Ethyl Acetoacetate → Ethyl 4-amino-5-(cyclopentylmethoxy)-2-methylquinoline-3-carboxylate

HRID 2047740Notes

Reaction equation

HRID 2047740 reaction equation
[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5].[C:17]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:18][C:19]([CH3:21])=O.Cl[Sn](Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:17]([C:18]1[C:19]([CH3:21])=[N:1][C:2]2[C:3]([C:4]=1[NH2:5])=[C:6]([O:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:7]=[CH:8][CH:9]=2)=[O:22])[CH3:25]

Participants

5

Reactant 3

HCID 8868Ethyl AcetoacetateHCID 24287Tin tetrachlorideHCID 24777778HCID 24777778, compound

Product 1

HCID 66745974Ethyl 4-amino-5-(cyclopentylmethoxy)-2-methylquinoline-3-carboxylateYield 75%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

To a solution of 2-amino-6-(cyclopentylmethoxy)benzonitrile (Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) (21.63 g, 100.0 mmol) and ethyl acetoacetate (12.6 mL, 100.0 mmol) in anhydrous toluene (300 mL) was added SnCl4 (23.1 mL, 200.0 mmol) over a period of 25 minutes at room temperature under nitrogen. The stirred reaction mixture was then refluxed for 5 h under nitrogen. After it was cooled down to room temperature, the reaction solution was concentrated to remove most of the solvent under reduced pressure. The residue was re-dissolved in EtOAc (3.5 L) and carefully neutralized to pH 8 with aqueous NaOH solution (6.0 N, ˜130 mL) at 0° C. The resultant mixture was stirred at room temperature overnight. The precipitate was filtered off, and the organic layer was separated and washed with brine (400 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 30% EtOAc in hexanes to give the title compound as a pale yellow solid (24.6 g, 75%). 1H NMR (400 MHz, DMSO-d6) δ 1.30-1.36 (m, 5H), 1.53-1.65 (m, 4H), 1.81-1.86 (m, 2H), 2.42-2.45 (m, 1H), 2.54 (s, 3H), 4.05 (d, J=7.2 Hz, 2H), 4.31 (q, J=7.2 Hz, 2H), 6.89 (d, J=7.6 Hz, 1H), 7.21-7.23 (m, 1H), 7.50 (t, J=8.0 Hz, 1H), 8.08 (s, 2H). MS 329 (MH+).

Workup

  1. customThe stirred reaction mixture
  2. temperaturewas then refluxed for 5 h under nitrogen
  3. concentrationthe reaction solution was concentrated
  4. customto remove most of the solvent under reduced pressure
  5. dissolutionThe residue was re-dissolved in EtOAc (3.5 L)
  6. customcarefully neutralized to pH 8 with aqueous NaOH solution (6.0 N, ˜130 mL) at 0° C
  7. filtrationThe precipitate was filtered off
  8. customthe organic layer was separated
  9. washwashed with brine (400 mL)
  10. dry with materialdried over Na2SO4
  11. concentrationconcentrated under reduced pressure
  12. customThe residue was purified by column chromatography on silica gel eluting with 30% EtOAc in hexanes

Sources & evidence

ORD record
ord-8f3a999abd0342b28b9b377d0ec39799
Source dataset
uspto-grants-2013_11
Patent number
US08592592B2

Reaction notes

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