2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl → 4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-5,6,7,8-tetrahydrophthalazin-1-amine

HRID 227778Notes

Reaction equation

HRID 227778 reaction equation
Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([Cl:12])=[N:4][N:3]=1.[NH2:13][C:14]1[CH:34]=[CH:33][C:17]([O:18][C:19]2[C:24]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH3:32])[N:26]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:16][CH:15]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.CC(C)([O-])C.[Na+]>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]>[Cl:12][C:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:2]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:18][C:19]3[C:24]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH3:32])[N:26]=4)=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:33][CH:34]=2)=[N:3][N:4]=1

Participants

6

Reactant 4

HCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 126224401,4-Dichloro-5,6,7,8-tetrahydrophthalazineHCID 23676156Sodium t-butoxideHCID 469295414-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine

Product 1

HCID 577562304-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-5,6,7,8-tetrahydrophthalazin-1-amine

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
150 °C

Procedure

A resealable reaction tube was charged with 1,4-dichloro-5,6,7,8-tetrahydrophthalazine (0.050 g, 0.246 mmol), 4-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (0.072 g, 0.246 mmol), tris(dibenzylideneacetone)dipalladium (0)(0.011 g, 0.012 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (0.020 g, 0.049 mmol), and sodium tert-butoxide (0.033 g, 0.345 mmol). The vial was purged with nitrogen for several minutes, followed by addition of 0.50 mL of toluene. The vial was capped and heated to 150° C. for 16 h. The reaction mixture was allowed to cool and was filtered through a plug of Celite, rinsing with dichloromethane. The filtrate was concentrated, and the crude material was purified by reverse phase chromatography, Gilson, 5-95% acetonitrile/H2O/0.1% TFA over 14 min. The product-containing fractions were combined, brought to basic pH by addition of 2M Na2CO3 and extracted with dichloromethane. The organic portion was dried with MgSO4, filtered, and concentrated to give 4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-5,6,7,8-tetrahydrophthalazin-1-amine as a light brown solid. MS m/z=460 [M+H]+. Calc'd for C24H22ClN7O: 459.93.

Workup

  1. customThe vial was purged with nitrogen for several minutes
  2. additionfollowed by addition of 0.50 mL of toluene
  3. customThe vial was capped
  4. temperatureto cool
  5. filtrationwas filtered through a plug of Celite
  6. washrinsing with dichloromethane
  7. concentrationThe filtrate was concentrated
  8. customthe crude material was purified by reverse phase chromatography, Gilson, 5-95% acetonitrile/H2O/0.1% TFA over 14 min
  9. additionbrought to basic pH by addition of 2M Na2CO3
  10. extractionextracted with dichloromethane
  11. dry with materialThe organic portion was dried with MgSO4
  12. filtrationfiltered
  13. concentrationconcentrated

Sources & evidence

ORD record
ord-f802663fe2614b6a816412cf1fc41794
Source dataset
uspto-grants-2009_07
Patent number
US07560551B2

Reaction notes

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