N-(2-chloroethyl)acetamide

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

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: Into a 1-neck round-bottom flask was added 7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.5 g, 2.20 mmol), N-(2-chloro-ethyl)-acetamide (0.45 mL, 4.41 mmol), potassium iodide (92 mg, 0.55 mmol), and potassium carbonate (900 mg, 7 mmol), in N-methylpyrrolidinone (5 mL), and the reaction was heated at 90 overnight. The reaction mixture was next partitioned between water and ethyl acetate, and the layers separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic extracts were washed with water, dried (MgSO4), filtered, and concentrated, and the product was isolated by flash chromatography on SiO2 (MeOH/dichloromethane 0-20%) to give N-[2-(7-Methoxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethyl]-acetamide (100 mg, 15%). 1H-NMR (CDCl3) δ 7.67 (s, 1H), 6.84 (s, 1H), 6.11 (br s, 1H), 3.94 (s, 3H), 3.38 (m, 2H), 2.95 (m, 2H), 2.89 (m, 2H), 2.66 (m, 6H), 2.01 (s, 3H); LC/MS (ESI+): 308.02 (M+H). The reaction mixture was next partitioned between water and ethyl acetate the layers separated The aqueous phase was extracted twice with ethyl acetate the combined organic extracts were washed with water dried (MgSO4) filtered concentrated the product was isolated by flash chromatography on SiO2 (MeOH/dichloromethane 0-20%)

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-(2-chloroethyl)acetamide (1.21 g) in ethyl acetate (10 mL) was added over 10 min to a stirred suspension of phosphorus pentachloride (2.08 g) in ethyl acetate (2 ml) at 0° C. under nitrogen to give a clear pale straw solution. After 45 min. at 0° C. toluene (12 ml) was added, and ethyl 2-(3-aminophenyl)-3-furoate hydrochloride (1.78 g) was added in one portion into the above solution at 0-5° C. The mixture was stirred at 0-5° C. for 10 min. and then allowed to warm up to 20° C. After 2 h formation of the amidine was essentially complete (HPLC ethyl 2-(3-aminophenyl)-3-furoate hydrochloride <2% (220 nm, a/a). The mixture was cooled to 0-5° C., crushed ice (18 g) was added over 20 min. to destroy phosphorus oxychloride. Ammonium hydroxide (28%, 6.49 mL) was added at a rate that the internal temperature was kept below 25° C. (ca. 15 min). After 1 h at 20° C. additional ethyl acetate (12 ml) added to the above mixture, the organic layer was separated, washed with deionized water (2×12 ml), and concentrated under reduced pressure. The residue was dissolved in acetone (5 ml) and ethyl acetate (5 ml), and treated with oxalic acid (0.72 g) at 40° C. for 30 min. After aging at <20° C. for at least 12 h, the precipitate was collected by filtration, washed with acetone (2×0.5 vol), and dried in vacuo at 45-50° C. to yield 1.9 g (73%) of white solid. to give a clear pale straw solution to warm up to 20° C The mixture was cooled to 0-5° C. was added over 20 min. to destroy phosphorus oxychloride Ammonium hydroxide (28%, 6.49 mL) was added at a rate that the internal temperature was kept below 25° C. (ca. 15 min) After 1 h at 20° C. additional ethyl acetate (12 ml) added to the above mixture the organic layer was separated washed with deionized water (2×12 ml) concentrated under reduced pressure The residue was dissolved in acetone (5 ml) ethyl acetate (5 ml), and treated with oxalic acid (0.72 g) at 40° C. for 30 min After aging at <20° C. for at least 12 h the precipitate was collected by filtration washed with acetone (2×0.5 vol) dried in vacuo at 45-50° C.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-(2-chloroethyl)acetamide (0.32 g) in ethyl acetate (5 ml) was added over 10 min. to a stirred suspension of phosphorus pentachloride (0.55 g) in ethyl acetate (2 ml) at 0° C. under nitrogen to give a clear pale straw solution. After 45 min. at 0° C. a solution of methyl 3-(3-aminophenyl)isonicotinate (0.4 g) in dichloromethane (10 ml) was added over 15 min. at 0-5° C. The mixture was stirred at 0° C. for 10 min. and then allowed to warm up to 20° C. After 3 h the mixture was treated with ammonium hydroxide solution (28%, 5 ml) over 10 min. and stirring continued for ca. 1 h. The layers were allowed to separate, the organic layer was collected, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane:methanol:ammonia=100:10:1, v/v/v) to give 0.25 g (48%) of yellow oil. to give a clear pale straw solution to warm up to 20° C stirring continued for ca. 1 h to separate the organic layer was collected dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel chromatography (dichloromethane:methanol:ammonia=100:10:1, v/v/v)

