2-异氰基丙烷

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

实验步骤: To a solution of (D)-leucine methyl ester hydrochloride (300 mg) in methanol (4 ml) was added triethylamine (230 μl) and 4-fluorobenzaldehyde (177 μl). The mixture was stirred for 2.5 hours before (2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-1H-inden-2-yl)ethanoic acid (481 mg) and isopropylisocyanide (225 μl) were sequentially added. After stirring for 16 hr, the solvent was removed in vacuo and the residue was dissolved in chloroform. This solution was washed with a saturated aqueous sodium carbonate solution (×2), aqueous citric acid (0.5M, ×2) and brine (×1), dried over magnesium sulphate and evaporated in vacuo. The residue was dissolved in dichloromethane (2 ml) and trifluoroacetic acid (5 ml) and stirred for 3 hours at ambient temperature. After this time, the solvent was removed in vacuo and the residue co-evaporation with toluene (×3) and cyclohexane/ether (1:1, ×2). The residue was treated with a solution of triethylamine in dioxane (2% solution, 10 ml) and was left to stir overnight. After this time, the dioxane was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with citric acid solution (0.5M, ×2), saturated aqueous sodium bicarbonate solution (×1) and brine (×1). The liquors were then dried over magnesium sulphate and in vacuo and were then co-evaporated with cyclohexane:ether (1:1, ×2). This crude material was purified by Biotage™ (90 g, silica) eluting with toluene: ethyl acetate:cyclohexane (5:3:2) with 5% triethylamine to give (2R)-2-(4-fluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide (149 mg) were sequentially added the solvent was removed in vacuo the residue was dissolved in chloroform This solution was washed with a saturated aqueous sodium carbonate solution (×2), aqueous citric acid (0.5M, ×2) and brine (×1) dried over magnesium sulphate evaporated in vacuo The residue was dissolved in dichloromethane (2 ml) trifluoroacetic acid (5 ml) and stirred for 3 hours at ambient temperature After this time, the solvent was removed in vacuo The residue was treated with a solution of triethylamine in dioxane (2% solution, 10 ml) was left to stir overnight After this time, the dioxane was removed in vacuo the residue was dissolved in ethyl acetate The solution was washed with citric acid solution (0.5M, ×2), saturated aqueous sodium bicarbonate solution (×1) and brine (×1) The liquors were then dried over magnesium sulphate and in vacuo This crude material was purified by Biotage™ (90 g, silica) eluting with toluene: ethyl acetate:cyclohexane (5:3:2) with 5% triethylamine

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

实验步骤: 5-(trifluoromethyl)pyridin-2-amine (100 mg, 617 μmol, Eq: 1.00), 3-chlorobenzaldehyde (86.7 mg, 70.2 μl, 617 μmol, Eq: 1.00) and p-toluenesulfonic acid monohydrate (35.2 mg, 185 μmol, Eq: 0.3) were dissolved in MeOH (1.00 mL) and the intensive yellow solution was stirred for 5 min. To this yellow solution was added dropwise 2-isocyanopropane (42.6 mg, 58.2 μL, 617 μmol, Eq: 1.00) and the corresponding yellow solution was stirred for 90 min. To the yellow solution was added dropwise water and oil was formed. The water/MeOH was separated from the oil and the yellow oily residue was purified by flash column chromatography (40 g SiO2, hexane/AcOEt 100:0 to 0:100) to yield a yellow solid (178 mg, 78.3%). MS: 354.0 [M+H]+; 1H-NMR (D6-DMSO): δ 8.92 (s, 1H), 8.29 (s, 1H), 8.19 (d, 1H), 7.72 (d, 1H), 7.51 (t, 1H), 7.47-7.36 (m, 2H), 5.13 (d, 1H), 3.26 (m, 1H), 1.08 (d, 6H). the corresponding yellow solution was stirred for 90 min oil was formed The water/MeOH was separated from the oil the yellow oily residue was purified by flash column chromatography (40 g SiO2, hexane/AcOEt 100:0 to 0:100)

