hexanamide

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:210.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-amino-5-cyanoimidazole (1.09 g, 11 mmol) and hexaneamide (4.39 g, 38 mmol) was heated at 210° C. for 15 h under N2 atmosphere. After cooling, the residue was dissolved in a mixture of DMF (200 ml) and water (50 ml). Benzyl chloride (3 ml) and K2CO3 (3 g) was added to the mixture, and heated at 70° C. for 6 h. Solvent was evaporated under vacuum, the residue was extracted by CH2Cl2. The resulting organic layer was evaporated under vacuum. 9-benzyl-2-pentyladenine was obtained by the purification of the residue by column chromatography (CH2Cl2 :MeOH=100:1-50:1). Bromine (2 ml) was added to the mixture of 9-benzyl-2-hexyladenine and NaOAc (5 g) in ACOH (40 ml) within an ice bath, and the mixture was heated at 70° C. for 6 h. Solvent was evaporated under vacuum, the residue was extracted by EtOAc. The resulting organic layer was evaporated under vacuum, 9-benzyl-8-bromo-2-pentyladenine was obtained by the purification of the residue by column chromatography (CH2Cl2 :MeOH=100:1). A mixture of 9-benzyl-8-bromo-2-pentyladenine and conc.HCl (20 ml) was refluxed for 6 h. After cooling, aqueous NH3 was added to neutralize and crystallize the product (pH=8), and the desired compound was collected by filtration (0.25 g, Yield: 8%). After cooling heated at 70° C. for 6 h Solvent was evaporated under vacuum the residue was extracted by CH2Cl2 The resulting organic layer was evaporated under vacuum

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The synthesis of 3 was performed similarly to example 1 above. The solids, hexanoamide (5 g) and 1,3-dichloroacetone (5.5 g), were mixed together in a round bottomed flask and heated at 120° C. under an argon atmosphere for 2 hours. The mixture was cooled to 25° C. for 1 hour, followed by the addition of concentrated H2SO4 (50 mL). The resulting syrup was poured onto ice and the pH was adjusted to 10 with NaOH (1M). The resulting solution was extracted with CHCl3, dried (Na2SO4) and evaporated to yield a brown liquid (1.56 g). This material was chromatographed according to Still et al. (J. Org. Chem., 1978, 43, 2923) on silica gel in EtOAc to yield 3 as a yellow liquid (1.4 g). The synthesis of 3 The mixture was cooled to 25° C. for 1 hour The resulting syrup was poured onto ice The resulting solution was extracted with CHCl3 dried (Na2SO4) evaporated

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The synthesis of 3 was performed similarly to example 1 above. The solids, hexanoamide (5 g) and 1,3-dichloroacetone (5.5 g), were mixed together in a round bottomed flask and heated at 120° C. under an argon atmosphere for 2 hours. The mixture was cooled to 25° C. for 1 hour, followed by the addition of concentrated H2SO4 (50 mL). The resulting syrup was poured onto ice and the pH was adjusted to 10 with NaOH (1M). The resulting solution was extracted with CHCl3, dried (Na2SO4) and evaporated to yield a brown liquid (1.56 g). This material was chromatographed according to Still et al. (J. Org. Chem., 1978, 43, 2923) on silica gel in EtOAc to yield 3 as a yellow liquid (1.4 g). The synthesis of 3 The mixture was cooled to 25° C. for 1 hour The resulting syrup was poured onto ice The resulting solution was extracted with CHCl3 dried (Na2SO4) evaporated

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

Procedure: 1.09 g (11 mmol) of 4-amino-5-cyanoimidazole and 4.39 g (38 mmol) of hexanamide were stirred at 210° C. for 15 hr with heating under an atmosphere of nitrogen. A mixed solvent composed of DMF (200 ml) and water (50 ml) was added thereto. Further, 3.0 ml of benzyl chloride and 3.00 g of potassium carbonate were added thereto. The resultant mixture stirred at 70° C. for 6 hr under heating. After the solvent was removed by vacuum distillation, the residue was taken into water and extracted with dichloromethane. The organic layer was vacuum-concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol=100:1-50:1) to thereby obtain a solid. This solid and 5.00 g of sodium acetate were dissolved in 40 ml of acetic acid. Then, 2 ml of bromine was added to the solution placed in ice bath. Subsequently, the resultant solution was stirred at 70° C. for 6 hours under heating. After the solvent was removed by vacuum distillation, the residue was extracted with ethyl acetate, and the organic layer was vacuum-concentrated. The residue was purified by column chromatography (eluent: dichloromethane:methanol=100:1) to obtain a solid. This solid was added to 20 ml of concentrated hydrochloric acid and heated for 6 hours under refluxing. After the reaction solution was cooled, its pH was adjusted to 8 with aqueous ammonia. The deposited solid was vacuum-filtered, washed with water and then dried to thereby obtain 0.25 g of the captioned compound (yield: 8%). with heating under an atmosphere of nitrogen was added under heating After the solvent was removed by vacuum distillation extracted with dichloromethane The organic layer was vacuum-concentrated The residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol=100:1-50:1) to thereby obtain a solid under heating After the solvent was removed by vacuum distillation the residue was extracted with ethyl acetate the organic layer was vacuum-concentrated The residue was purified by column chromatography (eluent: dichloromethane:methanol=100:1) to obtain a solid heated for 6 hours under refluxing After the reaction solution was cooled The deposited solid was vacuum-filtered washed with water dried

