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A solution of 4-chloroquinolin-3 -amine (3.70 g, 20.74 mmol) and 4-bromobutyryl chloride (11.54 g, 62.22 mmol) dissolved in 100 mL of 1 ,2-dichloroethane was heated to reflux. After 17 hours the reaction was cooled to room temperature, diluted with dichloromethane, washed with saturated aqueous K2CO3, H2O and brine, dried over Na2SO4, and concentrated under reduced pressure to give a brown solid. The solid was triturated with a mixture of hexane and ether, filtered and dried to give 4-bromo-iV-(4- chloroquinolin-3-yl)butanamide (3.65 g) as a brown solid.
A solution of 4-chloroquinolin-3 -amine (6.00 g, 33.59 mmol) and 3- chloropropionyl chloride (4.8 mL, 50.39 mmol) dissolved in 200 mL of 1 ,2-dichloroethane was heated to 50 0C in an oil bath. After 20 hrs the temperature of the oil bath was increased to 90 0C. After an additional 26 hours the reaction was cooled to room temperature, diluted with dichloromethane, washed with saturated aqueous K2CO3, H2O, and brine, dried over Na2SO4, and concentrated under reduced pressure to give 7.12 g of 3-chloro-lambda/-(4-chloroquinolin-3-yl)propanamide as a tan solid.
A mixture of 4-chloro[ 1,5 ]naphthyridin-3 -amine (2.0 g, 11 mmol) and 4- chlorobutyryl chloride (4.7 g, 33 mmol) in 1 ,2-dichloroethane (75 mL) was heated at <n="91"/>reflux for 20 hours. The reaction mixture was then concentrated under reduced pressure and the residue washed with two 25 mL portions of hexane. The solid was then taken up in methanol (35 mL), 1.0 mL of 10% solution of sodium hydroxide in water was added, and the solution was stirred at room temperature for 4 hours. The reaction mixture was then concentrated under reduced pressure to provide 4-chloro-iV-(4-chloro [ 1 ,5 ]naphthyridin-3 - yl)butanamide which was used directly in the next step without further purification. MS (ESI) m/z 284 (M + H)+.
With triethylamine; In dichloromethane; at 0 - 20℃;
Acetyl chloride (3.41 mL, 1.25 eq) and triethylamine (6.79 mL, 1.4 eq) were added sequentially to a solution of 3-amino-4-chloroquinoline (6.22 g, 1.0 eq) in dichloromethane (100 mL). The reaction mixture was stirred overnight and then washed sequentially with aqueous saturated sodium bicarbonate and brine, dried over magnesium sulfate, and then concentrated under reduced pressure to provide 6.68 g of N-(4- chloroquinolin-3-yl)acetamide.A solution of 3-amino-4-chloroquinoline (20.0 g, 112 rnmol) in dichloromethane (125 mL) was cooled to 0 C. Triethylamine (47.0 mL, 0.336 mol) was added followed by a solution of acetyl chloride (16.0 mL, 0.224 mol) in dichloromethane (45 mL), which was added dropwise. The reaction was stirred overnight at room temperature. An analysis by LC/MS indicated the presence of starting material, and additional acetyl chloride (4 mL, 56 mmol) was added. The reaction was stirred for four hours at room temperature. Saturated aqueous sodium bicarbonate (100 mL) was added, and the mixture was stirred for three days. The organic layer was separated and washed with saturated aqueous sodium bicarbonate (2 x 50 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide N-(4-chloroquinolin-3-yi)acetamide as a dark red solid.
A solution of acetoxyacetyl chloride (13.8 g, 101 mmol) in dichloromethane (20 niL) was added dropwise to a stirred solution of 3-amino-4-chloroquinoline (15 g, 84 mmol) and triethylamine (27 mL, 190 mmol) in dichloromethane (150 mL), and the reaction was stirred overnight at room temperature. An analysis by LC/MS indicated the presence of starting material, and additional acetoxyacetyl chloride (11.2 g, 82.0 mmol) in dichloromethane (35 mL) was added dropwise. The reaction was stirred overnight at room temperature and then stirred for five minutes with saturated aqueous sodium bicarbonate (75 mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate (2 x 25 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 22.3 g of a mixture of 1 :3 2-[(4- chloroquinolin-3-yl)amino]-2-oxoethyl acetate and N-(4-chloroquinolin-3-yl)-2- hydroxyacetamide as a brown, gummy solid.
