Potassium Phosphate, Tribasic → (5-Aminopyridin-3-yl){7-[(1S)-1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}methanone

HRID 82152Notes

Reaction equation

HRID 82152 reaction equation
C(=[NH:14])(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:16]1[CH:17]=[C:18]([C:22]([C:24]2[C:32]3[CH:31]=[N:30][CH:29]=[N:28][C:27]=3[N:26]([C@@H:33]([CH3:42])[CH2:34][O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[CH:25]=2)=[O:23])[CH:19]=[N:20][CH:21]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C(Cl)Cl.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]>[NH2:14][C:16]1[CH:17]=[C:18]([C:22]([C:24]2[C:32]3[CH:31]=[N:30][CH:29]=[N:28][C:27]=3[N:26]([C@@H:33]([CH3:42])[CH2:34][O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[CH:25]=2)=[O:23])[CH:19]=[N:20][CH:21]=1

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 136809Benzophenone imineHCID 11618717Di-tert-butyl(2',4',6'-tris(propan-2-yl)-(1,1'-biphenyl)-2-yl)phosphaneHCID 70817568(5-Bromopyridin-3-yl){7-[(1S)-1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}methanone

Product 1

HCID 70817242(5-Aminopyridin-3-yl){7-[(1S)-1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}methanoneYield 70%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6344DichloromethaneSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
50 °C

Procedure

Benzophenone imine (0.40 mL, 2.4 mmol) was added to (5-bromopyridin-3-yl){7-[(1S)-1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}methanone (891 mg, 2.0 mmol) (see Preparation 27), tris(dibenzylideneacetone)dipalladium (55 mg, 0.06 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (68 mg, 0.16 mmol) and freshly ground potassium phosphate tribasic (1.06 g, 5.0 mmol) in 1,2-dimethoxyethane (4 mL). The mixture was stirred at 50° C. for 17 hours. The reaction mixture diluted with DCM (10 mL), filtered through Arbocel™ and the pad was washed with DCM (5 mL). The filtrate was evaporated in vacuo and the crude material was dissolved in THF (10 mL). Aqueous citric acid (5 mL, 2M) was added and the mixture was stirred at room temperature for 16 hours. Water (40 mL) was added then sodium hydroxide was added to basify the mixture. The mixture was extracted with EtOAc (3×40 mL) and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (gradient of EtOAc:MeOH 100:0 to 80:20) to afford the title compound as a white solid in 70% yield, 506 mg.

Workup

  1. filtrationfiltered through Arbocel™
  2. washthe pad was washed with DCM (5 mL)
  3. customThe filtrate was evaporated in vacuo
  4. dissolutionthe crude material was dissolved in THF (10 mL)
  5. additionAqueous citric acid (5 mL, 2M) was added
  6. stirringthe mixture was stirred at room temperature for 16 hours
  7. additionWater (40 mL) was added
  8. additionsodium hydroxide was added
  9. extractionThe mixture was extracted with EtOAc (3×40 mL)
  10. dry with materialthe combined organic extracts were dried over magnesium sulfate
  11. customevaporated in vacuo
  12. customThe residue was purified by column chromatography on silica gel (gradient of EtOAc:MeOH 100:0 to 80:20)

Sources & evidence

ORD record
ord-3269078c1da64c78b9d2b41f28a9ecf7
Source dataset
uspto-grants-2014_09
Patent number
US08846698B2

Reaction notes

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