2-amino-4-chlorobenzaldehyde

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

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

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

Procedure: Pyridine (3.7 ml, 45.7 mmol) is added to a solution of 2-amino-4-chloro-benzaldehyde (6.18 g, 39.7 mmol) in 170 ml of anhydrous toluene, followed dropwise by a solution of chlorocarbonylmethylphosphonic acid diethyl ester (9.8 g, 45.7 mmol) in 15 ml of anhydrous toluene whilst maintaining the reaction mixture at a temperature of less than 30° C. When the addition is complete, the mixture is stirred for 1 hour at room temperature. The reaction mixture is washed several times with water and then with a 1N HCl solution, and then again with water. Finally the mixture is washed with an aqueous saturated NaCl solution. The organic phase is dried over MgSO4, and filtration is carried out, followed by evaporation to obtain the expected crude product in the form of an orange oil. The crude product is used in the following step. whilst maintaining the reaction mixture at a temperature of less than 30° C When the addition The reaction mixture is washed several times with water Finally the mixture is washed with an aqueous saturated NaCl solution The organic phase is dried over MgSO4, and filtration followed by evaporation

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

Procedure: Pyridine (3.7 ml, 45.7 mmol) is added to a solution of 2-amino-4-chlorobenzaldehyde (6.18 g, 39.7 mmol) in 170 ml of anhydrous toluene, followed dropwise by a solution of chlorocarbonylmethylphosphonic acid diethyl ester (9.8 g, 45.7 mmol) in 15 ml of anhydrous toluene whilst maintaining the reaction mixture at a temperature of less than 30° C. When the addition is complete, the mixture is stirred for 1 hour at room temperature. The reaction mixture is washed several times with water and then with a 1N HCl solution, and then again with water. Finally the mixture is washed with an aqueous saturated NaCl solution. The organic phase is dried over MgSO4, and filtration is carried out, followed by evaporation to obtain the expected crude product in the form of an orange oil. The crude product is used in the following step. whilst maintaining the reaction mixture at a temperature of less than 30° C When the addition The reaction mixture is washed several times with water Finally the mixture is washed with an aqueous saturated NaCl solution The organic phase is dried over MgSO4, and filtration followed by evaporation

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

Procedure: A solution of 4-chloro-2-aminobenzaldehyde (15 g, 96 mmol, 1 equiv) and 3-hydroxy-acrylic acid ethyl ester, sodium salt (6.65 g, 48 mmol, 0.5 equiv) in glacial acetic acid (175 mL), was heated at reflux for 3 hours. Additional 3-hydroxy-acrylic acid ethyl ester, sodium salt (6.65 grams, 48 mmol, 0.5 equivalents) was added and the reaction was heated at reflux for another 2.5 hours. Additional 3-hydroxy-acrylic acid ethyl ester, sodium salt (4 g, 28.8 mmol, 0.3 equiv) was added and the reaction was heated at reflux for an additional 12 hours. Additional 3-hydroxy-acrylic acid ethyl ester, sodium salt (4 g, 28.8 mmol, 0.3 equiv) was added and the reaction was heated at reflux for 4 hours. The reaction mixture was cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL) and washed with saturated sodium bicarbonate solution (200 mL). The organic layer was then washed with brine (200 mL), dried over sodium sulfate, and treated with activated charcoal (Darco G-60®) (20 g). The mixture was filtered through diatomaceous earth. Silica gel (15 g) (EM Science, Gibbstown, N.J., 230-400 mesh, 0.04-0.06 mm particle size) was added to the solution and stirred for 3 hours. The slurry was filtered, rinsed with toluene (100 ml) and then 10% ethyl acetate in toluene (200 mL). The combined organic layers were concentrated and the resulting solid was stirred in isopropanol overnight to yield 7-chloro-quinoline-3-carboxylic acid ethyl ester (3 g, 13% yield) as a pale yellow powder. at reflux for 3 hours the reaction was heated at reflux for another 2.5 hours the reaction was heated at reflux for an additional 12 hours the reaction was heated at reflux for 4 hours The reaction mixture was cooled concentrated in vacuo The residue was dissolved in ethyl acetate (200 mL) washed with saturated sodium bicarbonate solution (200 mL) The organic layer was then washed with brine (200 mL) dried over sodium sulfate treated with activated charcoal (Darco G-60®) (20 g) The mixture was filtered through diatomaceous earth Silica gel (15 g) (EM Science, Gibbstown, N.J., 230-400 mesh, 0.04-0.06 mm particle size) was added to the solution The slurry was filtered rinsed with toluene (100 ml) The combined organic layers were concentrated the resulting solid was stirred in isopropanol overnight