Part ATriethylamine (13.1 niL, 94.1 mmol) was added with stirring to a solution of 3- amino-4-chloroquinoline, see Surrey et al, Journal of the American Chemical Society, 73, pp. 2413-2416 (1951), (11.2 g, 62.7 mmol) in dichloromethane (125 mL). A solution of ethoxyacetyl chloride (9.2 g, 75 mmol) in dichloromethane (35 mL) was then added dropwise, and the reaction was stirred at room temperature overnight. An analysis by liquid chromatography/mass spectrometry (LC/MS) indicated the presence of starting material, and a solution of additional ethoxyacetyl chloride (2.3 g, 19 mmol) in dichloromethane (10 mL) was added dropwise. The reaction was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate (100 mL) was added, and the resulting mixture was stirred at room temperature for 30 minutes. The organic layer was separated and washed sequentially with saturated aqueous sodium bicarbonate (50 mL) and water (2 x 50 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 17.0 g of N-(4-chloroquinolin-3-yl)-2-ethoxyacetamide as a dark oil that crystallized upon standing.
In dichloromethane; at 20℃; for 1.5h;
A solution of ethoxyacetyl chloride (4.2 g, 34 mmol) in dichloromethane was added dropwise to a stirred solution of 3-amino-4-chloroquinoline (5.1 g, 29 mmol) in dichloromethane (75 mL), and the reaction was stirred for one hour at room temperature. Additional ethoxyacetyl chloride (0.5 g, 4 mmol) was added, and the reaction was stirred for 30 minutes and diluted with dichloromethane (75 mL). The resulting mixture was washed with saturated aqueous sodium bicarbonate (50 mL), dried over potassium carbonate, and filtered. Methanol was added to facilitate the filtration. The filtrate was concentrated under reduced pressure to provide 7.3 g of iV-(4-chloroquinolin-3-yl)-2- ethoxyacetamide as a dark solid.
0.6 g
With triethylamine; In dichloromethane; at 0 - 20℃;
Compound 1 (1.0 g, 5.6 mmol, 1 eq) and triethylamine (1.7 g, 16.8 mmol, 3 eq) were dissolved in DCM (20 mL) and the resulting mixture was cooled to 0 C. Compound 2a (1.37 g, 11.2 mmol, 2 eq) was added and the resulting mixture was stirred at rt overnight. The mixture was washed with 1 N HC1, concentrated in vacuo. The resulting crude product was purified via FCC (eluting with PE/EA: 1/1) to afford compound 5a (0.6 g, 40%). TLC: eluting with PE/EA: 1/1; compound 1 Rf = 0.4; compound 5a Rf = 0.5.
A mixture of 3-amino-4-chloroquinoline (8.00 g, 1 eq), trimethylacetyl chloride (11 niL g, 2 eq), and anhydrous dichloroethane (150 mL) was heated at 70 C. After 6 hours more trimethylacetyl chloride (2 eq) was added and heating was continued for a total of 23 hours. The reaction mixture was diluted with dichloromethane, washed sequentially with saturated aqueous potassium carbonate, water, and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was triturated with hexanes and then filtered to provide 7.16 g of N-(4-chloroqumolin-3- yl)trimethylacetamide as a solid. The filtrate was concentrated under reduced pressure to provide 5 g of crude iV-(4-chloroquinolin-3-yl)trimethylacetamide.
