4-Chloroaniline → 5-(3-(9-(4-methoxybenzyl)-9H-purin-6-yl)pyridin-2-yloxy)-N-(4-chlorophenyl)-6-methylisoquinolin-1-amine

HRID 1042282Notes

Reaction equation

HRID 1042282 reaction equation
[CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([CH2:7][N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[C:17]2[C:18]([O:23][C:24]3[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][N:28]=[C:29]4Cl)=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:5][CH:4]=1.[Cl:38][C:39]1[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([CH2:7][N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[C:17]2[C:18]([O:23][C:24]3[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][N:28]=[C:29]4[NH:43][C:42]3[CH:44]=[CH:45][C:39]([Cl:38])=[CH:40][CH:41]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:5][CH:4]=1

Participants

6

Reactant 4

HCID 78124-ChloroanilineHCID 2733832Lithium HexamethyldisilazideHCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenylHCID 866493135-(3-(9-(4-methoxybenzyl)-9H-purin-6-yl)pyridin-2-yloxy)-1-chloro-6-methylisoquinoline

Product 1

HCID 687422985-(3-(9-(4-methoxybenzyl)-9H-purin-6-yl)pyridin-2-yloxy)-N-(4-chlorophenyl)-6-methylisoquinolin-1-amine

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
50 °C

Procedure

A mixture of 5-(3-(9-(4-methoxybenzyl)-9H-purin-6-yl)pyridin-2-yloxy)-1-chloro-6-methylisoquinoline (0.250 g, 0.491 mmol) and 4-chloroaniline (0.0752 g, 0.589 mmol) in anhydrous 1,4 dioxane (10 mL) was vacuum purged with Ar three times, then 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.0309 g, 0.0786 mmol) and tris(dibenzylideneacetone)palladium (0) (0.0180 g, 0.0196 mmol) were added. The suspension was sonicated for 2 min, then treated dropwise with lithium bis(trimethylsilyl)amide (1.0 M solution in THF; 0.69 mL, 0.69 mmol). The resulting brown solution was stirred in a 50° C. oil bath for 45 min. The reaction mixture was allowed to cool to RT (22° C.) and quenched with 1N aq HCl (5 mL). After stirring at RT for 10 min, the mixture was added to satd NaHCO3 (70 mL) and extracted with EtOAc (2×50 mL). The combined extracts were washed with water (50 mL), satd NaCl (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give 530 mg as a yellow residue. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 30% to 60% EtOAc in CH2Cl2, to provide 5-(3-(9-(4-methoxybenzyl)-9H-purin-6-yl)pyridin-2-yloxy)-N-(4-chlorophenyl)-6-methylisoquinolin-1-amine as a clear film. MS (ESI, pos. ion) m/z: 600.2 [M+H]+.

Workup

  1. custompurged with Ar three times
  2. customThe suspension was sonicated for 2 min
  3. temperatureto cool to RT (22° C.)
  4. customquenched with 1N aq HCl (5 mL)
  5. stirringAfter stirring at RT for 10 min
  6. additionthe mixture was added to satd NaHCO3 (70 mL)
  7. extractionextracted with EtOAc (2×50 mL)
  8. washThe combined extracts were washed with water (50 mL), satd NaCl (50 mL)
  9. dry with materialdried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customto give 530 mg as a yellow residue
  13. customchromatographed through a Redi-Sep® pre-packed silica gel column (40 g)
  14. washeluting with a gradient of 30% to 60% EtOAc in CH2Cl2

Sources & evidence

ORD record
ord-a326c66eeca44c9588bce2ce9cd0b56d
Source dataset
uspto-grants-2013_10
Patent number
US08557830B2

Reaction notes

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