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

Procedure: A solution of 4-chloro-2-aminobenzaldehyde (15 g, 96 mmol, 1 equiv) and 3-hydroxy-acrylic acid ethyl ester, sodium salt (6.65 g, 48 mmol, 0.5 equiv) in glacial acetic acid (175 mL), was heated at reflux for 3 hours. Additional 3-hydroxy-acrylic acid ethyl ester, sodium salt (6.65 grams, 48 mmol, 0.5 equivalents) was added and the reaction was heated at reflux for another 2.5 hours. Additional 3-hydroxy-acrylic acid ethyl ester, sodium salt (4 g, 28.8 mmol, 0.3 equiv) was added and the reaction was heated at reflux for an additional 12 hours. Additional 3-hydroxy-acrylic acid ethyl ester, sodium salt (4 g, 28.8 mmol, 0.3 equiv) was added and the reaction was heated at reflux for 4 hours. The reaction mixture was cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL) and washed with saturated sodium bicarbonate solution (200 mL). The organic layer was then washed with brine (200 mL), dried over sodium sulfate, and treated with activated charcoal (Darco G-60®) (20 g). The mixture was filtered through diatomaceous earth. Silica gel (15 g) (EM Science, Gibbstown, N.J., 230-400 mesh, 0.04-0.06 mm particle size) was added to the solution and stirred for 3 hours. The slurry was filtered, rinsed with toluene (100 ml) and then 10% ethyl acetate in toluene (200 mL). The combined organic layers were concentrated and the resulting solid was stirred in isopropanol overnight to yield 7-chloro-quinoline-3-carboxylic acid ethyl ester (3 g, 13% yield) as a pale yellow powder. at reflux for 3 hours the reaction was heated at reflux for another 2.5 hours the reaction was heated at reflux for an additional 12 hours the reaction was heated at reflux for 4 hours The reaction mixture was cooled concentrated in vacuo The residue was dissolved in ethyl acetate (200 mL) washed with saturated sodium bicarbonate solution (200 mL) The organic layer was then washed with brine (200 mL) dried over sodium sulfate treated with activated charcoal (Darco G-60®) (20 g) The mixture was filtered through diatomaceous earth Silica gel (15 g) (EM Science, Gibbstown, N.J., 230-400 mesh, 0.04-0.06 mm particle size) was added to the solution The slurry was filtered rinsed with toluene (100 ml) The combined organic layers were concentrated the resulting solid was stirred in isopropanol overnight

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 3-neck flask fitted with a reflux condenser and a mechanical stirrer, were added 4-chloro-2-nitrobenzaldehyde (25 g, 135 mmol, 1 equiv), ethanol (375 mL), and water (100 mL). 4-Chloro-2-nitrobenzaldehyde can be obtained from P.H.T. International, Inc., Charlotte, N.C. Iron dust (225 mesh, Aldrich, Milwaukee, Wis.) (22.6 g, 405 mmol, 3 equiv) and concentrated hydrochloric acid (5.7 mL, 67.5 mmol, 0.5 equiv) was added. The slurry was heated to 85° C. for two hours, cooled to room temperature, filtered through diatomaceous earth and rinsed with ethanol (100 mL) and toluene (100 mL). The solution was transferred to a separatory funnel and toluene (300 mL) were added. The organic layer was washed with saturated sodium bicarbonate solution (300 mL) and brine (300 mL), then dried over sodium sulfate and then concentrated to provide 4-chloro-2-aminobenzaldehyde (17.4 g, 83%) as a yellow solid. To a 3-neck flask fitted with a reflux condenser and a mechanical stirrer cooled to room temperature filtered through diatomaceous earth rinsed with ethanol (100 mL) and toluene (100 mL) The solution was transferred to a separatory funnel toluene (300 mL) were added The organic layer was washed with saturated sodium bicarbonate solution (300 mL) and brine (300 mL) dried over sodium sulfate concentrated