Under a nitrogen atmosphere, a mixture of 3-amino-4~chloroquinoline (2.50 g, 1 eq), benzoyl chloride (3.0 g, 1.5 eq), and anhydrous dichloromethane (100 mL) was heated at 40 C. After 23 hours additional benzoyl chloride (3.0 g, 1.5 eq) was added and heating was continued for a total of 48 hours. The reaction mixture was diluted with ethyl acetate, washed sequentially with aqueous potassium carbonate (x2), water, and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The crude product was purified by column chromatography (230 g of silica gel eluted initially with a gradient of 20-50% ethyl acetate in hexanes and then with 4/3/3 dichloromethane/ethyl acetate/hexanes) to provide 1.01 g of N-(4-chloroquinolin-3-yl)benzamide as a white solid.
Under a nitrogen atmosphere, a mixture of 3-amino-4-chloroquinoline (8.00 g, 1 eq), cyclohexanecarbonyl chloride (18.2 mL, 3 eq) and anhydrous dichloro ethane (150 mL) was heated at 90 C for 23 hours. The reaction mixture was diluted with dichloromethane, washed sequentially with saturated aqueous potassium carbonate, water, and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was triturated with hexanes to provide a solid. The solid was combined with hexanes, stirred for 30 minutes, isolated by filtration, rinsed with hexanes, and then dried to provide 11.9 g of iV-(4-chloroquinolin-3-yl)cyclohexanecarboxamide.
With triethylamine; In dichloromethane; at 0 - 20℃;
Part AA solution of 3-amino-4-chloroquinoline (5.0 g, 28 mmol) and triethylamine (5.8 mL, 42 mmol) in dichloromethane (100 mL) was cooled to approximately 0 0C. A solution of propionyl chloride (2.8 g, 31 mmol) in dichloromethane (15 mL) was then added dropwise over a period of 15 minutes, and the reaction was allowed to warm to room temperature and stirred overnight. An analysis by high performance liquid chromatography (HPLC) indicated the presence of starting material, and additional triethylamine (1.95 mL, 14.0 mmol) and propionyl chloride (0.85 g, 9.2 mmol) in dichloromethane (5 mL) were added. The reaction was stirred at room temperature overnight; diluted with dichloromethane (100 mL); washed sequentially with water, saturated aqueous sodium carbonate, 10% w/w aqueous sodium hydroxide, saturated EPO <DP n="83"/>aqueous sodium carbonate, and brine; dried over magnesium sulfate and sodium sulfate, filtered, and concentrated under reduced pressure. The resulting brown solid (8.1 g) was recrystallized from toluene to provide 4.5 g of iV-(4-chloroquinolin-3-yl)propanamide as beige platelets, mp 151-152 0C.
With triethylamine; In dichloromethane;
Propionyl chloride (6.32 niL, 1.3 eq) and triethylamine (11.69 mL, 1.5 eq) were added sequentially to a solution of 3-amino-4-chloroquinolme (10.0 g, 1.0 eq) in dichloromethane (200 mL). The reaction mixture was stirred overnight and then quenched with aqueous saturated sodium bicarbonate. The organic layer was separated, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel eluting with 2% methanol in dichloromethane) to provide 5.8 g of iV-(4-chloroquinolin-3-yl)propionamide.
With triethylamine; In dichloromethane; at 20℃; for 3h;
Butyryl chloride (0.72 mL, 6.94 mmol, 1.2 eq.) and triethylamine (1.13 niL, 8.09 mmol, 1.4 eq) were added to a solution of 3-amino-4-chloroquinoline (1.03 g, 5.78 mmol, 1.0 eq) in anhydrous dichloromethane (25 mL). The reaction mixture was stirred at ambient temperature for 3 hours and then washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel eluting with 3% methanol in dichloromethane) to provide 0.70 g of iV-(4-chloroquinolin-3- yl)butyramide.Butyryl chloride (3.77 mL, 1.3 eq) and triethylamine (5.85 niL, 1.3 eq) were added sequentially to a chilled (0 C) solution of 3-amino-4-chloroquinoline (5.0 g, 1.0 eq) in dichloromethane (100 mL). The reaction mixture was warmed to ambient temperature and then allowed to stir overnight. The reaction mixture was quenched with aqueous saturated sodium bicarbonate. The organic layer was separated and concentrated under reduced pressure to provide 6.5 g of N-(4-chloroquinolin-3-yl)butyramide.
