Triethylamine → tert-butyl 4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-4-hydroxypiperidine-1-carboxylate

HRID 44699Notes

Reaction equation

HRID 44699 reaction equation
[NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1([OH:27])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[CH2:35]([O:37][CH2:38][C:39](Cl)=O)[CH3:36]>ClCCl>[CH2:35]([O:37][CH2:38][C:39]1[N:12]([CH2:13][C:14]2([OH:27])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]2)[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:36]

Participants

5

Reactant 3

HCID 8471Triethylamine2×HCID 84189Ethoxyacetyl chlorideHCID 57515385Tert-butyl 4-{[(3-aminoquinolin-4-yl)amino]methyl}-4-hydroxypiperidine-1-carboxylate

Product 1

HCID 57515386tert-butyl 4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-4-hydroxypiperidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of tert-butyl 4-{[(3-aminoquinolin-4-yl)amino]methyl}-4-hydroxypiperidine-1-carboxylate (50.3 mmol, prepared as described above) in dichloromethane (330 mL) at 0° C. was added triethylamine (8 mL, 57.4 mmol) followed by dropwise addition of ethoxyacetyl chloride (88%, 6.59 g, 50.3 mmol). After 3 h at rt, more triethylamine (4 mL) and acid chloride (1.70 g) were added. The solution was stirred 1 h, then concentrated in vacuo to a foam and ethanol (400 mL) and triethylamine (24 mL) were added. The resulting solution was heated at reflux for 20 h and then concentrated in vacuo. The residue was dissolved in dichloromethane (600 mL) and washed with water (2×200 mL) and brine (2×250 mL). The organic layer was dried twice over MgSO4, filtered, and concentrated to an oil. The oil was purified twice by flash chromatography (silica gel, gradient elution with 3-5% methanol/dichloromethane) to provide tert-butyl 4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-hydroxypiperidine-1-carboxylate as a yellow foam containing dichloromethane (13.13 g). Based on 1H NMR integration, the calculated amount of product was 12.59 g (57%).

Workup

  1. concentrationconcentrated in vacuo to a foam and ethanol (400 mL) and triethylamine (24 mL)
  2. additionwere added
  3. temperatureThe resulting solution was heated
  4. temperatureat reflux for 20 h
  5. concentrationconcentrated in vacuo
  6. dissolutionThe residue was dissolved in dichloromethane (600 mL)
  7. washwashed with water (2×200 mL) and brine (2×250 mL)
  8. dry with materialThe organic layer was dried twice over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated to an oil
  11. customThe oil was purified twice by flash chromatography (silica gel, gradient elution with 3-5% methanol/dichloromethane)

Sources & evidence

ORD record
ord-ae18bbfba257436195879f597ee3490e
Source dataset
uspto-grants-2013_09
Patent number
US08541438B2

Reaction notes

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