4-Toluenesulfonyl chloride → 1-{[4-Amino-2-(ethoxymethyl)-1h-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol

HRID 44687Notes

Reaction equation

HRID 44687 reaction equation
[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.ClCCl.O>[NH2:38][C:9]1[C:8]2[N:17]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:18][C:19]3([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1

Participants

8

Reactant 4

HCID 73974-Toluenesulfonyl chlorideHCID 14923Ammonium HydroxideHCID 70297m-Chloroperbenzoic acid2×HCID 575153771-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol

Product 1

HCID 116460811-{[4-Amino-2-(ethoxymethyl)-1h-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6212ChloroformSolventHCID 6344DichloromethaneSolvent

Procedure

To a solution of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol (1.90 g, 5.60 mmol) in CHCl3 (43 mL) was added m-chloroperoxybenzoic acid (m-CPBA, 77% w/w, 1.26 g, 5.60 mmol) over 15 min. The reaction was monitored by thin layer chromatography (TLC) and more m-CPBA was added over 1 h until the starting material was consumed. Water (40 mL) and solid K2CO3 were added to the reaction mixture until the pH=10. The mixture was poured into a separatory funnel and extracted with chloroform, resulting in an emulsion. The aqueous layer was extracted with chloroform three times. The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and concentrated to yield a crude white solid (1.51 g). The white solid (1.51 g, 4.24 mmol) was dissolved in dichloromethane (25 mL) at rt and concentrated ammonium hydroxide (16 mL) was added, followed by p-toluenesulfonyl chloride (TsCl, 0.81 g, 4.24 mmol). The mixture was stirred 1 day (d). Water (25 mL) was added and the aqueous layer was extracted with dichloromethane (2×30 mL). The combined organic layers were washed with brine (25 mL) and were dried over MgSO4, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, gradient elution with 98:1:1 CH2Cl2/MeOH/NH4OH to 94:5:1 CH2Cl2/MeOH/NH4OH) then crystallized from acetonitrile to yield 1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol as pale orange crystals that were dried under high vacuum (0.32 g, 16% over two steps), mp 186-188° C. 1H NMR (300 MHz, CDCl3) δ 8.15 (dm, J=8.4 Hz, 1H), 7.81 (dm, J=8.4 Hz, 1H), 7.52 (m, 1H), 7.32 (m, 1H), 5.38 (br s, 2H), 4.90 (br s, 2H), 4.74 (br s, 2H), 3.66 (q, J=7.0 Hz, 2H), 3.00 (s, 1H), 1.71-1.52 (m, 10), 1.25 (t, J=7.0 Hz, 3H). MS (APCI) m/z 355 (M+H+). Anal. calcd for C20H26O2N4: C, 67.77; H, 7.39; N, 15.81. Found: C, 67.52; H, 7.57; N, 15.78

Workup

  1. additionwas added over 1 h until the starting material
  2. customwas consumed
  3. additionWater (40 mL) and solid K2CO3 were added to the reaction mixture until the pH=10
  4. additionThe mixture was poured into a separatory funnel
  5. extractionextracted with chloroform
  6. customresulting in an emulsion
  7. extractionThe aqueous layer was extracted with chloroform three times
  8. washThe combined organic layers were washed with water and brine
  9. dry with materialdried over MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customto yield a crude white solid (1.51 g)
  13. extractionthe aqueous layer was extracted with dichloromethane (2×30 mL)
  14. washThe combined organic layers were washed with brine (25 mL)
  15. dry with materialwere dried over MgSO4
  16. filtrationfiltered
  17. concentrationconcentrated
  18. customThe crude product was purified by flash chromatography (silica gel, gradient elution with 98:1:1 CH2Cl2/MeOH/NH4OH to 94:5:1 CH2Cl2/MeOH/NH4OH)
  19. customthen crystallized from acetonitrile

Sources & evidence

ORD record
ord-e9a8b4f4cbbe4fcd8e8f7b5b898a49a9
Source dataset
uspto-grants-2013_09
Patent number
US08541438B2

Reaction notes

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