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

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

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-(2-chloroethyl)acetamide (1.21 g) in ethyl acetate (10 mL) was added over 10 min to a stirred suspension of phosphorus pentachloride (2.08 g) in ethyl acetate (2 ml) at 0° C. under nitrogen to give a clear pale straw solution. After 45 min. at 0° C. toluene (12 ml) was added, and ethyl 2-(3-aminophenyl)-3-furoate hydrochloride (1.78 g) was added in one portion into the above solution at 0-5° C. The mixture was stirred at 0-5° C. for 10 min. and then allowed to warm up to 20° C. After 2 h formation of the amidine was essentially complete (HPLC ethyl 2-(3-aminophenyl)-3-furoate hydrochloride <2% (220 nm, a/a). The mixture was cooled to 0-5° C., crushed ice (18 g) was added over 20 min. to destroy phosphorus oxychloride. Ammonium hydroxide (28%, 6.49 mL) was added at a rate that the internal temperature was kept below 25° C. (ca. 15 min). After 1 h at 20° C. additional ethyl acetate (12 ml) added to the above mixture, the organic layer was separated, washed with deionized water (2×12 ml), and concentrated under reduced pressure. The residue was dissolved in acetone (5 ml) and ethyl acetate (5 ml), and treated with oxalic acid (0.72 g) at 40° C. for 30 min. After aging at <20° C. for at least 12 h, the precipitate was collected by filtration, washed with acetone (2×0.5 vol), and dried in vacuo at 45-50° C. to yield 1.9 g (73%) of white solid. to give a clear pale straw solution to warm up to 20° C The mixture was cooled to 0-5° C. was added over 20 min. to destroy phosphorus oxychloride Ammonium hydroxide (28%, 6.49 mL) was added at a rate that the internal temperature was kept below 25° C. (ca. 15 min) After 1 h at 20° C. additional ethyl acetate (12 ml) added to the above mixture the organic layer was separated washed with deionized water (2×12 ml) concentrated under reduced pressure The residue was dissolved in acetone (5 ml) ethyl acetate (5 ml), and treated with oxalic acid (0.72 g) at 40° C. for 30 min After aging at <20° C. for at least 12 h the precipitate was collected by filtration washed with acetone (2×0.5 vol) dried in vacuo at 45-50° C.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-(2-chloroethyl)acetamide (0.32 g) in ethyl acetate (5 ml) was added over 10 min. to a stirred suspension of phosphorus pentachloride (0.55 g) in ethyl acetate (2 ml) at 0° C. under nitrogen to give a clear pale straw solution. After 45 min. at 0° C. a solution of methyl 3-(3-aminophenyl)isonicotinate (0.4 g) in dichloromethane (10 ml) was added over 15 min. at 0-5° C. The mixture was stirred at 0° C. for 10 min. and then allowed to warm up to 20° C. After 3 h the mixture was treated with ammonium hydroxide solution (28%, 5 ml) over 10 min. and stirring continued for ca. 1 h. The layers were allowed to separate, the organic layer was collected, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane:methanol:ammonia=100:10:1, v/v/v) to give 0.25 g (48%) of yellow oil. to give a clear pale straw solution to warm up to 20° C stirring continued for ca. 1 h to separate the organic layer was collected dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel chromatography (dichloromethane:methanol:ammonia=100:10:1, v/v/v)

