Potassium Phosphate, Tribasic → (2-(2-Amino-7-fluoro-3-morpholinoquinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone

HRID 1029020Notes

Reaction equation

HRID 1029020 reaction equation
Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH2:58][C:59]1[C:68]([N:69]2[CH2:74][CH2:73][O:72][CH2:71][CH2:70]2)=[CH:67][C:66]2[C:61](=[CH:62][C:63]([F:78])=[C:64](B(O)O)[CH:65]=2)[N:60]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[NH2:58][C:59]1[C:68]([N:69]2[CH2:70][CH2:71][O:72][CH2:73][CH2:74]2)=[CH:67][C:66]2[C:61](=[CH:62][C:63]([F:78])=[C:64]([C:2]3[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=3[C:9]([N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[O:10])[CH:65]=2)[N:60]=1

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 665791491-(2-Bromo-3-methylbenzoyl)pyrrolidineHCID 712535742-Amino-7-fluoro-3-morpholinoquinolin-6-ylboronic acid

Product 1

HCID 67324606(2-(2-Amino-7-fluoro-3-morpholinoquinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
140 °C

Procedure

A microwave vessel was charged with (2-bromo-3-methylphenyl)(pyrrolidin-1-yl)methanone (0.081 g, 0.301 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.018 g, 0.038 mmol), Pd2(dba)3 (0.018 g, 0.020 mmol), potassium phosphate (0.106 g, 0.502 mmol), 2-amino-7-fluoro-3-morpholinoquinolin-6-ylboronic acid (0.073 g, 0.251 mmol), dioxane (1.6 mL) and water (0.8 mL). The vessel was purged with argon, sealed and heated by microwave radiation at 140° C. for 15 min. The mixture was concentrated, diluted with EtOAc (10 mL) and the suspension was filtered through celite rinsing with EtOAc. The filtrate was washed with saturated brine (5 mL), dried over sodium sulfate and concentrated. The material was purified by column chromatography on silica gel (33 mL) which had been deactivated with Et3N (3.3 mL) eluting with 1.5% MeOH/EtOAc to afford (2-(2-amino-7-fluoro-3-morpholinoquinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone. MS (ESI, pos. ion) m/z: 435 (M+1).

Workup

  1. customThe vessel was purged with argon
  2. customsealed
  3. concentrationThe mixture was concentrated
  4. additiondiluted with EtOAc (10 mL)
  5. filtrationthe suspension was filtered
  6. washthrough celite rinsing with EtOAc
  7. washThe filtrate was washed with saturated brine (5 mL)
  8. dry with materialdried over sodium sulfate
  9. concentrationconcentrated
  10. customThe material was purified by column chromatography on silica gel (33 mL) which
  11. washeluting with 1.5% MeOH/EtOAc

Sources & evidence

ORD record
ord-595640603edb46baa4d8b12b38d1f2ad
Source dataset
uspto-grants-2014_05
Patent number
US08735384B2

Reaction notes

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