Chloroform → HCID 57515389, compound

HRID 44702Notes

Reaction equation

HRID 44702 reaction equation
Cl.Cl.[NH2:3][C:4]1[C:13]2[N:14]=[C:15]([CH2:25][O:26][CH2:27][CH3:28])[N:16]([CH2:17][C:18]3([OH:24])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1.C(Cl)(Cl)Cl.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>CN(C)C=O.N1C=CC=CC=1>[NH2:3][C:4]1[C:13]2[N:14]=[C:15]([CH2:25][O:26][CH2:27][CH3:28])[N:16]([CH2:17][C:18]3([OH:24])[CH2:19][CH2:20][N:21]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:22][CH2:23]3)[C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1

Participants

7

Reactant 4

HCID 6212ChloroformHCID 8471Triethylamine3×HCID 31297Methanesulfonyl chloride3×HCID 575153874-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidin-4-ol dihydrochloride

Product 1

HCID 57515389HCID 57515389, compoundYield 36%

Reagents, catalysts & solvents 2

HCID 1049PyridineSolventHCID 6228DimethylformamideSolvent

Procedure

To the 1.5 hydrate of 4-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidin-4-ol dihydrochloride (1.00 g, 2.20 mmol, prepared in a similar manner as described in Example 5) was added chloroform (150 mL) and triethylamine (1.1 mL, 7.7 mmol). The starting material did not completely dissolve. To the mixture was added methanesulfonyl chloride (MeSO2Cl, 0.19 mL, 2.42 mmol) and more triethylamine (0.3 mL). After 4 h at rt, more MeSO2Cl (0.06 mL) and triethylamine (0.3 mL) were added and the mixture was stirred overnight. Pyridine (20 mL) and dimethylformamide (DMF, 20 mL) were added, followed by MeSO2Cl (0.06 mL). To the mixture was added methanesulfonyl anhydride (115 mg) and the mixture was allowed to stand for 2 d. The mixture was filtered, and the filtrate was concentrated to approximately 25 mL, which was diluted with chloroform (400 mL) and extracted with 1 M NaOH (2×150 mL), water (150 mL), and brine (200 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to a yellow oil. The crude product was purified by flash chromatography (silica gel, eluted with 1% CMA/CHCl3 where CMA is a solution comprised of 80:18:2 chloroform/methanol/concentrated ammonium hydroxide) to afford 4-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-1-(methylsulfonyl)piperidin-4-ol as a white solid (0.34 g, 36%) after drying at 60° C. under reduced pressure, mp 254-256° C. 1H NMR (300 MHz, DMSO-d6) δ 8.35 (dm, J=8.4 Hz, 1H), 7.59 (dd, J=8.4, 1.4 Hz, 1H), 7.41 (m, 1H), 7.23 (m, 1H), 6.57 (br s, 2H), 5.16-4.60 (br m, 4H), 5.05 (s, 1H), 3.53 (q, J=7.0 Hz, 2H), 3.37-3.27 (br s, 2H), 2.89-2.79 (m, 2H), 2.81 (s, 3H), 1.93-1.78 (m, 2H), 1.62-1.29 (br s, 2H), 1.14 (t, J=7.0 Hz, 3H); MS (APCI) m/z 434 (M+H)+; Anal. calcd for C20H27N5O4S: C, 55.41; H, 6.28; N, 16.15; S, 7.40. Found: C, 55.21; H, 6.11; N, 16.35; S, 7.37.

Workup

  1. dissolutionThe starting material did not completely dissolve
  2. waitto stand for 2 d
  3. filtrationThe mixture was filtered
  4. concentrationthe filtrate was concentrated to approximately 25 mL, which
  5. additionwas diluted with chloroform (400 mL)
  6. extractionextracted with 1 M NaOH (2×150 mL), water (150 mL), and brine (200 mL)
  7. dry with materialThe organic phase was dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated to a yellow oil
  10. customThe crude product was purified by flash chromatography (silica gel
  11. washeluted with 1% CMA/CHCl3 where CMA

Sources & evidence

ORD record
ord-5db6ecae169b4d23bb9b5b5e46db5e08
Source dataset
uspto-grants-2013_09
Patent number
US08541438B2

Reaction notes

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