Triethylamine → 2-Butyl-7-methoxycarbonyl-4-{4-[(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl]cyclohexanecarboxamido}-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinoline

HRID 574010

Reaction equation

HRID 574010 reaction equation
[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH2:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:24]([O:26][CH3:27])=[O:25])=[CH:5][C:4]=2[N:3]=1.[O:28]=[C:29]1[CH:33]=[CH:32][C:31](=[O:34])[N:30]1[CH2:35][CH:36]1[CH2:41][CH2:40][CH:39]([C:42](ON2C(=O)CCC2=O)=[O:43])[CH2:38][CH2:37]1.CCN(CC)CC>CN(C=O)C>[CH2:20]([C:13]1[N:14]([CH2:15][C:16]([OH:19])([CH3:17])[CH3:18])[C:10]2[C:9]3[CH:8]=[CH:7][C:6]([C:24]([O:26][CH3:27])=[O:25])=[CH:5][C:4]=3[N:3]=[C:2]([NH:1][C:42]([CH:39]3[CH2:38][CH2:37][CH:36]([CH2:35][N:30]4[C:29](=[O:28])[CH:33]=[CH:32][C:31]4=[O:34])[CH2:41][CH2:40]3)=[O:43])[C:11]=2[N:12]=1)[CH2:21][CH2:22][CH3:23]

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 125175Succinimidyl 4-(N-maleimidomethyl)cyclohexanecarboxylateHCID 712840524-Amino-2-butyl-1-(2-hydroxy-2-methylpropyl)-7-methoxycarbonyl-1H-imidazo[4,5-c]quinoline

Product 1

HCID 712922232-Butyl-7-methoxycarbonyl-4-{4-[(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl]cyclohexanecarboxamido}-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolineYield 68%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of 4-amino-2-butyl-1-(2-hydroxy-2-methylpropyl)-7-methoxycarbonyl-1H-imidazo[4,5-c]quinoline S7 (37 mg, 0.1 mmol, 1.0 equiv) and 2,5-dioxopyrrolidin-1-yl 4-[(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl]cyclohexanecarboxylate (66 mg, 0.20 mmol, 2.0 equiv) in DMF (2.0 mL) at 25° C. was added NEt3 (40 μL, 0.30 mmol, 3.0 equiv) in one injection. The reaction was heated at 50° C. for 24 h. The solvent was then removed in vacuo and the solid was redissolved in 1:9 MeOH/EtOAc (50 mL), washed successively with saturated NaHCO3 solution (15 mL), H2O (15 mL) and saturated aqueous NaCl (15 mL) and the organic layer concentrated. TLC and MS analysis indicated existence of both the imidazoquinoline starting material and the desired product. Purification by flash column chromatography on silica gel (CH2Cl2-1/9 MeOH/CH2Cl2, gradient) afforded the title compound 550 (40 mg, 68%) as a white solid: 1H NMR (CD3OD, 600 Hz) δ1.04 (t, J=7.2 Hz, 3H), 1.11-1.18 (m, 2H), 1.26 (br s, 6H), 1.51-1.66 (m, 4H), 1.68-1.85 (m, 3H), 1.91 (pent, J=7.2 Hz, 2H), 3.13 (t, J=7.2 Hz, 2H), 3.40 (d, J=7.2 Hz, 2H), 6.83 (s, 2H), 7.98 (d, J=9.0 Hz, 1H), 8.41 (d, J=9.0 Hz, 1H), 8.66 (s, 1H); 13C NMR (CD3OD, 150 Hz) δ 12.9, 22.3, 27.2, 28.5, 28.7, 29.5, 29.6, 36.6, 43.1, 45.4, 51.4, 54.9, 71.1, 119.9, 121.4, 123.7, 126.5, 126.6, 126.6, 128.0, 128.8, 130.5, 133.9, 135.2, 142.5, 144.3, 158.2, 159.9, 160.0, 166.8, 171.4; MS (APCI+): calcd C32H40N5O6 [M+H]+ 590.3. found 590.3.

Workup

  1. customThe solvent was then removed in vacuo
  2. dissolutionthe solid was redissolved in 1:9 MeOH/EtOAc (50 mL)
  3. washwashed successively with saturated NaHCO3 solution (15 mL), H2O (15 mL) and saturated aqueous NaCl (15 mL)
  4. concentrationthe organic layer concentrated
  5. customPurification by flash column chromatography on silica gel (CH2Cl2-1/9 MeOH/CH2Cl2, gradient)

Sources & evidence

ORD record
ord-ba0f90409722447185dc2e271573665b
Source dataset
uspto-grants-2015_05
Patent number
US09034336B2

Linked notes

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