(2,5-dioxopyrrolidin-1-yl) 3-tritylsulfanylpropanoate

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-(2-aminoethoxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (30 mg, 0.10 mmol) and succinimido 3-(triphenylmethylthio)propanoate (54 mg, 0.12 mmol) in dichloromethane (1 mL) was stirred for 24 hours at room temperature. Methanol (1 mL) was added and stirring was continued for another 5 days. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane (2 mL) and triethylsilane (0.16 mL) and cooled to 0° C. Trifluoroacetic acid (0.4 mL) was added. The solution was stirred for 30 min; then it was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (gradient elution with a solution of 2% ammonium hydroxide in methanol and chloroform) to provide 18.2 mg of N-(2-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]oxy}ethyl)-3-mercaptopropanamide as a solid. HRMS (ESI) calcd for C18H24N5O3S+H 390.1600, found 390.1579. The mixture was filtered the filtrate was concentrated The residue was dissolved in dichloromethane (2 mL) Trifluoroacetic acid (0.4 mL) was added The solution was stirred for 30 min then it was concentrated under reduced pressure The crude product was purified by flash chromatography on silica gel ( gradient elution with a solution of 2% ammonium hydroxide in methanol and chloroform)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-(aminomethyl)-1-benzyl-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.3 mmol) and succinimido 3-(triphenylmethylthio)propanoate (2.2 g, 4.9 mmol) in dichloromethane (33 mL) was stirred overnight at room temperature. The reaction mixture was warmed and the solvent was removed under reduced pressure. Dichloromethane (30 mL) and trifluoroacetic acid (3 mL) were added and the mixture was stirred over the weekend. Additional trifluoroacetic acid was added. After 4 hours, the mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel (gradient elution with a solution of 2% ammonium hydroxide in methanol and chloroform) followed by crystallization from ethyl acetate/acetonitrile. HRMS (ESI) calcd for C21H21N5OS+H 392.1545, found 392.1534. The reaction mixture was warmed the solvent was removed under reduced pressure Dichloromethane (30 mL) and trifluoroacetic acid (3 mL) were added the mixture was stirred over the weekend Additional trifluoroacetic acid was added After 4 hours the mixture was concentrated under reduced pressure purified by flash chromatography on silica gel ( gradient elution with a solution of 2% ammonium hydroxide in methanol and chloroform) followed by crystallization from ethyl acetate/acetonitrile

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Succinimido 3-(triphenylmethylthio)propanoate (246 mg, 0.553 mmol) was added to a 0° C. solution of N-{2-[4-amino-2-(ethoxymethyl)-7-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide (280 mg, 0.553 mmol) in DMF (5 mL). The solution was stirred at 0° C. for 3 hours, then was diluted with ethyl acetate (100 mL) and washed with water (3×20 mL) and brine (40 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by HPFC on silica gel (gradient elution with 2-50% CMA in chloroform) to provide 0.22 g of N-{6-[(4-amino-2-(ethoxymethyl)-1-{2-methyl-2-[(methylsulfonyl)amino]propyl}-1H-imidazo[4,5-c]quinolin-7-yl)oxy]hexyl}-3-(tritylthio)propanamide as a white solid. washed with water (3×20 mL) and brine (40 mL) The organic phase was dried over sodium sulfate filtered concentrated under reduced pressure The crude product was purified by HPFC on silica gel (gradient elution with 2-50% CMA in chloroform)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Succinimido 3-(triphenylmethylthio)propanoate (4.06 mg, 9.12 mmol) was added to a 0° C. solution of 2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}ethanol (C. Bertozzi and M. Bednarski, J. Org. Chem. 1991, 56, 4326-4329) (9.12 mmol) in dichloromethane (20 mL). The solution was stirred at room temperature for 2 days and concentrated ammonium hydroxide (1 mL) was added. After 20 minutes, the mixture was filtered and the filtrate was subjected to an extractive workup. The organic layer were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by HPFC on silica gel (gradient elution with 2-19% CMA in chloroform) to provide 3.95 g of N-(2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethyl)-3-(tritylthio)propanamide as a colorless oil. After 20 minutes the mixture was filtered The organic layer were dried over sodium sulfate concentrated under reduced pressure The crude product was purified by HPFC on silica gel (gradient elution with 2-19% CMA in chloroform)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N1-(3-aminopropyl)-2-methyl-1H-imidazo[4,5-c]quinoline-1,4-diamine hydrochloride (1.00 g, 3.26 mmol), succinimido 3-(triphenylmethylthio)propanoate (A. Bray et. al. Aust. J. Chem. 1990, 43, 629-634; 2.22 g, 4.89 mmol), triethylamine (0.45 mL, 3.26 mmol), dichloromethane (33 mL), and methanol (15 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (gradient elution with a solution of 2% ammonium hydroxide in methanol and chloroform). The purified compound was treated with trifluoroacetic acid (3 mL) and triethylsilane (2 mL) in dichloromethane (30 mL) at room temperature overnight. More trifluoroacetic acid was added and after an additional day the reaction was complete. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel (gradient elution with a solution of 2% ammonium hydroxide in methanol and chloroform) to yield 327 mg of N-{3-[(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)amino]propyl}-3-mercaptopropanamide. MS (ESI) m/z 359 (M+H)+. The reaction mixture was concentrated under reduced pressure the residue was purified by flash chromatography on silica gel ( gradient elution with a solution of 2% ammonium hydroxide in methanol and chloroform) The purified compound was treated with trifluoroacetic acid (3 mL) and triethylsilane (2 mL) in dichloromethane (30 mL) at room temperature overnight More trifluoroacetic acid was added and after an additional day the reaction The reaction mixture was concentrated under reduced pressure purified by flash chromatography on silica gel ( gradient elution with a solution of 2% ammonium hydroxide in methanol and chloroform)