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

实验步骤: 5-(trifluoromethyl)pyridin-2-amine (100 mg, 617 μmol, Eq: 1.00), 3-chlorobenzaldehyde (86.7 mg, 70.2 μl, 617 μmol, Eq: 1.00) and p-toluenesulfonic acid monohydrate (35.2 mg, 185 μmol, Eq: 0.3) were dissolved in MeOH (1.00 mL) and the intensive yellow solution was stirred for 5 min. To this yellow solution was added dropwise 2-isocyanopropane (42.6 mg, 58.2 μL, 617 μmol, Eq: 1.00) and the corresponding yellow solution was stirred for 90 min. To the yellow solution was added dropwise water and oil was formed. The water/MeOH was separated from the oil and the yellow oily residue was purified by flash column chromatography (40 g SiO2, hexane/AcOEt 100:0 to 0:100) to yield a yellow solid (178 mg, 78.3%). MS: 354.0 [M+H]+; 1H-NMR (D6-DMSO): δ 8.92 (s, 1H), 8.29 (s, 1H), 8.19 (d, 1H), 7.72 (d, 1H), 7.51 (t, 1H), 7.47-7.36 (m, 2H), 5.13 (d, 1H), 3.26 (m, 1H), 1.08 (d, 6H). the corresponding yellow solution was stirred for 90 min oil was formed The water/MeOH was separated from the oil the yellow oily residue was purified by flash column chromatography (40 g SiO2, hexane/AcOEt 100:0 to 0:100)

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

实验步骤: 5-(trifluoromethyl)pyridin-2-amine (100 mg, 617 μmol, Eq: 1.00), 3-ethynylbenzaldehyde (84.3 mg, 648 μmol, Eq: 1.05) and p-toluenesulfonic acid monohydrate (35.2 mg, 185 μmol, Eq: 0.3) were dissolved in MeOH (1.00 mL) and the intensive yellow solution was stirred for 5 min. To this yellow solution was added dropwise 2-isocyanopropane (42.6 mg, 58.2 μL, 617 μmol, Eq: 1.00) and the corresponding yellow solution was stirred for 2 h. Upon addition of water a yellow precipitate was formed. The solid was filtered off, washed with MeOH/water (1:1) and dried under vacuum to yield the product as a yellow solid (153 mg, 72.2%). MS: 344.0 [M+H]+; 1H-NMR (D6-DMSO): δ 8.90 (s, 1H), 8.36 (s, 1H), 8.25 (d, 1H), 7.71 (d, 1H), 7.50 (t, 1H), 7.46-7.39 (m, 2H), 5.10 (d, 1H), 4.24 (s, 1H), 3.25 (m, 1H), 1.08 (d, 6H). the corresponding yellow solution was stirred for 2 h was formed The solid was filtered off washed with MeOH/water (1:1) dried under vacuum

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

实验步骤: 5-Chloropyridin-2-amine (130 mg, 1.01 mmol), 3-chlorobenzaldehyde (171 mg, 1.21 mmol) and p-toluenesulfonic acid monohydrate (77 mg, 0.40 mmol) were combined in 2 mL of methanol to give a clear solution. To this solution was added 2-isocyanopropane (78 mg, 1.13 mmol) and the resulting clear solution was stirred at room temperature for 45 minutes. The mixture was filtered and the white solid was rinsed with methanol three times. The white solid was dried to afford [6-chloro-2-(3-chloro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-isopropyl-amine (48 mg, 15%). MS: 320.0 and 322.0 [M+H]+; 1H-NMR (DMSO-d6): δ 8.53 (s, 1H), 8.23 (s, 1H), 8.13 (d, 1H), 7.52 (d, 1H), 7.46 (t, 1H), 7.32 (d, 1H), 7.20 (d, 1H), 4.92 (d, 1H), 3.20 (m, 1H), 1.04 (d, 6H). to give a clear solution The mixture was filtered the white solid was rinsed with methanol three times The white solid was dried