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Urea (115 g, 1915 mmol) was melted in a 500 mL 3 neck flask under nitrogen and heated at 160° C. The crude aminobenzaldehyde from step 1 (8.4 g) was added, one of the necks of the flask was opened to the atmosphere and the temperature of the oil bath raised to 190° C. When the bath temperature reached 175° C., a white precipitate was observed. The mixture was cooled and water (400 mL) was added. It was stirred for 15 minutes then filtered through a sintered glass frit. The collected solids were dried by azeotroping with toluene at reduced pressure (3×300 mL) then further dried under high vacuum at 70° C. The crude material was used without further purification. the temperature of the oil bath raised to 190° C reached 175° C. The mixture was cooled then filtered through a sintered glass frit The collected solids were dried by azeotroping with toluene at reduced pressure (3×300 mL) then further dried under high vacuum at 70° C The crude material was used without further purification

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

Procedure: (2-amino-4-chlorophenyl)methanol (10.08 g, 64.0 mmol) was suspended in chloroform (250 mL) and treated with manganese dioxide (15.87 g, 183 mmol). The mixture was stirred vigorously and heated at reflux. The oxidation was followed by TLC and found to be complete after 1 hour. The suspension was filtered through a pad of CELITE™ and evaporated to dryness under reduced pressure. Further drying under high vacuum gave a dark red solid which was used in the next step without further purification. heated at reflux The suspension was filtered through a pad of CELITE™ evaporated to dryness under reduced pressure Further drying under high vacuum gave a dark red solid which was used in the next step without further purification

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

Procedure: (2-amino-4-chlorophenyl)methanol (10.08 g, 64.0 mmol) was suspended in chloroform (250 mL) and treated with manganese dioxide (15.87 g, 183 mmol). The mixture was stirred vigorously and heated at reflux. The oxidation was followed by TLC and found to be complete after 1 hour. The suspension was filtered through a pad of CELITE™ and evaporated to dryness under reduced pressure. Further drying under high vacuum gave a dark red solid which was used in the next step without further purification. heated at reflux The suspension was filtered through a pad of CELITE™ evaporated to dryness under reduced pressure Further drying under high vacuum gave a dark red solid which was used in the next step without further purification

Conditions: temp:170.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 500 mL round bottom flask, the uniform mixture of 2-amino-4-chlorobenzaldehyde (16 g, 103.2 2 mmol) and urea (123.8 g, 2063 mmol) was heated at 170° C. with vigorous stirring for 2 h. On completion of reaction, the reaction mixture was cooled to rt and diluted with ice-cold water. The solid that formed was collected by filtration and washed with ice-cold water. The solid was dried under reduced pressure to give crude 7-chloroquinazolin-2-ol as a yellow solid. Yield: 19 g. LCMS (ESI, m/z): 181 (M+1)+ On completion of reaction the reaction mixture was cooled to rt diluted with ice-cold water The solid that formed was collected by filtration washed with ice-cold water The solid was dried under reduced pressure

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

Procedure: In a 2 L 3-neck round bottom flask, the stirred solution of (2-amino-4-chlorophenyl)methanol 2 (32 g, 203.82 mmol) in DCM (765 mL), manganese (IV) oxide (150 g, 1.724 mol) was added at rt. The resulting reaction mixture was stirred at rt under argon atmosphere for 40 h. On completion of reaction the reaction mixture was filtered through CELITE™ pad and solid residue was washed thoroughly with DCM (1000 mL). The combined filtrate was concentrated under reduced pressure to give 2-amino-4-chlorobenzaldehyde as orange solid. The resulting reaction mixture On completion of reaction the reaction mixture was filtered through CELITE™ pad and solid residue was washed thoroughly with DCM (1000 mL) The combined filtrate was concentrated under reduced pressure