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

Procedure: 2-(1-Cyclohexenyl)cyclohexanone (17.8 g., 0.1 mole), hexanamide (11.5 g., 0.1 mole), 5.0 g. of a highly acidic resin, Amberlyst 15, and toluene (150 ml) are mixed, stirred and heated at reflux for 16 hours. The water formed in the course of the reaction is azeotroped from the reaction mixture. The hot solution is decanted from the Amberlyst catalyst, the catalyst washed with toluene (200 ml.), and the toluene fractions are combined. Pentane (300 ml.) is added to the toluene solution, the mixture chilled in ice and filtered to remove 3.65 g. of unreacted hexanamide. The orange filtrate is stripped to yield 24 g. of crude product, an oil. heated at reflux for 16 hours is azeotroped from the reaction mixture The hot solution is decanted from the Amberlyst catalyst the catalyst washed with toluene (200 ml.) Pentane (300 ml.) is added to the toluene solution the mixture chilled in ice filtered to remove 3.65 g to yield 24 g

Conditions: temp:210.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-amino-5-cyanoimidazole (1.09 g, 11 mmol) and hexaneamide (4.39 g, 38 mmol) was heated at 210° C. for 15 h under N2 atmosphere. After cooling, the residue was dissolved in a mixture of DMF (200 ml) and water (50 ml). Benzyl chloride (3 ml) and K2CO3 (3 g) was added to the mixture, and heated at 70° C. for 6 h. Solvent was evaporated under vacuum, the residue was extracted by CH2Cl2. The resulting organic layer was evaporated under vacuum. 9-benzyl-2-pentyladenine was obtained by the purification of the residue by column chromatography (CH2Cl2 :MeOH=100:1-50:1). Bromine (2 ml) was added to the mixture of 9-benzyl-2-hexyladenine and NaOAc (5 g) in ACOH (40 ml) within an ice bath, and the mixture was heated at 70° C. for 6 h. Solvent was evaporated under vacuum, the residue was extracted by EtOAc. The resulting organic layer was evaporated under vacuum, 9-benzyl-8-bromo-2-pentyladenine was obtained by the purification of the residue by column chromatography (CH2Cl2 :MeOH=100:1). A mixture of 9-benzyl-8-bromo-2-pentyladenine and conc.HCl (20 ml) was refluxed for 6 h. After cooling, aqueous NH3 was added to neutralize and crystallize the product (pH=8), and the desired compound was collected by filtration (0.25 g, Yield: 8%). After cooling heated at 70° C. for 6 h Solvent was evaporated under vacuum the residue was extracted by CH2Cl2 The resulting organic layer was evaporated under vacuum

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

Procedure: Compound 53 was prepared from hexanamide and 4-(diethylamino)benzaldehyde using method 1. Yield: 76%. 1H NMR (400 MHz, CD3OD) δ 7.19 (d, J=8.8 Hz, 2H), 6.71 (d, J=8.8 Hz, 2H), 6.58 (t, J=8.4 Hz, 1H), 3.35-3.41 (m, 4H), 2.19-2.26 (m, 4H), 1.61-1.68 (m, 4H), 1.32-1.35 (m, 8H), 1.14 (t, J=6.8 Hz, 6H), 0.94 (t, J=2.8 Hz, 6H). LC-MS (ESI): m/z 390.3 (M+H)+. HRMS (ESI) for C23H40N3O2 (MH+): calcd, 390.3115. found 390.3108.

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

Procedure: Compound 53 was prepared from hexanamide and 4-(diethylamino)benzaldehyde using method 1. Yield: 76%. 1H NMR (400 MHz, CD3OD) δ 7.19 (d, J=8.8 Hz, 2H), 6.71 (d, J=8.8 Hz, 2H), 6.58 (t, J=8.4 Hz, 1H), 3.35-3.41 (m, 4H), 2.19-2.26 (m, 4H), 1.61-1.68 (m, 4H), 1.32-1.35 (m, 8H), 1.14 (t, J=6.8 Hz, 6H), 0.94 (t, J=2.8 Hz, 6H). LC-MS (ESI): m/z 390.3 (M+H)+. HRMS (ESI) for C23H40N3O2 (MH+): calcd, 390.3115. found 390.3108.

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

Procedure: Alternatively, N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-6-{[3-(pyridin-2-yldithio)propanoyl]amino}hexanamide was synthesized from 6-amino-N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}hexanamide hydrochloride in one step. A mixture of 6-amino-N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}hexanamide hydrochloride (68 mg, 0.16 mmol), triethylamine (0.046 mL, 0.32 mmol), and N-succinimidyl 3-(2-pyridyldithio)propionate in tetrahydrofuran (1.6 mL) and DMF (0.5 mL) was stirred at room temperature for 5 hours. The reaction mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel to provide 36 mg of N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-6-{[3-pyridin-2-yldithio)propanoyl]amino}hexanamide as a colorless oil. The reaction mixture was partitioned between water and ethyl acetate The aqueous phase was extracted with ethyl acetate washed with water and brine dried over sodium sulfate filtered concentrated under reduced pressure The crude product was purified by chromatography on silica gel

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

Procedure: Compound 53 was prepared from hexanamide and 4-(diethylamino)benzaldehyde using method 1. Yield: 76%. 1H NMR (400 MHz, CD3OD) δ 7.19 (d, J=8.8 Hz, 2H), 6.71 (d, J=8.8 Hz, 2H), 6.58 (t, J=8.4 Hz, 1H), 3.35-3.41 (m, 4H), 2.19-2.26 (m, 4H), 1.61-1.68 (m, 4H), 1.32-1.35 (m, 8H), 1.14 (t, J=6.8 Hz, 6H), 0.94 (t, J=2.8 Hz, 6H). LC-MS (ESI): m/z 390.3 (M+H)+. HRMS (ESI) for C23H40N3O2 (MH+): calcd, 390.3115. found 390.3108.