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

实验步骤: To a solution of (D)-leucine methyl ester hydrochloride (300 mg) in methanol (4 ml) was added triethylamine (230 μl) and 4-fluorobenzaldehyde (177 μl). The mixture was stirred for 2.5 hours before (2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-1H-inden-2-yl)ethanoic acid (481 mg) and isopropylisocyanide (225 μl) were sequentially added. After stirring for 16 hr, the solvent was removed in vacuo and the residue was dissolved in chloroform. This solution was washed with a saturated aqueous sodium carbonate solution (×2), aqueous citric acid (0.5M, ×2) and brine (×1), dried over magnesium sulphate and evaporated in vacuo. The residue was dissolved in dichloromethane (2 ml) and trifluoroacetic acid (5 ml) and stirred for 3 hours at ambient temperature. After this time, the solvent was removed in vacuo and the residue co-evaporation with toluene (×3) and cyclohexane/ether (1:1, ×2). The residue was treated with a solution of triethylamine in dioxane (2% solution, 10 ml) and was left to stir overnight. After this time, the dioxane was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with citric acid solution (0.5M, ×2), saturated aqueous sodium bicarbonate solution (×1) and brine (×1). The liquors were then dried over magnesium sulphate and in vacuo and were then co-evaporated with cyclohexane:ether (1:1, ×2). This crude material was purified by Biotage™ (90 g, silica) eluting with toluene: ethyl acetate:cyclohexane (5:3:2) with 5% triethylamine to give (2R)-2-(4-fluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide (149 mg) were sequentially added the solvent was removed in vacuo the residue was dissolved in chloroform This solution was washed with a saturated aqueous sodium carbonate solution (×2), aqueous citric acid (0.5M, ×2) and brine (×1) dried over magnesium sulphate evaporated in vacuo The residue was dissolved in dichloromethane (2 ml) trifluoroacetic acid (5 ml) and stirred for 3 hours at ambient temperature After this time, the solvent was removed in vacuo The residue was treated with a solution of triethylamine in dioxane (2% solution, 10 ml) was left to stir overnight After this time, the dioxane was removed in vacuo the residue was dissolved in ethyl acetate The solution was washed with citric acid solution (0.5M, ×2), saturated aqueous sodium bicarbonate solution (×1) and brine (×1) The liquors were then dried over magnesium sulphate and in vacuo This crude material was purified by Biotage™ (90 g, silica) eluting with toluene: ethyl acetate:cyclohexane (5:3:2) with 5% triethylamine

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

实验步骤: To a solution of (D)-leucine methyl ester hydrochloride (300 mg) in methanol (4 ml) was added triethylamine (230 μl) and 4-fluorobenzaldehyde (177 μl). The mixture was stirred for 2.5 hours before (2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-1H-inden-2-yl)ethanoic acid (481 mg) and isopropylisocyanide (225 μl) were sequentially added. After stirring for 16 hr, the solvent was removed in vacuo and the residue was dissolved in chloroform. This solution was washed with a saturated aqueous sodium carbonate solution (×2), aqueous citric acid (0.5M, ×2) and brine (×1), dried over magnesium sulphate and evaporated in vacuo. The residue was dissolved in dichloromethane (2 ml) and trifluoroacetic acid (5 ml) and stirred for 3 hours at ambient temperature. After this time, the solvent was removed in vacuo and the residue co-evaporation with toluene (×3) and cyclohexane/ether (1:1, ×2). The residue was treated with a solution of triethylamine in dioxane (2% solution, 10 ml) and was left to stir overnight. After this time, the dioxane was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with citric acid solution (0.5M, ×2), saturated aqueous sodium bicarbonate solution (×1) and brine (×1). The liquors were then dried over magnesium sulphate and in vacuo and were then co-evaporated with cyclohexane:ether (1:1, ×2). This crude material was purified by Biotage™ (90 g, silica) eluting with toluene: ethyl acetate:cyclohexane (5:3:2) with 5% triethylamine to give (2R)-2-(4-fluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide (149 mg) were sequentially added the solvent was removed in vacuo the residue was dissolved in chloroform This solution was washed with a saturated aqueous sodium carbonate solution (×2), aqueous citric acid (0.5M, ×2) and brine (×1) dried over magnesium sulphate evaporated in vacuo The residue was dissolved in dichloromethane (2 ml) trifluoroacetic acid (5 ml) and stirred for 3 hours at ambient temperature After this time, the solvent was removed in vacuo The residue was treated with a solution of triethylamine in dioxane (2% solution, 10 ml) was left to stir overnight After this time, the dioxane was removed in vacuo the residue was dissolved in ethyl acetate The solution was washed with citric acid solution (0.5M, ×2), saturated aqueous sodium bicarbonate solution (×1) and brine (×1) The liquors were then dried over magnesium sulphate and in vacuo This crude material was purified by Biotage™ (90 g, silica) eluting with toluene: ethyl acetate:cyclohexane (5:3:2) with 5% triethylamine