With triethylamine; In dichloromethane; at 20℃;
Triethylamine (22.3 mL, 0.160 mmol) was added with stirring to a solution of 3-amino-4-chloroquinoline, see Surrey et al., Journal of the American Chemical Society, 73, pp. 2413-2416 (1951), (13.2 g, 74.0 mmol) in anhydrous dichloromethane (100 mL). A solution of butyryl chloride (13 mL, 125 mmol) in dichloromethane (50 mL) was then added dropwise, and the reaction mixture was stirred at ambient temperature overnight. Methanol (25 mL) was added, and the reaction mixture was stirred for one hour at ambient temperature. Saturated aqueous sodium bicarbonate (50 mL) was added, and the resulting mixture was stirred at ambient temperature for 30 minutes and then allowed to stand. The aqueous layer was separated and extracted with dichloromethane (75 mL), and the combined organic fractions were then washed with saturated aqueous sodium bicarbonate (2*50 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure. The crude product (22.8 g) was recrystallized from a mixture of toluene (45 mL) and hexane (15 mL) to provide 9.2 of N-(4-chloroquinolin-3-yl)butanamide as brown needles.
With triethylamine; In dichloromethane; at 0 - 20℃;Heating / reflux;
A solution of 3-amino-4-chloroquinoline (8.5 g, 48 mmol) in dichloromethane (100 mL) was cooled to 0 0C. Triethylamine (42 mL, 0.30 mol) was added followed by a solution of isobutyryl chloride (9.6 mL, 0.10 mol) in dichloromethane (35 mL), which was added dropwise. The reaction was stirred overnight at room temperature. An analysis by LC/MS indicated the presence of starting material, and the reaction was heated at reflux for two hours. The reaction was still incomplete. The volatiles were removed under reduced pressure, and the residue was dissolved in dichloromethane (75 mL). Additional isobutyryl chloride (9.6 mL, 0.10 mol) was added, the reaction was stirred for three days at room temperature. The reaction was still incomplete, and additional isobutyryl chloride (3 mL) was added. The reaction was stirred overnight, diluted with methanol (10 mL), stirred for 30 minutes, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (150 mL), and the solution was washed with saturated aqueous sodium bicarbonate (3 x 50 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 9.6 g of N-(4-chloroquinolin-3-yl)-2- methylpropanamide as a brown solid.
A solution of valeryl chloride (13.3 mL, 112 mmol) in dichloromethane (35 mL) was added dropwise to a stirred solution of 3-amino-4-chloroquinoline (10.0 g, 56 mmol) and triethylamine (2.1 mL, 15 mmol) in dichloromethane (100 mL), and the reaction was stirred overnight at room temperature and then stirred for one hour with saturated aqueous sodium bicarbonate (150 mL). The aqueous layer was separated and extracted with dichloromethane (2 x 50 mL). The combined organic fractions were washed with saturated aqueous sodium bicarbonate (50 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure. The residue was recrystallized from toluene/hexane to provide 11.1 g of N-(4-chloroquinolin-3-yi)pentanamide as a light brown solid.
Part A Formic acid (0.36 mL) was slowly added with stirring to acetic anhydride (0.8 mL), and the reaction was stirred at room temperature for 2.75 hours and then added to a solution of 3-amino-4-chloroquinoline (0.50 g, 2.8 mmol) in tetrahydrofuran (5 mL). The resulting mixture was stirred for one hour at room temperature. A solid was present and was collected by filtration and washed with diethyl ether to provide 0.48 g of 4- chloroquinolin-3-ylformamide as a beige solid, mp 175-177 0C.
