Sodium Hydroxide → 1-[2-(4-Amino-2-hydroxymethyl-1h-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]-3-(1-methylethyl)urea

HRID 81888Notes

Reaction equation

HRID 81888 reaction equation
[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:26][O:27]CC)[N:14]([CH2:15][C:16]([NH:19][C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.B(Br)(Br)Br.[OH-].[Na+]>ClCCl.C(#N)C.Cl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:26][OH:27])[N:14]([CH2:15][C:16]([NH:19][C:20]([NH:22][CH:23]([CH3:24])[CH3:25])=[O:21])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1

Participants

7

Reactant 3

HCID 14798Sodium HydroxideHCID 25134Boron tribromide2×HCID 67519537HCID 67519537, compound

Product 1

HCID 575558421-[2-(4-Amino-2-hydroxymethyl-1h-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]-3-(1-methylethyl)ureaYield 30,244.4%

Reagents, catalysts & solvents 3

HCID 313Hydrochloric AcidSolventHCID 6342AcetonitrileSolvent2×HCID 6344DichloromethaneSolvent2×

Procedure

Under a nitrogen atmosphere, a suspension of 1-[2-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]-3-(1-methylethyl)urea (1.19 g, 2.99 mmol) in dichloromethane (30 mL) was chilled in an ice bath. Boron tribromide (7.47 mL of 1 M in dichloromethane) was added. The reaction mixture was allowed to warm slowly to ambient temperature and then stirred for 18 hours. Additional boron tribromide (2 eq) was added. After 2 hours the reaction mixture was diluted with acetonitrile (10 mL) and the reaction mixture was stirred overnight. The reaction mixture was diluted with dichloromethane (10 mL) and acetonitrile (10 mL), stirred for an additional 16 hours, quenched with methanol (25 mL), and then concentrated under reduced pressure to provide an orange foam. The foam was dissolved in hydrochloric acid (25 mL of 6 N) and heated at 50° C. for 2 hours. The solution was neutralized with 50% sodium hydroxide. The resulting gummy precipitate was extracted with chloroform (3×15 mL). The combined organics were washed with brine (15 mL), dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide an off white solid. This material was purified by prep HPLC (HORIZON HPFC system, eluting with a gradient of 15-50% CMA in chloroform) and then recrystallized from acetonitrile to provide 335 g of 1-[2-(4-amino-2-hydroxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]-3-(1-methylethyl)urea as a white crystalline solid, mp 196-199° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.38 (d, J=8.0 Hz, 1H), 7.59 (d, J=7.5 Hz, 1H), 7.43-7.38 (m, 1H), 7.24-7.19 (m, 1H), 6.54 (s, 2H), 5.72 (s, 1H), 5.63 (d, J=7.6 Hz, 1H), 5.46 (t, J=5.7 Hz, 1H), 5.01 (s, 2H), 4.78 (s, 2H), 3.78-3.67 (m, 1H), 1.17 (bs, 6H), 1.05 (d, J=6.9 Hz, 6H); 13C NMR (75 MHz, DMSO-d6) δ 157.2, 154.2, 152.3, 145.6, 134.3, 126.8, 126.7, 121.5, 120.9, 115.8, 56.5, 54.2, 52.1, 26.4, 23.6; MS (APCI) m/z 371 (M+H)+; Anal. Calcd for C19H26N6O2.0.3H2O: % C, 60.72; % H, 7.13; % N, 22.36. Found: % C, 60.44; % H, 7.42; % N, 22.52.

Workup

  1. temperaturewas chilled in an ice bath
  2. stirringthe reaction mixture was stirred overnight
  3. stirringstirred for an additional 16 hours
  4. customquenched with methanol (25 mL)
  5. concentrationconcentrated under reduced pressure
  6. customto provide an orange foam
  7. temperatureheated at 50° C. for 2 hours
  8. extractionThe resulting gummy precipitate was extracted with chloroform (3×15 mL)
  9. washThe combined organics were washed with brine (15 mL)
  10. dry with materialdried over magnesium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated under reduced pressure
  13. customto provide an off white solid
  14. customThis material was purified by prep HPLC (HORIZON HPFC system
  15. washeluting with a gradient of 15-50% CMA in chloroform) and
  16. customthen recrystallized from acetonitrile

Sources & evidence

ORD record
ord-0cf53e9007ba444f8d3bc0b3d65b1bab
Source dataset
uspto-grants-2014_09
Patent number
US08846710B2

Reaction notes

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