Α-对甲苯磺酰基苄基异腈

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Methylamine (33% in industrial methylated spirits, 60.3 mL) was added to a solution of glycolaldehyde dimer (2.7 g) in THF (320 mL). After 75 minutes 1-{[isocyano(phenyl)methyl]sulfonyl}-4-methylbenzene (PhTosMIC) (Org. Syn., 77, 198-205) (10.8 g) was added, cooling to keep the reaction temperature below 30° C. The reaction was stirred for 90 minutes and the solvent evaporated to a volume of 100 mL. Water (500 mL) was added, and the title compound (4.94 g, 66%) collected by filtration as a white solid. The filtrate was extracted into EtOAc, dried, and the solvent removed in vacuo. The residue was triturated with EtOAc to give a further 1.06 g (14%) as a white solid. cooling the reaction temperature below 30° C the solvent evaporated to a volume of 100 mL Water (500 mL) was added the title compound (4.94 g, 66%) collected by filtration as a white solid The filtrate was extracted into EtOAc dried the solvent removed in vacuo The residue was triturated with EtOAc to give a further 1.06 g (14%) as a white solid

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Heat a mixture of 1-isobutyl-2-amino-6-(methyliminomethyl)-1H-benzimidazole (504 mg, 2.19 mmol), α-(p-toluenesulfonyl)benzylisocyanide (1.48 g, 5.47 mmol), methanol (7 mL), and methylamine (5.5 mL, 2M in tetrahydrofuran) in a sealed tube at 80° C. for 20 hours. Cool to room temperature and concentrate under reduced pressure. Subject residue to silica gel chromatography, eluting with a 1:1 mixture of acetonitrile and dichloromethane containing 5% methanol to provide the desired compound. Heat concentrate under reduced pressure Subject residue to silica gel chromatography, eluting with a 1:1 mixture of acetonitrile and dichloromethane containing 5% methanol

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Heat a mixture of 1-isobutyl-2-amino-6-(methyliminomethyl)-1H-benzimidazole (504 mg, 2.19 mmol), α-(p-toluenesulfonyl)benzylisocyanide (1.48 g, 5.47 mmol), methanol (7 mL), and methylamine (5.5 mL, 2M in tetrahydrofuran) in a sealed tube at 80° C. for 20 hours. Cool to room temperature and concentrate under reduced pressure. Subject residue to silica gel chromatography, eluting with a 1:1 mixture of acetonitrile and dichloromethane containing 5% methanol to provide the desired compound. Heat concentrate under reduced pressure Subject residue to silica gel chromatography, eluting with a 1:1 mixture of acetonitrile and dichloromethane containing 5% methanol

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Heat a mixture of 1-isobutyl-2-amino-6-(methyliminomethyl)-1H-benzimidazole (504 mg, 2.19 mmol), α-(p-toluenesulfonyl)benzylisocyanide (1.48 g, 5.47 mmol), methanol (7 mL), and methylamine (5.5 mL, 2M in tetrahydrofuran) in a sealed tube at 80° C. for 20 hours. Cool to room temperature and concentrate under reduced pressure. Subject residue to silica gel chromatography, eluting with a 1:1 mixture of acetonitrile and dichloromethane containing 5% methanol to provide the desired compound. Heat concentrate under reduced pressure Subject residue to silica gel chromatography, eluting with a 1:1 mixture of acetonitrile and dichloromethane containing 5% methanol