Acetic anhydride (16 mL, 170 mmol) was cooled to 0 C, and formic acid (7.2 mL of 97% pure material, 190 mmol) was added over a period often mintues. The solution was stirred for 2.5 hours at room temperature and then added to a stirred solution of 3- amino-4-chloroquinoline (10.0 g, 56.0 mmol) in tetrahydroforan (THF) (100 mL). The reaction was stirred for one hour at room temperature and then concentrated under reduced pressure. Methanol (50 mL) was added to the residue, stirred for 30 minutes, and removed under reduced pressure. The residue was then stirred with dichloromethane (150 mL) and saturated aqueous sodium bicarbonate (50 mL) for three days. A solid was present and was isolated by filtration and dried under high vacuum. The filtrate was concentrated under reduced pressure, and the residue was dissolved in methanol (400 mL). The solution was dried over potassium carbonate, filtered, and concentrated under reduced pressure. The residue was combined with the solid isolated by filtration to provide 9.6 g of 4-chloroqumolin-3-ylformamide as a brown solid.
With pyridine;pyridine hydrochloride; at 20 - 60℃; for 19h;
A solution of valeric anhydride (6.03 g) and pyridine hydrochloride (0.198 g) in pyridine (8.28 g) was added to a solution of 3-amino-4-chloroquinoline (2.94 g) in pyridine (5.0 g) and the reaction was stirred at room temperature for 16 hours followed by heating at 60 C for 3 hours. The reaction was concentrated under reduced pressure and sodium carbonate (15 mL of a 10% aqueous solution) was added. The reaction was stirred for 30 minutes and then filtered. The resulting solid was washed with water (60 mL) and dried under vacuum for 4 hours to provide 4.59 g of crude N-(4-chloroquinolin-3- yl)valeramide as brown flakes. The crude product was recrystallized from heptane (10 mL) and the recovered product was further purified by soxhlet extraction using refluxing heptane for 16 hours. The collection flask from the soxhlet extraction apparatus was cooled in a freezer for 2 hours. The resulting solid was collected by filtration and dried under vacuum to yield 2.00 g of N-(4-chloroquinolin-3- yl)valeramide as a white solid.
With pyridine hydrochloride; In pyridine; at 20 - 60℃; for 19h;
A solution of valeric anhydride (6.03 g) and pyridine hydrochloride (0.198 g) in pyridine (8.28 g) was added to a solution of 3-amino-4-chloroquinoline (2.94 g) in pyridine (5.0 g) and the reaction was stirred at room temperature for 16 hours followed by heating at 60 C for 3 hours. The reaction was concentrated under reduced pressure and sodium carbonate (15 mL of a 10% aqueous solution) was added. The reaction was stirred for 30 minutes and then filtered. The resulting solid was washed with water (60 mL) and dried under vacuum for 4 hours to provide 4.59 g of crude N-(4-chloroquinolin-3- yl)valeramide as brown flakes. The crude product was recrystallized from heptane (10 mL) and the recovered product was further purified by soxhlet extraction using refluxing heptane for 16 hours. The collection flask from the soxhlet extraction apparatus was cooled in a freezer for 2 hours. The resulting solid was collected by filtration and dried under vacuum to yield 2.00 g of N-(4-chloroquinolin-3- yl)valeramide as a white solid
2-chloro-N-(4-chloroquinolin-3-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39.5%
With triethylamine; In dichloromethane; at 0 - 20℃;
To a solution of compound 1 (2.0 g, 11.2 mmol, 1 eq) and triethylamine (3.4 g, 33.6 mmol, 3 eq) in DCM (40 mL) at 0 C was added chloroacetyl chloride (2.52 g, 22.4 mmol, 2 eq) and the resulting mixture was stirred overnight at rt. The reaction mixture was washed with IN HCl, water and brine, and concentrated in vacuo. The crude residue was purified via FCC (eluting with PE/EA: 1/1) to give compound 3 (1.2 g, 39.5%). TLC: eluting with PE/EA: 1/1; compound 1 Rf = 0.4; compound 3 Rf = 0.6.