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

实验步骤: To a solution of (D)-leucine methyl ester hydrochloride (300 mg) in methanol (4 ml) was added triethylamine (230 μl) and 4-fluorobenzaldehyde (177 μl). The mixture was stirred for 2.5 hours before (2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-1H-inden-2-yl)ethanoic acid (481 mg) and isopropylisocyanide (225 μl) were sequentially added. After stirring for 16 hr, the solvent was removed in vacuo and the residue was dissolved in chloroform. This solution was washed with a saturated aqueous sodium carbonate solution (×2), aqueous citric acid (0.5M, ×2) and brine (×1), dried over magnesium sulphate and evaporated in vacuo. The residue was dissolved in dichloromethane (2 ml) and trifluoroacetic acid (5 ml) and stirred for 3 hours at ambient temperature. After this time, the solvent was removed in vacuo and the residue co-evaporation with toluene (×3) and cyclohexane/ether (1:1, ×2). The residue was treated with a solution of triethylamine in dioxane (2% solution, 10 ml) and was left to stir overnight. After this time, the dioxane was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with citric acid solution (0.5M, ×2), saturated aqueous sodium bicarbonate solution (×1) and brine (×1). The liquors were then dried over magnesium sulphate and in vacuo and were then co-evaporated with cyclohexane:ether (1:1, ×2). This crude material was purified by Biotage™ (90 g, silica) eluting with toluene:ethyl acetate:cyclohexane (5:3:2) with 5% triethylamine to give (2R)-2-(4-fluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide (149 mg) were sequentially added the solvent was removed in vacuo the residue was dissolved in chloroform This solution was washed with a saturated aqueous sodium carbonate solution (×2), aqueous citric acid (0.5M, ×2) and brine (×1) dried over magnesium sulphate evaporated in vacuo The residue was dissolved in dichloromethane (2 ml) trifluoroacetic acid (5 ml) and stirred for 3 hours at ambient temperature After this time, the solvent was removed in vacuo The residue was treated with a solution of triethylamine in dioxane (2% solution, 10 ml) was left to stir overnight After this time, the dioxane was removed in vacuo the residue was dissolved in ethyl acetate The solution was washed with citric acid solution (0.5M, ×2), saturated aqueous sodium bicarbonate solution (×1) and brine (×1) The liquors were then dried over magnesium sulphate and in vacuo This crude material was purified by Biotage™ (90 g, silica) eluting with toluene:ethyl acetate:cyclohexane (5:3:2) with 5% triethylamine

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

实验步骤: To a solution of (D)-leucine methyl ester hydrochloride (300 mg) in methanol (4 ml) was added triethylamine (230 μl) and 4-fluorobenzaldehyde (177 μl). The mixture was stirred for 2.5 hours before (2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-1H-inden-2-yl)ethanoic acid (481 mg) and isopropylisocyanide (225 μl) were sequentially added. After stirring for 16 hr, the solvent was removed in vacuo and the residue was dissolved in chloroform. This solution was washed with a saturated aqueous sodium carbonate solution (×2), aqueous citric acid (0.5M, ×2) and brine (×1), dried over magnesium sulphate and evaporated in vacuo. The residue was dissolved in dichloromethane (2 ml) and trifluoroacetic acid (5 ml) and stirred for 3 hours at ambient temperature. After this time, the solvent was removed in vacuo and the residue co-evaporation with toluene (×3) and cyclohexane/ether (1:1, ×2). The residue was treated with a solution of triethylamine in dioxane (2% solution, 10 ml) and was left to stir overnight. After this time, the dioxane was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with citric acid solution (0.5M, ×2), saturated aqueous sodium bicarbonate solution (×1) and brine (×1). The liquors were then dried over magnesium sulphate and in vacuo and were then co-evaporated with cyclohexane:ether (1:1, ×2). This crude material was purified by Biotage™ (90 g, silica) eluting with toluene:ethyl acetate:cyclohexane (5:3:2) with 5% triethylamine to give (2R)-2-(4-fluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide (149 mg) were sequentially added the solvent was removed in vacuo the residue was dissolved in chloroform This solution was washed with a saturated aqueous sodium carbonate solution (×2), aqueous citric acid (0.5M, ×2) and brine (×1) dried over magnesium sulphate evaporated in vacuo The residue was dissolved in dichloromethane (2 ml) trifluoroacetic acid (5 ml) and stirred for 3 hours at ambient temperature After this time, the solvent was removed in vacuo The residue was treated with a solution of triethylamine in dioxane (2% solution, 10 ml) was left to stir overnight After this time, the dioxane was removed in vacuo the residue was dissolved in ethyl acetate The solution was washed with citric acid solution (0.5M, ×2), saturated aqueous sodium bicarbonate solution (×1) and brine (×1) The liquors were then dried over magnesium sulphate and in vacuo This crude material was purified by Biotage™ (90 g, silica) eluting with toluene:ethyl acetate:cyclohexane (5:3:2) with 5% triethylamine

