Morpholine → (2-(3-Fluorophenyl)-8-morpholinoquinolin-3-yl)methanamine

HRID 1397686Notes

Reaction equation

HRID 1397686 reaction equation
Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:8]([CH2:19][N:20]1C(=O)C3C(=CC=CC=3)C1=O)=[CH:7]2.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.[NH:77]1[CH2:82][CH2:81][O:80][CH2:79][CH2:78]1.NN>O1CCOCC1.CCO.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]>[F:18][C:14]1[CH:13]=[C:12]([C:9]2[C:8]([CH2:19][NH2:20])=[CH:7][C:2]3[C:11](=[C:6]([N:77]4[CH2:82][CH2:81][O:80][CH2:79][CH2:78]4)[CH:5]=[CH:4][CH:3]=3)[N:10]=2)[CH:17]=[CH:16][CH:15]=1

Participants

8

Reactant 4

HCID 8083MorpholineHCID 9321HydrazineHCID 634876Binap, (A+-)-HCID 577078392-((8-Bromo-2-(3-fluorophenyl)quinolin-3-yl)methyl)isoindoline-1,3-dione

Product 1

HCID 57708008(2-(3-Fluorophenyl)-8-morpholinoquinolin-3-yl)methanamine

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 702EthanolSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of 2-((8-bromo-2-(3-fluorophenyl)quinolin-3-yl)methyl)isoindoline-1,3-dione (100 mg, 0.22 mmol), racemic BINAP (16.2 mg, 0.12 eq), Pd2(dba)3 (10 mg, 0.05 eq), NaOBut (29.2 mg, 1.4 eq) and morpholine (38 mg, 2 eq) in dioxane (2 mL) was heated to 120° C. under N2 for 8 h. LCMS showed a mixture of starting material and product. To the reaction was added the reactants again. The reaction was further heated for 2 h before partitioned between water and EtOAc. The water layer was extracted once with EtOAc and acidified to pH 2 by 3 N HCl and extracted with DCM (5 mL×3). Removal of solvent gave a foam, which was treated with NH2NH2 (0.5 mL) in EtOH (2 mL) at reflux. Solvents were removed and the residue was worked up and purified by CombiFlash® (DCM/MeOH/Et3N, 20/1/0.1). A white solid was obtained as (2-(3-fluorophenyl)-8-morpholinoquinolin-3-yl)methanamine. N-((2-(3-fluorophenyl)-8-morpholinoquinolin-3-yl)methyl)-9H-purin-6-amine was prepared according to Procedures H. 1H-NMR (400 Hz, CD3OD) δ 8.77 (s, 1H), 8.54 (s, 1H), 8.50 (s, 1H), 8.25 (d, J=8.0 Hz, 2H), 7.85 (t, J=8.0 Hz, 1H), 7.61-7.54 (m, 3H), 7.24 (t, J=8.0 Hz, 1H), 5.24 (s, 2H), 4.20 (s, 4H), 4.02 (s, 4H). Mass Spectrum (ESI) m/e=456 (M+1).

Workup

  1. additiona mixture of starting material and product
  2. additionTo the reaction was added the reactants again
  3. temperatureThe reaction was further heated for 2 h
  4. custombefore partitioned between water and EtOAc
  5. extractionThe water layer was extracted once with EtOAc
  6. extractionextracted with DCM (5 mL×3)
  7. customRemoval of solvent
  8. customgave a foam, which
  9. temperatureat reflux
  10. customSolvents were removed
  11. custompurified by CombiFlash® (DCM/MeOH/Et3N, 20/1/0.1)

Sources & evidence

ORD record
ord-84ac404fd9f649bda6a39673cd974ef6
Source dataset
uspto-grants-2014_12
Patent number
US08901135B2

Reaction notes

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