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of tert-butyl 4-aminopiperidine-1-carboxylate (3.88 g), oxoacetic acid hydrate (1.48 g), and potassium carbonate (4.46 g) in DMF (60 mL) was stirred at room temperature for 3 hours. Then, 1-{[isocyano(phenyl)methyl]sulfonyl}-4-methylbenzene (3.5 g) was added thereto, followed by stirring at room temperature for 14 hours. The solvent was evaporated under reduced pressure, to the residue were added ethyl acetate and water, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate, the combined organic phase was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 90/10) to obtain tert-butyl 4-(4-phenyl-1H-imidazol-1-yl)piperidine-1-carboxylate (3.1 g). by stirring at room temperature for 14 hours The solvent was evaporated under reduced pressure, to the residue were added ethyl acetate and water the organic phase was separated The aqueous phase was extracted with ethyl acetate the combined organic phase was washed with water and saturated brine dried over magnesium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 90/10)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Methylamine (33% in industrial methylated spirits, 60.3 mL) was added to a solution of glycolaldehyde dimer (2.7 g) in THF (320 mL). After 75 minutes 1-{[isocyano(phenyl)methyl]sulfonyl}-4-methylbenzene (PhTosMIC) (Org. Syn., 77, 198-205) (10.8 g) was added, cooling to keep the reaction temperature below 30° C. The reaction was stirred for 90 minutes and the solvent evaporated to a volume of 100 mL. Water (500 mL) was added, and the title compound (4.94 g, 66%) collected by filtration as a white solid. The filtrate was extracted into EtOAc, dried, and the solvent removed in vacuo. The residue was triturated with EtOAc to give a further 1.06 g (14%) as a white solid. cooling the reaction temperature below 30° C the solvent evaporated to a volume of 100 mL Water (500 mL) was added the title compound (4.94 g, 66%) collected by filtration as a white solid The filtrate was extracted into EtOAc dried the solvent removed in vacuo The residue was triturated with EtOAc to give a further 1.06 g (14%) as a white solid

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of tert-butyl 4-aminopiperidine-1-carboxylate (3.88 g), oxoacetic acid hydrate (1.48 g), and potassium carbonate (4.46 g) in DMF (60 mL) was stirred at room temperature for 3 hours. Then, 1-{[isocyano(phenyl)methyl]sulfonyl}-4-methylbenzene (3.5 g) was added thereto, followed by stirring at room temperature for 14 hours. The solvent was evaporated under reduced pressure, to the residue were added ethyl acetate and water, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate, the combined organic phase was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 90/10) to obtain tert-butyl 4-(4-phenyl-1H-imidazol-1-yl)piperidine-1-carboxylate (3.1 g). by stirring at room temperature for 14 hours The solvent was evaporated under reduced pressure, to the residue were added ethyl acetate and water the organic phase was separated The aqueous phase was extracted with ethyl acetate the combined organic phase was washed with water and saturated brine dried over magnesium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 90/10)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Methylamine (33% in industrial methylated spirits, 60.3 mL) was added to a solution of glycolaldehyde dimer (2.7 g) in THF (320 mL). After 75 minutes 1-{[isocyano(phenyl)methyl]sulfonyl}-4-methylbenzene (PhTosMIC) (Org. Syn., 77, 198-205) (10.8 g) was added, cooling to keep the reaction temperature below 30° C. The reaction was stirred for 90 minutes and the solvent evaporated to a volume of 100 mL. Water (500 mL) was added, and the title compound (4.94 g, 66%) collected by filtration as a white solid. The filtrate was extracted into EtOAc, dried, and the solvent removed in vacuo. The residue was triturated with EtOAc to give a further 1.06 g (14%) as a white solid. cooling the reaction temperature below 30° C the solvent evaporated to a volume of 100 mL Water (500 mL) was added the title compound (4.94 g, 66%) collected by filtration as a white solid The filtrate was extracted into EtOAc dried the solvent removed in vacuo The residue was triturated with EtOAc to give a further 1.06 g (14%) as a white solid

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of tert-butyl 4-(5-acetyl-4-phenyl-1H-imidazol-1-yl)piperidine-1-carboxylate [C24, prepared according to the general procedure for the synthesis of tert-butyl 3-[5-acetyl-4-(4-fluorophenyl)-1H-imidazol-1-yl]azetidine-1-carboxylate (C3) in Example 1, except that tert-butyl 4-aminopiperidine-1-carboxylate was used in place of tert-butyl 3-aminoazetidine-1-carboxylate, and 1-{[isocyano(phenyl)methyl]sulfonyl}-4-methylbenzene (C21) was employed rather than 1-fluoro-4-{isocyano[(4-methylphenyl)sulfonyl]methyl}benzene (C2)] (414 mg, 1.12 mmol) and N,N-dimethylformamide dimethyl acetal (4 mL) was heated to 100° C. for 18 hours, then cooled and concentrated in vacuo. The residue was dissolved in anhydrous methanol (2 ml) and added to a solution of N-methylguanidine in methanol [prepared by reacting sodium metal (70 mg, 3 mmol) with anhydrous methanol (2 mL), then adding N-methylguanidine hydrochloride (413 mg, 3.77 mmol) to the resulting sodium methoxide solution]. The reaction mixture was heated at 50° C. for 21 hours, then cooled to room temperature and treated with water (1 mL). The solids were collected by filtration, rinsed with saturated aqueous sodium bicarbonate solution and water and dried to provide the product as a light tan solid. Yield: 230 mg, 0.53 mmol, 47%. APCI m/z 435.0 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.49 (s, 9H), 1.82-1.93 (m, 2H), 2.19 (br d, J=12 Hz, 2H), 2.73-2.82 (m, 2H), 3.06 (d, J=5.1 Hz, 3H), 4.26-4.35 (m, 2H), 4.81-4.90 (m, 1H), 5.16-5.21 (m, 1H), 6.45 (d, J=5.1 Hz, 1H), 7.28-7.34 (m, 3H), 7.48-7.51 (m, 2H), 7.75 (s, 1H), 8.15 (br d, J=4.9 Hz, 1H). prepared cooled concentrated in vacuo The residue was dissolved in anhydrous methanol (2 ml) added to a solution of N-methylguanidine in methanol [ prepared The reaction mixture was heated at 50° C. for 21 hours cooled to room temperature The solids were collected by filtration rinsed with saturated aqueous sodium bicarbonate solution and water dried

