Methyl 2-amino-4-iodobenzoate

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodobenzoic acid methyl ester. To a solution of methyl 2-amino-4-iodobenzoate (EXAMPLE 4, Step B, 1.6 g, 5.8 mmol) in DCM (45 mL) at room temperature was added 4-chlorosulfonyl-2,1,3-benzothiadiazole (1.76 g, 7.51 mmol), and pyridine (0.93 mL, 11 mmol). The mixture was stirred at room temperature overnight, poured into 1 N HCl (200 mL), and extracted with DCM (2×100 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by flash chromatography (hexanes/EtOAc) to afford the title sulfonamide as a tan solid (1.87 g, 68%). MS (ESI): calculated for C14H10IN3O4S2, 474.9; m/z found, 474 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.26 (br s, 1H), 8.40 (dd, J=7.0, 1.0 Hz, 1H), 8.24 (dd, J=8.8, 1.0 Hz, 1H), 8.12 (d, J=1.5 Hz, 1H), 7.74 (dd, J=8.8, 7.0 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.32 (dd, J=8.5, 1.5 Hz, 1H), 3.91 (s, 3H). B. 2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodobenzoic acid. To a stirred suspension of 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodobenzoic acid methyl ester (1.87 g, 3.93 mmol) in THF (20 mL) at room temperature was added LiOH (2 M in H2O, 18 mL). The resulting orange mixture was stirred overnight at room temperature then poured into 0.5 M HCl (150 mL) causing precipitation of the desired benzoic acid. After stirring the mixture for several minutes to complete precipitation, the product was collected by suction filtration and air-dried to afford the acid as a tan solid (1.24 g, 69%). 1H NMR (500 MHz, CDCl3): 11.03 (br s, 1H), 8.34 (dd, J=7.2, 1.1 Hz, 1H), 8.19 (dd, J=8.8, 1.1 Hz, 1H), 8.09 (d, J=1.6 Hz, 1H), 7.69 (dd, J=8.8, 7.2 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.30 (dd, J=8.5, 1.6 Hz, 1H), (COOH not observed). C. Benzo[1,2,5]thiadiazole-4-sulfonic acid [5-iodo-2-(morpholine-4-carbonyl)-phenyl]-amide. The title compound was prepared from the HATU-mediated coupling of 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodobenzoic acid and morpholine and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C17H15IN4O4S2, 530.0; m/z found, 531 [M+H]+, 553 [M+Na]+. HPLC (reverse phase): RT═8.50 min. 1H NMR (400 MHz, CDCl3): (rotameric broadening) 8.91 (s, 1H), 8.31 (dd, J=7.0, 0.9 Hz, 1H), 8.27 (dd, J=8.8, 0.9 Hz, 1H), 7.97 (d, J=1.5 Hz, 1H), 7.74 (dd, J=8.8, 7.0 Hz, 1H), 7.41 (dd, J=8.1, 1.6 Hz, 1H), 6.78 (d, J=8.1 Hz, 1H), 3.75-3.05 (br m, 8H). D. Quinoxaline-5-sulfonic acid [5-iodo-2-(morpholine-4-carbonyl)-phenyl]-amide. Zinc powder (1.1 g, 19 mmol) was added to a mixture of benzo[1,2,5]thiadiazole-4-sulfonic acid [5-iodo-2-(morpholine-4-carbonyl)-phenyl]amide (1.0 g, 1.9 mmol) and AcOH (20 mL), and the resulting mixture was heated at 50° C. for 1 h with vigorous stirring. The mixture was filtered through a pad of diatomaceous earth, rinsing well with methanol, and the clear solution was concentrated to a yellow solid. This material was dissolved in methanol (20 mL) and added to a mixture of glyoxal sodium bisulfite adduct (1.5 g, 5.7 mmol), AcOH (0.85 mL), NaOAc (0.16 g, 2.0 mmol), and H2O (6 mL). The reaction was allowed to proceed under reflux for 3 h, then was diluted with EtOAc (200 mL) and filtered through a pad of diatomaceous earth, rinsing well with EtOAc. The filtrate was washed with H2O (100 mL) and brine (100 mL), then was dried and concentrated to a yellow solid. Purification by flash chromatography gave the titled compound as a light yellow solid (0.69 g, 70%). extracted with DCM (2×100 mL) The combined organic layers