2-fluoro-6-methoxybenzoyl chloride

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium ethylmalonate (2.1 g, 12 mmol, 2.1 equiv) was suspended in acetonitrile (20 mL), cooled to 5° C. and treated with successively with triethylamine (2.6 mL, 18 mmol, 3.2 equiv) and magnesium(II) chloride (1.4 g, 14 mmol, 2.5 equiv). The ice bath was removed and the mixture was warmed and stirred at ambient temperature for 2.5 hours. An acetonitrile solution (5 mL) of 2-fluoro-6-(methyloxy)benzoyl chloride (1.1 g, 5.8 mmol) was added and the mixture was stirred for 2 hours at ambient temperature. The mixture was concentrated in vacuo and the residue was suspended in toluene (50 mL), cooled to 0° C. and treated with hydrochloric acid (20 mL, 12 N aqueous) with vigorous stirring. The ice bath was removed after 10 minutes and the mixture was warmed to ambient temperature and stirred for an additional 15 minutes. The mixture was poured into water (50 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 1:1; hexanes:ethyl acetate), providing the titled compound. The ice bath was removed the mixture was warmed the mixture was stirred for 2 hours at ambient temperature The mixture was concentrated in vacuo cooled to 0° C. treated with hydrochloric acid (20 mL, 12 N aqueous) with vigorous stirring The ice bath was removed after 10 minutes the mixture was warmed to ambient temperature stirred for an additional 15 minutes The mixture was poured into water (50 mL) extracted with ethyl acetate (3×75 mL) The combined organic extracts were dried with sodium sulfate filtered concentrated in vacuo The residue was purified by silica gel gradient chromatography (100:0 to 1:1; hexanes:ethyl acetate)

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

Procedure: By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and 2-fluoro-6-methoxybenzoyl chloride, the title compound (yield 78%) was obtained in the same manner as that of Example 1, (4).

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium ethylmalonate (2.1 g, 12 mmol, 2.1 equiv) was suspended in acetonitrile (20 mL), cooled to 5° C. and treated with successively with triethylamine (2.6 mL, 18 mmol, 3.2 equiv) and magnesium(II) chloride (1.4 g, 14 mmol, 2.5 equiv). The ice bath was removed and the mixture was warmed and stirred at ambient temperature for 2.5 hours. An acetonitrile solution (5 mL) of 2-fluoro-6-(methyloxy)benzoyl chloride (1.1 g, 5.8 mmol) was added and the mixture was stirred for 2 hours at ambient temperature. The mixture was concentrated in vacuo and the residue was suspended in toluene (50 mL), cooled to 0° C. and treated with hydrochloric acid (20 mL, 12 N aqueous) with vigorous stirring. The ice bath was removed after 10 minutes and the mixture was warmed to ambient temperature and stirred for an additional 15 minutes. The mixture was poured into water (50 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 1:1; hexanes:ethyl acetate), providing the titled compound. The ice bath was removed the mixture was warmed the mixture was stirred for 2 hours at ambient temperature The mixture was concentrated in vacuo cooled to 0° C. treated with hydrochloric acid (20 mL, 12 N aqueous) with vigorous stirring The ice bath was removed after 10 minutes the mixture was warmed to ambient temperature stirred for an additional 15 minutes The mixture was poured into water (50 mL) extracted with ethyl acetate (3×75 mL) The combined organic extracts were dried with sodium sulfate filtered concentrated in vacuo The residue was purified by silica gel gradient chromatography (100:0 to 1:1; hexanes:ethyl acetate)

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium ethylmalonate (2.1 g, 12 mmol, 2.1 equiv) was suspended in acetonitrile (20 mL), cooled to 5° C. and treated with successively with triethylamine (2.6 mL, 18 mmol, 3.2 equiv) and magnesium(II) chloride (1.4 g, 14 mmol, 2.5 equiv). The ice bath was removed and the mixture was warmed and stirred at ambient temperature for 2.5 hours. An acetonitrile solution (5 mL) of 2-fluoro-6-(methyloxy)benzoyl chloride (1.1 g, 5.8 mmol) was added and the mixture was stirred for 2 hours at ambient temperature. The mixture was concentrated in vacuo and the residue was suspended in toluene (50 mL), cooled to 0° C. and treated with hydrochloric acid (20 mL, 12 N aqueous) with vigorous stirring. The ice bath was removed after 10 minutes and the mixture was warmed to ambient temperature and stirred for an additional 15 minutes. The mixture was poured into water (50 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 1:1; hexanes:ethyl acetate), providing the titled compound. The ice bath was removed the mixture was warmed the mixture was stirred for 2 hours at ambient temperature The mixture was concentrated in vacuo cooled to 0° C. treated with hydrochloric acid (20 mL, 12 N aqueous) with vigorous stirring The ice bath was removed after 10 minutes the mixture was warmed to ambient temperature stirred for an additional 15 minutes The mixture was poured into water (50 mL) extracted with ethyl acetate (3×75 mL) The combined organic extracts were dried with sodium sulfate filtered concentrated in vacuo The residue was purified by silica gel gradient chromatography (100:0 to 1:1; hexanes:ethyl acetate)

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

Procedure: By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and 2-fluoro-6-methoxybenzoyl chloride, the title compound (yield 78%) was obtained in the same manner as that of Example 1, (4).

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium ethylmalonate (2.1 g, 12 mmol, 2.1 equiv) was suspended in acetonitrile (20 mL), cooled to 5° C. and treated with successively with triethylamine (2.6 mL, 18 mmol, 3.2 equiv) and magnesium(II) chloride (1.4 g, 14 mmol, 2.5 equiv). The ice bath was removed and the mixture was warmed and stirred at ambient temperature for 2.5 hours. An acetonitrile solution (5 mL) of 2-fluoro-6-(methyloxy)benzoyl chloride (1.1 g, 5.8 mmol) was added and the mixture was stirred for 2 hours at ambient temperature. The mixture was concentrated in vacuo and the residue was suspended in toluene (50 mL), cooled to 0° C. and treated with hydrochloric acid (20 mL, 12 N aqueous) with vigorous stirring. The ice bath was removed after 10 minutes and the mixture was warmed to ambient temperature and stirred for an additional 15 minutes. The mixture was poured into water (50 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 1:1; hexanes:ethyl acetate), providing the titled compound. The ice bath was removed the mixture was warmed the mixture was stirred for 2 hours at ambient temperature The mixture was concentrated in vacuo cooled to 0° C. treated with hydrochloric acid (20 mL, 12 N aqueous) with vigorous stirring The ice bath was removed after 10 minutes the mixture was warmed to ambient temperature stirred for an additional 15 minutes The mixture was poured into water (50 mL) extracted with ethyl acetate (3×75 mL) The combined organic extracts were dried with sodium sulfate filtered concentrated in vacuo The residue was purified by silica gel gradient chromatography (100:0 to 1:1; hexanes:ethyl acetate)