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of potassium carbonate (107 mg, 0.774 mmol), 1-{[isocyano(phenyl)methyl]sulfonyl}-4-methylbenzene (C21, see Organic Syntheses; Wiley & Sons: New York, 2004; Collect. Vol. 10, p. 692) (0.209 g, 0.770 mmol) and tert-butyl 4-{[(1E)-pyrimidin-4-ylmethylene]amino}piperidine-1-carboxylate (C13) (582 mg, 2.00 mmol) in DMF (3 mL) was stirred for 18 hours at room temperature, then diluted with aqueous sodium hydroxide solution (1 N, 50 mL). The mixture was extracted with ethyl acetate, and the combined organic layers were washed with aqueous lithium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Eluants: 50%, then 75% ethyl acetate in heptane) provided the product as a cream-colored solid. Yield: 267 mg, 0.658 mmol, 85%. APCI m/z 406.0 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.49 (s, 9H), 1.82-1.92 (m, 2H), 2.17 (br d, J=12 Hz, 2H), 2.77-2.86 (m, 2H), 4.26-4.34 (m, 2H), 4.93 (tt, J=12, 4 Hz, 1H), 7.20 (dd, J=5.3, 1.5 Hz, 1H), 7.32-7.36 (m, 3H), 7.42-7.45 (m, 2H), 7.80 (s, 1H), 8.54 (d, J=5.3 Hz, 1H), 9.28 (d, J=1.3 Hz, 1H). The mixture was extracted with ethyl acetate the combined organic layers were washed with aqueous lithium chloride solution dried over magnesium sulfate filtered concentrated in vacuo Purification via silica gel chromatography (Eluants

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Heat a mixture of 1-isobutyl-2-amino-6-(methyliminomethyl)-1H-benzimidazole (504 mg, 2.19 mmol), α-(p-toluenesulfonyl)benzylisocyanide (1.48 g, 5.47 mmol), methanol (7 mL), and methylamine (5.5 mL, 2M in tetrahydrofuran) in a sealed tube at 80° C. for 20 hours. Cool to room temperature and concentrate under reduced pressure. Subject residue to silica gel chromatography, eluting with a 1:1 mixture of acetonitrile and dichloromethane containing 5% methanol to provide the desired compound. Heat concentrate under reduced pressure Subject residue to silica gel chromatography, eluting with a 1:1 mixture of acetonitrile and dichloromethane containing 5% methanol

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of tert-butyl 4-aminopiperidine-1-carboxylate (3.88 g), oxoacetic acid hydrate (1.48 g), and potassium carbonate (4.46 g) in DMF (60 mL) was stirred at room temperature for 3 hours. Then, 1-{[isocyano(phenyl)methyl]sulfonyl}-4-methylbenzene (3.5 g) was added thereto, followed by stirring at room temperature for 14 hours. The solvent was evaporated under reduced pressure, to the residue were added ethyl acetate and water, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate, the combined organic phase was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 90/10) to obtain tert-butyl 4-(4-phenyl-1H-imidazol-1-yl)piperidine-1-carboxylate (3.1 g). by stirring at room temperature for 14 hours The solvent was evaporated under reduced pressure, to the residue were added ethyl acetate and water the organic phase was separated The aqueous phase was extracted with ethyl acetate the combined organic phase was washed with water and saturated brine dried over magnesium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 90/10)