Cesium carbonate → N-(4-(3-(Pyrrolidin-1-YL)pyridin-2-yloxy)phenyl)pyridin-2-amine

HRID 473615Notes

Reaction equation

HRID 473615 reaction equation
Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH:74]1[CH2:78][CH2:77][CH2:76][CH2:75]1>C1(C)C=CC=CC=1.CO.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]>[N:74]1([C:2]2[C:3]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:78][CH2:77][CH2:76][CH2:75]1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 31268PyrrolidineHCID 634876Binap, (A+-)-HCID 59373954N-(4-(3-bromopyridin-2-yloxy)phenyl)pyridin-2-amine

Product 1

HCID 46830615N-(4-(3-(Pyrrolidin-1-YL)pyridin-2-yloxy)phenyl)pyridin-2-amine

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 887MethanolSolventHCID 1140TolueneSolvent

Conditions

Temperature
95 °C

Procedure

A mixture of N-(4-(3-bromopyridin-2-yloxy)phenyl)pyridin-2-amine (300 mg, 0.88 mmol), rac-BINAP (109 mg, 0.17 mmol), Pd2(dba)3 (80 mg, 0.088 mmol), Cs2CO3 (857 mg, 2.6 mmol) and pyrrolidine (1.31 mmol) in toluene (3.5 mL) was heated to 95° C. for 18 h. The mixture was cooled to room temperature, diluted with MeOH and filtered through Celite. The filtrate was concentrated, dissolved in MeOH and purified with reverse-phase HPLC (Phenomenex Gemini 80 A column, 100×50 mm, 80 ml/min, 10-95% CH3CN/H2O, 0.1% TFA, 15 min gradient). The residue was re-purified by column chromatography (EtOAc/Hexanes=0-40%, followed by recrystallization from MeOH to give the title compound. MS (ESI, pos. ion) m/z: 333 (M+1). IC50 (uM) 0.063.

Workup

  1. temperatureThe mixture was cooled to room temperature
  2. filtrationfiltered through Celite
  3. concentrationThe filtrate was concentrated
  4. dissolutiondissolved in MeOH
  5. custompurified with reverse-phase HPLC (Phenomenex Gemini 80 A column, 100×50 mm, 80 ml/min, 10-95% CH3CN/H2O, 0.1% TFA, 15 min gradient)
  6. customThe residue was re-purified by column chromatography (EtOAc/Hexanes=0-40%
  7. customfollowed by recrystallization from MeOH

Sources & evidence

ORD record
ord-210c3d5bd8a44c1b8c48f032f62e2c3a
Source dataset
uspto-grants-2014_01
Patent number
US08637500B2

Reaction notes

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