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

实验步骤: To a solution of (D)-leucine methyl ester hydrochloride (300 mg) in methanol (4 ml) was added triethylamine (230 μl) and 4-fluorobenzaldehyde (177 μl). The mixture was stirred for 2.5 hours before (2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-1H-inden-2-yl)ethanoic acid (481 mg) and isopropylisocyanide (225 μl) were sequentially added. After stirring for 16 hr, the solvent was removed in vacuo and the residue was dissolved in chloroform. This solution was washed with a saturated aqueous sodium carbonate solution (x2), aqueous citric acid (0.5M, x2) and brine (x1l), dried over magnesium sulphate and evaporated in vacuo. The residue was dissolved in dichloromethane (2 ml) and trifluoroacetic acid (5 ml) and stirred for 3 hours at ambient temperature. After this time, the solvent was removed in vacuo and the residue co-evaporation with toluene (x3) and cyclohexane/ether (1:1, x2). The residue was treated with a solution of triethylamine in dioxane (2% solution, 10 ml) and was left to stir overnight. After this time, the dioxane was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with citric acid solution (0.5M, x2), saturated aqueous sodium bicarbonate solution (x1) and brine (x1). The liquors were then dried over magnesium sulphate and in vacuo and were then co-evaporated with cyclohexane: ether (1: 1, x2). This crude material was purified by Biotage™ (90 g, silica) eluting with toluene:ethyl acetate:cyclohexane (5:3:2) with 5% triethylamine to give (2R)-2-(4-fluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide (149 mg) were sequentially added the solvent was removed in vacuo the residue was dissolved in chloroform This solution was washed with a saturated aqueous sodium carbonate solution (x2), aqueous citric acid (0.5M, x2) and brine (x1l) dried over magnesium sulphate evaporated in vacuo The residue was dissolved in dichloromethane (2 ml) trifluoroacetic acid (5 ml) and stirred for 3 hours at ambient temperature After this time, the solvent was removed in vacuo The residue was treated with a solution of triethylamine in dioxane (2% solution, 10 ml) was left to stir overnight After this time, the dioxane was removed in vacuo the residue was dissolved in ethyl acetate The solution was washed with citric acid solution (0.5M, x2), saturated aqueous sodium bicarbonate solution (x1) and brine (x1) The liquors were then dried over magnesium sulphate and in vacuo This crude material was purified by Biotage™ (90 g, silica) eluting with toluene:ethyl acetate:cyclohexane (5:3:2) with 5% triethylamine

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

实验步骤: 1H-Benzoimidazol-5-ylamine (1 mmol) and 2,4-Dimethyl-cyclohex-3-ene carbaldehyde (1 mmol) were combined in methanol (2 ml, dry). After 2 hours 2 ml of a solution of KOCN (KSCN) (2 mmol) and Pyridinehydrochloride (2 mmol) in MeOH is added was added. Finally 2-Isocyano-propane (1 mmol) is added. The reaction was stirred at room temperature for 48 h. After evaporation of the solvent the residue was purified with chromatographic methods. was added After evaporation of the solvent the residue was purified with chromatographic methods

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

实验步骤: To a mixture of 5-amino-1H-pyrazole-4-carbonitrile (771 mg, 7.13 mmol) and 2,4-dimethoxybenzaldehyde (1.19 g, 7.13 mmol) in a vial under nitrogen atmosphere were added methanol (20 mL) followed by iso-propyl isonitrile (500 mg, 581 μL, 7.13 mmol) and perchloric acid (143 mg, 128 μL, 1.43 mmol) at RT. Then, the resulting brown solution was stirred for 15 h by which time LC/MS analysis indicated the presence of the desired product. Then, the solvent was removed under vacuum and the residue was purified using an ISCO (80 g) column chromatography eluting with 0-50% ethyl acetate in hexanes. The desired fractions were combined and the solvent was removed under vacuum to obtain 647 mg (28% yield) of 2-(2,4-dimethoxyphenyl)-3-(iso-propylamino)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile as a light yellow solid. LC/MS calcd. for C17H19N5O2 (m/e) 325.37, obsd. 326.0 (M+H, ES+).