Citric Acid → (5,7-Difluoroquinolin-6-yl)methanamine

HRID 1404777Notes

Reaction equation

HRID 1404777 reaction equation
C1(P([N:15]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.C(O)(C)(C)C.[F:30][C:31]1[C:40]([CH2:41]C(O)=O)=[C:39]([F:45])[CH:38]=[C:37]2[C:32]=1[CH:33]=[CH:34][CH:35]=[N:36]2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.Cl>O1CCOCC1.CCOCC.ClCCl.C(OCC)(=O)C>[F:30][C:31]1[C:40]([CH2:41][NH2:15])=[C:39]([F:45])[CH:38]=[C:37]2[C:32]=1[CH:33]=[CH:34][CH:35]=[N:36]2

Participants

11

Reactant 6

HCID 311Citric AcidHCID 313Hydrochloric AcidHCID 6386tert-ButanolHCID 8471TriethylamineHCID 199401P,P-Diphenylphosphinic azideHCID 577423352-(5,7-Difluoroquinolin-6-yl)acetic acid

Product 1

HCID 66994774(5,7-Difluoroquinolin-6-yl)methanamine

Reagents, catalysts & solvents 4

HCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
110 °C

Procedure

Diphenyl phosphoryl azide (0.5 ml, 2.32 mmol), triethylamine (0.34 ml, 2.43 mmol) and tert-butanol (1.3 ml, 13.78 mmol) were added to a solution of the product from step 1 (0.5 g, 2.24 mmol) in dioxan (6.5 ml) and heated at 110° C. for 4 h. The mixture was cooled to RT and distributed between ethyl acetate and aq, 10% citric acid. The organic layer was separated, dried over Na2SO4 and concentrated to leave a brown residue which was dissolved in dioxane (5 ml) and dichloromethane (1.5 ml) and treated with ether saturated with HCl (10 ml) and stirred at RT overnight. After removing the solvents completely, aq, NaHCO3 was added to the residue and extracted into ethyl acetate, the organic layer dried over Na2SO4 and the solvent was removed. Purification of the residue by column chromatography gave the title compound as a mixture containing ca. 35 mol % of 1,3-bis((5,7-difluoroquinolin-6-yl)methyl)urea, which was used as such in the next step. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ8.95 (d, J=3.8 Hz, 2H); 8.45 (dd, J=7.5, 5.2, 2H): 7.65 (d, J=10.9, 2H); 7.59 (dd, J=8.29, 4.2, 2H); 6.50 (t, J=5.6, 1H), 4.44 (d, J=5.6, 2H); 3.90 (s, 2H).

Workup

  1. temperatureThe mixture was cooled to RT
  2. customThe organic layer was separated
  3. dry with materialdried over Na2SO4
  4. concentrationconcentrated
  5. customto leave a brown residue which
  6. customAfter removing the solvents completely
  7. additionaq, NaHCO3 was added to the residue
  8. extractionextracted into ethyl acetate
  9. dry with materialthe organic layer dried over Na2SO4
  10. customthe solvent was removed
  11. customPurification of the residue by column chromatography

Sources & evidence

ORD record
ord-a79c84580d8a42f8ae81498e1d4afe84
Source dataset
uspto-grants-2014_12
Patent number
US08912331B2

Reaction notes

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