were dried (Na2SO4) concentrated in vacuo The crude residue was purified by flash chromatography (hexanes/EtOAc)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Iodo-2-nitrobenzoic acid. 4-Iodo-2-nitrotoluene (9.0 g, 34 mmol), KMnO4 (22.0 g, 139 mmol), and H2O (340 mL) were heated at reflux for 5 h. The resulting brown suspension was filtered through a pad of diatomaceous earth, and the filter cake was washed with H2O. The basic filtrate was acidified with concentrated HCl causing precipitation of the desired acid. The solid was collected by suction filtration and dried, affording 1.86 g of the acid. The mother liquor was extracted with DCM (3×200 mL), and the combined extracts were dried (Na2SO4) and concentrated in vacuo to afford an additional 0.16 g of the benzoic acid (total 2.02 g, 20%). 1H NMR (400 MHz, CD3OD): 8.13 (d, J=1.6 Hz, 1H), 8.01 (dd, J=8.1, 1.6 Hz, 1H), 7.50 (d, J=8.1 Hz, 1H). B. Methyl 2-amino-4-iodobenzoate. To a stirred solution of 4-iodo-2-nitrobenzoic acid (2.3 g, 7.9 mmol) in DMF (30 mL) at 0° C. was added DBU (2.4 mL, 16 mmol) followed by iodomethane (1.5 mL, 24 mmol). The reaction mixture was stirred 15 min at 0° C., then was allowed to warm to room temperature and was stirred overnight. The mixture was poured into H2O and extracted with EtOAc (2×). The combined organic extracts were washed with H2O (2×), dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc) to afford methyl 4-iodo-2-nitrobenzoate as a pale yellow solid (2.30 g, 95%). To a solution of the nitrobenzoate (2.3 g, 7.4 mmol) in 1:1 EtOAc/DCM (10 mL) at room temperature was added SnCl2.2H2O (8.3 g, 37 mmol). The reaction mixture was allowed to stir overnight. The solvents were evaporated in vacuo, and the residue was partitioned between satd. aq. NaHCO3 and DCM. The layers were separated, and the aqueous layer was further extracted with DCM (2×). The combined organic layers were dried (MgSO4) and concentrated in vacuo to provide the pure aminobenzoate as a yellow solid (1.87 g, 91%). 1H NMR (500 MHz, CDCl3): 7.52 (d, J=8.5 Hz, 1H), 7.07 (d, J=1.6 Hz, 1H), 6.96 (dd, J=8.5, 1.6 Hz, 1H), 5.72 (br s, 2H), 3.86 (s, 3H). C. 4-Iodo-2-(Quinoxaline-5-sulfonylamino)benzoic acid methyl ester. A solution of methyl 2-amino-4-iodobenzoate (1.2 g, 4.4 mmol), quinoxaline-5-sulfonyl chloride (1.2 g, 5.3 mmol), pyridine (1.7 mL, 22 mmol) and DCM (25 mL) was maintained at 23° C. for 24 h. The reaction mixture was diluted with DCM (200 mL) and washed with satd. aq. NaHCO3, then dried and concentrated to a tan solid. This residue was chromatographed (0 to 100% EtOAc/CH2Cl2) to afford the sulfonamide as a light yellow solid (1.6 g, 77%). MS (ESI): calculated for C16H12IN3O4S, 469.0; m/z found, 470 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 11.10 (s, 1H), 9.07 (d, J=1.8 Hz, 1H), 9.01 (d, J=1.8 Hz, 1H), 8.60 (dd, J=7.4, 1.3 Hz, 1H), 8.40 (dd, J=8.5, 1.3 Hz, 1H), 8.04 (dd, J=7.5, 1.0 Hz, 1H), 7.99 (d, J=1.6 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.37 (dd, J=8.3, 1.6 Hz, 1H), 3.88 (s, 3H). D. 4-Iodo-2-(Quinoxaline-5-sulfonylamino)benzoic acid. A solution of LiOH·H2O (0.16 g, 3.9 mmol) in H2O (5 mL) was added to a solution of 4-iodo-2-(quinoxaline-5-sulfonylamino)benzoic acid methyl ester (0.37 mg, 0.78 mmol) and THF (10 mL), and the mixture was rapidly stirred for 16 h. The mixture was concentrated to a volume of 5 mL, then was adjusted to pH 5 with 1 M HCl. The resulting precipitate was collected by filtration to provide the acid as a white solid (0.35 g, 99%). MS (ESI): calculated for C15H10IN3O4S, 