Hydrochloric Acid → 2-Hydroxyquinoline

HRID 1170025Notes

Reaction equation

HRID 1170025 reaction equation
ClCC1[O:8][CH2:7][CH2:6]N(C[C:10]2[CH:15]=[CH:14]C=CC=2)C1.Cl[C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([N+:24]([O-])=O)[CH:18]=1.[NH2:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:29]=1[C:30]#[N:31].CNC[CH:40]1[O:45][CH2:44][CH2:43][N:42]([CH2:46]C2C=CC=CC=2)[CH2:41]1.Cl.C=[O:55].[N:56]1[CH:61]=CC=C[CH:57]=1>NC.CCO.[Pd]>[NH:27]1[C:28]2[C:29](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:6][C:7]1=[O:8].[NH2:31][C:30]1[C:29]2[C:28](=[CH:35][CH:34]=[CH:33][C:32]=2[F:36])[NH:27][C:14](=[O:55])[C:15]=1[C:10]1[NH:24][C:19]2[CH:18]=[C:17]([N:56]([CH3:61])[CH2:57][CH:41]3[CH2:40][O:45][CH2:44][CH2:43][N:42]3[CH3:46])[CH:23]=[CH:22][C:20]=2[N:21]=1

Participants

12

Reactant 7

HCID 313Hydrochloric AcidHCID 712FormaldehydeHCID 1049PyridineHCID 69794-Chloro-2-nitroanilineHCID 5226592-Amino-6-fluorobenzonitrileHCID 28015624-Benzyl-2-(chloromethyl)morpholineHCID 513583991-(4-Benzylmorpholin-2-yl)-N-methylmethanamine

Product 2

HCID 60382-HydroxyquinolineHCID 136078223HCID 136078223, compound

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 702EthanolSolvent2×HCID 6329MethylamineSolvent2×

Conditions

Temperature
110 °C

Procedure

Quinolinone I was synthesized from commercially available 2-chloromethyl-4-benzyl morpholine, methylamine, 4-chloro-2-nitroaniline, and 2-amino-6-fluorobenzonitrile following the general procedure of Example 49. (2-(methylamino)methyl-4-benzyl morpholine was dissolved in an 8 M solution of NH2Me in EtOH and heated in a glass bomb at 110° C. overnight to form the product 2-(methylamino)methyl-4-benzyl morpholine following removal of the solvent). Compound I (1.0 equivalent) and 10% Pd/C (0.1 equivalents) were suspended in 1:1 ethanol and 1 N aqueous HCl at room temperature. The reaction flask was evacuated and subsequently filled with H2. The resulting mixture was stirred under a hydrogen atmosphere overnight, filtered through Celite, and concentrated under vacuum. The solution was made basic with 30% aq. KOH and the product was extracted with EtOAc. The combined organic layers were concentrated and resuspended in CH2Cl2:MeOH:AcOH (2:2:1). Paraformaldehyde (1.2 equivalents) and BH3.pyridine (3 equivalents, 8 M) was then added and the mixture was stirred overnight at room temperature. The solvent was removed in vacuo and washed with water. The aqueous layer was extracted with EtOAc (3×), and the combined organic layers were concentrated and purified by silica gel chromatography (10% MeOH/CH2Cl2) to afford the desired product. MH+=437.4.

Workup

  1. customto form
  2. customthe product 2-(methylamino)methyl-4-benzyl morpholine following removal of the solvent)
  3. customThe reaction flask was evacuated
  4. additionsubsequently filled with H2
  5. filtrationfiltered through Celite
  6. concentrationconcentrated under vacuum
  7. extractionthe product was extracted with EtOAc
  8. concentrationThe combined organic layers were concentrated
  9. stirringthe mixture was stirred overnight at room temperature
  10. customThe solvent was removed in vacuo
  11. washwashed with water
  12. extractionThe aqueous layer was extracted with EtOAc (3×)
  13. concentrationthe combined organic layers were concentrated
  14. custompurified by silica gel chromatography (10% MeOH/CH2Cl2)

Sources & evidence

ORD record
ord-0ee496e2be5a4b8d895ffa1a48415c92
Source dataset
uspto-grants-2010_11
Patent number
US07825132B2

Reaction notes

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