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-(2-chloroethyl)acetamide (1.21 g) in ethyl acetate (10 mL) was added over 10 min to a stirred suspension of phosphorus pentachloride (2.08 g) in ethyl acetate (2 ml) at 0° C. under nitrogen to give a clear pale straw solution. After 45 min. at 0° C. toluene (12 ml) was added, and ethyl 2-(3-aminophenyl)-3-furoate hydrochloride (1.78 g) was added in one portion into the above solution at 0-5° C. The mixture was stirred at 0-5° C. for 10 min. and then allowed to warm up to 20° C. After 2 h formation of the amidine was essentially complete (HPLC ethyl 2-(3-aminophenyl)-3-furoate hydrochloride <2% @220 nm, a/a). The mixture was cooled to 0-5° C., crushed ice (18 g) was added over 20 min. to destroy phosphorus oxychloride. Ammonium hydroxide (28%, 6.49 mL) was added at a rate that the internal temperature was kept below 25° C. (ca. 15 min). After 1 h at 20° C. additional ethyl acetate (12 ml) added to the above mixture, the organic layer was separated, washed with deionized water (2×12 ml), and concentrated under reduced pressure. The residue was dissolved in acetone (5 ml) and ethyl acetate (5 ml), and treated with oxalic acid (0.72 g) at 40° C. for 30 min. After aging at <20° C. for at least 12 h, the precipitate was collected by filtration, washed with acetone (2×0.5 vol), and dried in vacuo at 45-50° C. to yield 1.9 g (73%) of white solid. to give a clear pale straw solution to warm up to 20° C The mixture was cooled to 0-5° C. was added over 20 min. to destroy phosphorus oxychloride Ammonium hydroxide (28%, 6.49 mL) was added at a rate that the internal temperature was kept below 25° C. (ca. 15 min) After 1 h at 20° C. additional ethyl acetate (12 ml) added to the above mixture the organic layer was separated washed with deionized water (2×12 ml) concentrated under reduced pressure The residue was dissolved in acetone (5 ml) ethyl acetate (5 ml), and treated with oxalic acid (0.72 g) at 40° C. for 30 min After aging at <20° C. for at least 12 h the precipitate was collected by filtration washed with acetone (2×0.5 vol) dried in vacuo at 45-50° C.

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-(2-chloroethyl)acetamide (1.21 g) in ethyl acetate (10 mL) was added over 10 min to a stirred suspension of phosphorus pentachloride (2.08 g) in ethyl acetate (2 ml) at 0° C. under nitrogen to give a clear pale straw solution. After 45 min. at 0° C. toluene (12 ml) was added, and ethyl 2-(3-aminophenyl)-3-furoate hydrochloride (1.78 g) was added in one portion into the above solution at 0-5° C. The mixture was stirred at 0-5° C. for 10 min. and then allowed to warm up to 20° C. After 2 h formation of the amidine was essentially complete (HPLC ethyl 2-(3-aminophenyl)-3-furoate hydrochloride <2% @220 nm, a/a). The mixture was cooled to 0-5° C., crushed ice (18 g) was added over 20 min. to destroy phosphorus oxychloride. Ammonium hydroxide (28%, 6.49 mL) was added at a rate that the internal temperature was kept below 25° C. (ca. 15 min). After 1 h at 20° C. additional ethyl acetate (12 ml) added to the above mixture, the organic layer was separated, washed with deionized water (2×12 ml), and concentrated under reduced pressure. The residue was dissolved in acetone (5 ml) and ethyl acetate (5 ml), and treated with oxalic acid (0.72 g) at 40° C. for 30 min. After aging at <20° C. for at least 12 h, the precipitate was collected by filtration, washed with acetone (2×0.5 vol), and dried in vacuo at 45-50° C. to yield 1.9 g (73%) of white solid. to give a clear pale straw solution to warm up to 20° C The mixture was cooled to 0-5° C. was added over 20 min. to destroy phosphorus oxychloride Ammonium hydroxide (28%, 6.49 mL) was added at a rate that the internal temperature was kept below 25° C. (ca. 15 min) After 1 h at 20° C. additional ethyl acetate (12 ml) added to the above mixture the organic layer was separated washed with deionized water (2×12 ml) concentrated under reduced pressure The residue was dissolved in acetone (5 ml) ethyl acetate (5 ml), and treated with oxalic acid (0.72 g) at 40° C. for 30 min After aging at <20° C. for at least 12 h the precipitate was collected by filtration washed with acetone (2×0.5 vol) dried in vacuo at 45-50° C.