455.0; m/z found, 456 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 14.0 (br s, 1H), 11.6 (s, 1H), 9.10 (d, J=1.5 Hz, 1H), 9.97 (d, J=1.5 Hz, 1H), 8.60 (d, J=7.4 Hz, 1H), 8.42 (d, J=8.4 Hz, 1H), 8.06 (t, J=7.5 Hz, 1H), 7.95 (d, J=1.2 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.37 (dd, J=8.3, 1.2 Hz, 1H). E. Quinoxaline-5-sulfonic acid [5-iodo-2-(piperidine-1-carbonyl)-phenyl]-amide washed with satd aq. NaHCO3, then dried concentrated to a tan solid This residue was chromatographed (0 to 100% EtOAc/CH2Cl2)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Iodo-2-nitrobenzoic acid. 4-Iodo-2-nitrotoluene (9.0 g, 34 mmol), KMnO4 (22.0 g, 139 mmol), and H2O (340 mL) were heated at reflux for 5 h. The resulting brown suspension was filtered through a pad of diatomaceous earth, and the filter cake was washed with H2O. The basic filtrate was acidified with concentrated HCl causing precipitation of the desired acid. The solid was collected by suction filtration and dried, affording 1.86 g of the acid. The mother liquor was extracted with DCM (3×200 mL), and the combined extracts were dried (Na2SO4) and concentrated in vacuo to afford an additional 0.16 g of the benzoic acid (total 2.02 g, 20%). 1H NMR (400 MHz, CD3OD): 8.13 (d, J=1.6 Hz, 1H), 8.01 (dd, J=8.1, 1.6 Hz, 1H), 7.50 (d, J=8.1 Hz, 1H). B. Methyl 2-amino-4-iodobenzoate. To a stirred solution of 4-iodo-2-nitrobenzoic acid (2.3 g, 7.9 mmol) in DMF (30 mL) at 0° C. was added DBU (2.4 mL, 16 mmol) followed by iodomethane (1.5 mL, 24 mmol). The reaction mixture was stirred 15 min at 0° C., then was allowed to warm to room temperature and was stirred overnight. The mixture was poured into H2O and extracted with EtOAc (2×). The combined organic extracts were washed with H2O (2×), dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc) to afford methyl 4-iodo-2-nitrobenzoate as a pale yellow solid (2.30 g, 95%). To a solution of the nitrobenzoate (2.3 g, 7.4 mmol) in 1:1 EtOAc/DCM (10 mL) at room temperature was added SnCl2.2H2O (8.3 g, 37 mmol). The reaction mixture was allowed to stir overnight. The solvents were evaporated in vacuo, and the residue was partitioned between satd. aq. NaHCO3 and DCM. The layers were separated, and the aqueous layer was further extracted with DCM (2×). The combined organic layers were dried (MgSO4) and concentrated in vacuo to provide the pure aminobenzoate as a yellow solid (1.87 g, 91%). 1H NMR (500 MHz, CDCl3): 7.52 (d, J=8.5 Hz, 1H), 7.07 (d, J=1.6 Hz, 1H), 6.96 (dd, J=8.5, 1.6 Hz, 1H), 5.72 (br s, 2H), 3.86 (s, 3H). C. 4-Iodo-2-(Quinoxaline-5-sulfonylamino)benzoic acid methyl ester. A solution of methyl 2-amino-4-iodobenzoate (1.2 g, 4.4 mmol), quinoxaline-5-sulfonyl chloride (1.2 g, 5.3 mmol), pyridine (1.7 mL, 22 mmol) and DCM (25 mL) was maintained at 23° C. for 24 h. The reaction mixture was diluted with DCM (200 mL) and washed with satd. aq. NaHCO3, then dried and concentrated to a tan solid. This residue was chromatographed (0 to 100% EtOAc/CH2Cl2) to afford the sulfonamide as a light yellow solid (1.6 g, 77%). MS (ESI): calculated for C16H12IN3O4S, 469.0; m/z found, 470 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 11.10 (s, 1H), 9.07 (d, J=1.8 Hz, 1H), 9.01 (d, J=1.8 Hz, 1H), 8.60 (dd, J=7.4, 1.3 Hz, 1H), 8.40 (dd, J=8.5, 1.3 Hz, 1H), 8.04 (dd, J=7.5, 1.0 Hz, 1H), 7.99 (d, J=1.6 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.37 (dd, J=8.3, 1.6 Hz, 1H), 3.88 (s, 3H). D. 4-Iodo-2-(Quinoxaline-5-sulfonylamino)benzoic acid. A solution of LiOH·H2O (0.16 g, 3.9 mmol) in H2O (5 