3×10 mL), and the combined organic extracts were washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated. The crude mixture was purified by column chromatography, gradient 0-33% MeOH in dichloromethane, to afford 0.140 g (50%) of N-(3-(6-Methoxy-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)pyridine-3-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-carboxamide (18) as a solid.

Workup

  1. customIn a 48-mL seal tube
  2. customequipped with a magnetic stirring bar
  3. customAfter the mixture was degassed for 15 min.
  4. temperatureThen, the reaction mixture was cooled to room temperature
  5. additionpoured into H2O (10 mL)
  6. additionTo this was added dichloromethane (10 mL)
  7. customthe layers were separated
  8. extractionThe aqueous phase was extracted with dichloromethane (3×10 mL)
  9. washthe combined organic extracts were washed with H2O (5 mL) and brine (5 mL)
  10. dry with materialdried (Na2SO4)
  11. concentrationconcentrated
  12. customThe crude mixture was purified by column chromatography, gradient 0-33% MeOH in dichloromethane

Sources & evidence

ORD record
ord-fe95fb84c94d4895942ac86527f59e96
Source dataset
uspto-grants-2011_11
Patent number
US08058446B2

Reaction notes

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