Boron tribromide → N-[4-(4-amino-2-hydroxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]isobutyramide

HRID 1925467Notes

Reaction equation

HRID 1925467 reaction equation
B(Br)(Br)Br.[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:29][O:30]CC)[N:18]([CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1>ClCCl>[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:29][OH:30])[N:18]([CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1

Participants

4

Reactant 2

HCID 25134Boron tribromide2×HCID 67519393HCID 67519393, compound

Product 1

HCID 57555847N-[4-(4-amino-2-hydroxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]isobutyramideYield 2.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Boron tribromide (2.5 equivalents, 15.6 mL of 1 M solution in dichloromethane) was added dropwise to a cooled (ice bath) suspension of N-[4-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]isobutyramide (2.4 g, 6.2 mmol) in dichloromethane (25 mL). The reaction mixture was allowed to slowly warm to ambient temperature and then stirred for 1 day. Additional boron tribromide (5 equivalents, 31 mmol, 31 mL) was added to the mixture. The reaction was quenched slowly with methanol (100 mL) and then concentrated under reduced pressure. The residue was combined with 6 M hydrochloric acid (100 mL), heated to 50° C., and stirred for 2 hours. The resulting solution was cooled (ice bath) and then free-based (pH 9) with the addition of 6 M sodium hydroxide. A brown gummy solid formed in the basic aqueous solution. The resulting solid was extracted with dichloromethane (6×50 mL). The combined extracts were washed with brine (100 mL), dried with magnesium sulfate, filtered, and then concentrated under reduced pressure. This material was purified by prep HPLC (Analogix Separation System, Biotage Si 40+M column, eluted with a gradient of 0-20% methanol in dichloromethane with 1% ammonium hydroxide) to provide a light brown solid. The solid was triturated with hot acetonitrile, allowed to cool, isolated by filtration, washed with ether, and dried under vacuum to provide N-[4-(4-amino-2-hydroxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]isobutyramide (0.049 g) as a white solid, mp 222-224° C.; MS (ESI) m/z 356 (M+H)+; Anal. Calcd for C19H25N5O2.0.25HBr.0.10H2O: C, 60.46; H, 6.80; N, 18.55; Found C, 60.26; H, 6.64; N, 18.43.

Workup

  1. temperaturea cooled
  2. customThe reaction was quenched slowly with methanol (100 mL)
  3. concentrationconcentrated under reduced pressure
  4. temperatureheated to 50° C.
  5. stirringstirred for 2 hours
  6. temperatureThe resulting solution was cooled (ice bath)
  7. additionfree-based (pH 9) with the addition of 6 M sodium hydroxide
  8. customA brown gummy solid formed in the basic aqueous solution
  9. extractionThe resulting solid was extracted with dichloromethane (6×50 mL)
  10. washThe combined extracts were washed with brine (100 mL)
  11. dry with materialdried with magnesium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated under reduced pressure
  14. customThis material was purified by prep HPLC (
  15. customAnalogix Separation System, Biotage Si 40+M column
  16. washeluted with a gradient of 0-20% methanol in dichloromethane with 1% ammonium hydroxide)
  17. customto provide a light brown solid
  18. customThe solid was triturated with hot acetonitrile
  19. temperatureto cool
  20. customisolated by filtration
  21. washwashed with ether
  22. customdried under vacuum

Sources & evidence

ORD record
ord-f5e70886bcda498692bfc9c57d273dab
Source dataset
uspto-grants-2012_05
Patent number
US08178677B2

Reaction notes

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