mL) was added to a solution of 4-iodo-2-(quinoxaline-5-sulfonylamino)benzoic acid methyl ester (0.37 mg, 0.78 mmol) and THF (10 mL), and the mixture was rapidly stirred for 16 h. The mixture was concentrated to a volume of 5 mL, then was adjusted to pH 5 with 1 M HCl. The resulting precipitate was collected by filtration to provide the acid as a white solid (0.35 g, 99%). MS (ESI): calculated for C15H10IN3O4S, 455.0; m/z found, 456 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 14.0 (br s, 1H), 11.6 (s, 1H), 9.10 (d, J=1.5 Hz, 1H), 9.97 (d, J=1.5 Hz, 1H), 8.60 (d, J=7.4 Hz, 1H), 8.42 (d, J=8.4 Hz, 1H), 8.06 (t, J=7.5 Hz, 1H), 7.95 (d, J=1.2 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.37 (dd, J=8.3, 1.2 Hz, 1H). E. Quinoxaline-5-sulfonic acid [5-iodo-2-(piperidine-1-carbonyl)-phenyl]-amide The mother liquor was extracted with DCM (3×200 mL) the combined extracts were dried (Na2SO4) concentrated in vacuo to afford an additional 0.16 g of the benzoic acid (total 2.02 g, 20%) to warm to room temperature was stirred overnight extracted with EtOAc (2×) The combined organic extracts were washed with H2O (2×) dried (MgSO4) concentrated in vacuo The residue was purified by flash chromatography (hexanes/EtOAc)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Iodo-2-nitrobenzoic acid. 4-Iodo-2-nitrotoluene (9.0 g, 34 mmol), KMnO4 (22.0 g, 139 mmol), and H2O (340 mL) were heated at reflux for 5 h. The resulting brown suspension was filtered through a pad of diatomaceous earth, and the filter cake was washed with H2O. The basic filtrate was acidified with concentrated HCl causing precipitation of the desired acid. The solid was collected by suction filtration and dried, affording 1.86 g of the acid. The mother liquor was extracted with DCM (3×200 mL), and the combined extracts were dried (Na2SO4) and concentrated in vacuo to afford an additional 0.16 g of the benzoic acid (total 2.02 g, 20%). 1H NMR (400 MHz, CD3OD): 8.13 (d, J=1.6 Hz, 1H), 8.01 (dd, J=8.1, 1.6 Hz, 1H), 7.50 (d, J=8.1 Hz, 1H). B. Methyl 2-amino-4-iodobenzoate. To a stirred solution of 4-iodo-2-nitrobenzoic acid (2.3 g, 7.9 mmol) in DMF (30 mL) at 0° C. was added DBU (2.4 mL, 16 mmol) followed by iodomethane (1.5 mL, 24 mmol). The reaction mixture was stirred 15 min at 0° C., then was allowed to warm to room temperature and was stirred overnight. The mixture was poured into H2O and extracted with EtOAc (2×). The combined organic extracts were washed with H2O (2×), dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc) to afford methyl 4-iodo-2-nitrobenzoate as a pale yellow solid (2.30 g, 95%). To a solution of the nitrobenzoate (2.3 g, 7.4 mmol) in 1:1 EtOAc/DCM (10 mL) at room temperature was added SnCl2.2H2O (8.3 g, 37 mmol). The reaction mixture was allowed to stir overnight. The solvents were evaporated in vacuo, and the residue was partitioned between satd. aq. NaHCO3 and DCM. The layers were separated, and the aqueous layer was further extracted with DCM (2×). The combined organic layers were dried (MgSO4) and concentrated in vacuo to provide the pure aminobenzoate as a yellow solid (1.87 g, 91%). 1H NMR (500 MHz, CDCl3): 7.52 (d, J=8.5 Hz, 1H), 7.07 (d, J=1.6 Hz, 1H), 6.96 (dd, J=8.5, 1.6 Hz, 1H), 5.72 (br s, 2H), 3.86 (s, 3H). C. 4-Iodo-2-(Quinoxaline-5-sulfonylamino)benzoic acid methyl ester. A solution of methyl 2-amino-4-iodobenzoate (1.2 g, 4.4 mmol), quinoxaline-5-sulfonyl chloride (1.2 g, 5.3 mmol), pyridine (1.7 mL, 22 mmol) and DCM (25 mL) was maintained at 23° C. for 24 h. The reaction mixture was diluted with DCM (200 mL) and washed with satd. aq. NaHCO3, then dried and concentrated to a tan solid. This residue was chromatographed (0 to 100% EtOAc/CH2Cl2) to afford the sulfonamide as a light yellow solid (1.6 g, 77%). MS (ESI): calculated for C16H12IN3O4S, 469.0; m/z found, 470 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 11.10 (s, 1H), 9.07 (d, J=1.8 Hz, 1H), 9.01 (d, J=1.8 Hz, 1H), 8.60 (dd, J=7.4, 1.3 Hz, 1H), 8.40 (dd, J=8.5, 1.3 Hz, 1H), 8.04 (dd, J=7.5, 1.0 Hz, 1H), 7.99 (d, J=1.6 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.37 (dd, J=8.3, 1.6 Hz, 1H), 3.88 (s, 3H). D. 4-Iodo-2-(Quinoxaline-5-sulfonylamino)benzoic acid. A solution of LiOH·H2O (0.16 g, 3.9 mmol) in H2O (5 mL) was added to a solution of 4-iodo-2-(quinoxaline-5-sulfonylamino)benzoic acid methyl ester (0.37 mg, 0.78 mmol) and THF (10 mL), and the mixture was rapidly stirred for 16 h. The mixture was concentrated to a volume of 5 mL, then was adjusted to pH 5 with 1 M HCl. The resulting precipitate was collected by filtration to provide the acid as a white solid (0.35 g, 99%). MS (ESI): calculated for C15H10IN3O4S, 455.0; m/z found, 456 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 14.0 (br s, 1H), 11.6 (s, 1H), 9.10 (d, J=1.5 Hz, 1H), 9.97 (d, J=1.5 Hz, 1H), 8.60 (d, J=7.4 Hz, 1H), 8.42 (d, J=8.4 Hz, 1H), 8.06 (t, J=7.5 Hz, 1H), 7.95 (d, J=1.2 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.37 (dd, J=8.3, 1.2 Hz, 1H). E. Quinoxaline-5-sulfonic acid [5-iodo-2-(piperidine-1-carbonyl)-phenyl]-amide The mother liquor was extracted with DCM (3×200 mL) the combined extracts were dried (Na2SO4) concentrated in vacuo to afford an additional 0.16 g of the benzoic acid (total 2.02 g, 20%) to warm to room temperature was stirred overnight extracted with EtOAc (2×) The combined organic extracts were washed with H2O (2×) dried (MgSO4) concentrated in vacuo The residue was purified by flash chromatography (hexanes/EtOAc)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl 2-amino-4-iodobenzoate. To a stirred solution of 4-iodo-2-nitrobenzoic acid (2.3 g, 7.9 mmol) in DMF (30 mL) at 0° C. was added DBU (2.4 mL, 16 mmol) followed by iodomethane (1.5 mL, 24 mmol). The reaction mixture was stirred 15 min at 0° C., then was allowed to warm to room temperature and was stirred overnight. The mixture was poured into H2O and extracted with EtOAc (2×). The combined organic extracts were washed with H2O (2×), dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc) to afford methyl 4-iodo-2-nitrobenzoate as a pale yellow solid (2.30 g, 95%). To a solution of the nitrobenzoate (2.3 g, 7.4 mmol) in 1:1 EtOAc/DCM (10 mL) at room temperature was added SnCl2.2H2O (8.3 g, 37 mmol). The reaction mixture was allowed to stir overnight. The solvents were evaporated in vacuo, and the residue was partitioned between satd. aq. NaHCO3 and DCM. The layers were separated, and the aqueous layer was further extracted with DCM (2×). The combined organic layers were dried (MgSO4) and concentrated in vacuo to provide the pure aminobenzoate as a yellow solid (1.87 g, 91%). 1H NMR (500 MHz, CDCl3): 7.52 (d, J=8.5 Hz, 1H), 7.07 (d, J=1.6 Hz, 1H), 6.96 (dd, J=8.5, 1.6 Hz, 1H), 5.72 (br s, 2H), 3.86 (s, 3H). to warm to room temperature was stirred overnight extracted with EtOAc (2×) The combined organic extracts were washed with H2O (2×) dried (MgSO4) concentrated in vacuo The residue was purified by flash chromatography (hexanes/EtOAc)

反応条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 2-acetylamino-4-iodo-benzoic acid (13.8 g, 45.3 mmol) in 200 mL of dry methanol was added SOCl2 (32.7 mL, 453 mmol) dropwise at 0° C. The reaction mixture was then heated at 65° C. for 2 h. The reaction was then cooled to 0° C., an additional portion of SOCl2 (10 mL, 137 mmol) was added, and the reaction was heated at 65° C. for 2 h. The reaction was then cooled to 0° C., a final portion of SOCl2 (10 mL, 137 mmol) was added, and the reaction was heated at 65° C. for 48 h. The reaction was then cooled to 22° C. and concentrated in vacuo. The resulting residue was diluted with H2O and extracted with 3×150 mL CH2Cl2. The combined organic fractions were washed with brine and dried over Na2SO4 to give i-b (11.7 g, 93%): MS m/z=278 (M+H). The reaction was then cooled to 0° C. the reaction was heated at 65° C. for 2 h The reaction was then cooled to 0° C. the reaction was heated at 65° C. for 48 h The reaction was then cooled to 22° C. concentrated in vacuo The resulting residue was diluted with H2O extracted with 3×150 mL CH2Cl2 The combined organic fractions were washed with brine dried over Na2SO4 to give i-b (11.7 g, 93%)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl 2-amino-4-iodobenzoate. To a stirred solution of 4-iodo-2-nitrobenzoic acid (2.3 g, 7.9 mmol) in DMF (30 mL) at 0° C. was added DBU (2.4 mL, 16 mmol) followed by iodomethane (1.5 mL, 24 mmol). The reaction mixture was stirred 15 min at 0° C., then was allowed to warm to room temperature and was stirred overnight. The mixture was poured into H2O and extracted with EtOAc (2×). The combined organic extracts were washed with H2O (2×), dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc) to afford methyl 4-iodo-2-nitrobenzoate as a pale yellow solid (2.30 g, 95%). To a solution of the nitrobenzoate (2.3 g, 7.4 mmol) in 1:1 EtOAc/DCM (10 mL) at room temperature was added SnCl2.2H2O (8.3 g, 37 mmol). The reaction mixture was allowed to stir overnight. The solvents were evaporated in vacuo, and the residue was partitioned between satd. aq. NaHCO3 and DCM. The layers were separated, and the aqueous layer was further extracted with DCM (2×). The combined organic layers were dried (MgSO4) and concentrated in vacuo to provide the pure aminobenzoate as a yellow solid (1.87 g, 91%). 1H NMR (500 MHz, CDCl3): 7.52 (d, J=8.5 Hz, 1H), 7.07 (d, J=1.6 Hz, 1H), 6.96 (dd, J=8.5, 1.6 Hz, 1H), 5.72 (br s, 2H), 3.86 (s, 3H). to warm to room temperature was stirred overnight extracted with EtOAc (2×) The combined organic extracts were washed with H2O (2×) dried (MgSO4) concentrated in vacuo The residue was purified by flash chromatography (hexanes/EtOAc)

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of sodium hydroxide (0.048 g, 1.2 mM) in methanol (4.5 mL) was added 7-iodo-2H-3,1-benzoxazine-2,4(1H)-dione (2.6 g, 9.0 mM). The mixture was heated at 60° C. for 7 hr and the resulting solution was cooled, poured into water and extracted with ethyl acetate. The combined extracts were washed once with dilute sodium hydroxide, dried (MgSO4), filtered and concentrated to leave the title compound (2.0 g, 80%) as a brown oil which slowly crystallized; MS(CI): 278 (M+H). the resulting solution was cooled extracted with ethyl acetate The combined extracts were washed once with dilute sodium hydroxide dried (MgSO4) filtered concentrated

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl 2-amino-4-iodobenzoate. To a stirred solution of 4-iodo-2-nitrobenzoic acid (2.3 g, 7.9 mmol) in DMF (30 mL) at 0° C. was added DBU (2.4 mL, 16 mmol) followed by iodomethane (1.5 mL, 24 mmol). The reaction mixture was stirred 15 min at 0° C., then was allowed to warm to room temperature and was stirred overnight. The mixture was poured into H2O and extracted with EtOAc (2×). The combined organic extracts were washed with H2O (2×), dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc) to afford methyl 4-iodo-2-nitrobenzoate as a pale yellow solid (2.30 g, 95%). To a solution of the nitrobenzoate (2.3 g, 7.4 mmol) in 1:1 EtOAc/DCM (10 mL) at room temperature was added SnCl2.2H2O (8.3 g, 37 mmol). The reaction mixture was allowed to stir overnight. The solvents were evaporated in vacuo, and the residue was partitioned between satd. aq. NaHCO3 and DCM. The layers were separated, and the aqueous layer was further extracted with DCM (2×). The combined organic layers were dried (MgSO4) and concentrated in vacuo to provide the pure aminobenzoate as a yellow solid (1.87 g, 91%). 1H NMR (500 MHz, CDCl3): 7.52 (d, J=8.5 Hz, 1H), 7.07 (d, J=1.6 Hz, 1H), 6.96 (dd, J=8.5, 1.6 Hz, 1H), 5.72 (br s, 2H), 3.86 (s, 3H). to warm to room temperature was stirred overnight extracted with EtOAc (2×) The combined organic extracts were washed with H2O (2×) dried (MgSO4) concentrated in vacuo The residue was purified by flash chromatography (hexanes/EtOAc)

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of sodium hydroxide (0.048 g, 1.2 mM) in methanol (4.5 mL) was added 7-iodo-2H-3,1-benzoxazine-2,4(1H)-dione (2.6 g, 9.0 mM). The mixture was heated at 60° C. for 7 hr and the resulting solution was cooled, poured into water and extracted with ethyl acetate. The combined extracts were washed once with dilute sodium hydroxide, dried (MgSO4), filtered and concentrated to leave the title compound (2.0 g, 80%) as a brown oil which slowly crystallized; MS(CI): 278 (M+H). the resulting solution was cooled extracted with ethyl acetate The combined extracts were washed once with dilute sodium hydroxide dried (MgSO4) filtered concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of methyl 2-amino-4-iodobenzoate (17 g, 61.3 mmol) in DCM (200 mL), was added DIEA (10.6 mL, 64.4 mmol) and DMAP (37.5 mg, 0.31 mmol). To this solution was added 3-(carbomethoxy)propionyl chloride (8.3 mL, 67.4 mmol) dropwise, and the reaction mixture was allowed to stir at rt for 2 h. To the reaction mixture was then added H2O (80 mL) and the mixture was allowed to stir for 30 min. The organic solution was separated and the aqueous solution was extracted with DCM (2×100 mL). The organic solutions were combined, washed with H2O (2×100 mL) and brine (1×100 mL), dried over Na2SO4, filtered and concentrated to give methyl 4-iodo-2-[(4-methoxy-4-oxobutanoyl)amino]benzoate (24.6 g, 99%). to stir for 30 min The organic solution was separated the aqueous solution was extracted with DCM (2×100 mL) washed with H2O (2×100 mL) and brine (1×100 mL) dried over Na2SO4 filtered concentrated

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of sodium hydroxide (0.048 g, 1.2 mM) in methanol (4.5 mL) was added 7-iodo-2H-3,1-benzoxazine-2,4(1H)-dione (2.6 g, 9.0 mM). The mixture was heated at 60° C. for 7 hr and the resulting solution was cooled, poured into water and extracted with ethyl acetate. The combined extracts were washed once with dilute sodium hydroxide, dried (MgSO4), filtered and concentrated to leave the title compound (2.0 g, 80%) as a brown oil which slowly crystallized; MS(CI): 278 (M+H). the resulting solution was cooled extracted with ethyl acetate The combined extracts were washed once with dilute sodium hydroxide dried (MgSO4) filtered concentrated