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Stage #1: With hydrazine In ethanol at 85℃; for 15 h; Stage #2: With acetone In ethanol at 2℃; for 2 h;
Intermediate 77 (Stage 2) <n="116"/>4-[4-chlorophenyl]methyl}-1(2H)-phthalazinone(3.pound.)-3-[(4-Chlorophenyl)methyhdene]-2-benzofuran-1 (3H)-one (as prepared, for example, in stage 1) (1 0 eq, corrected for loss on drying) is suspended in EtOH (3 7 vol) and heated to approximately 85 0C at slight reflux A solution of hydrazine hydrate (commercially available, for example, from Aldrich) (1 2 eq) in EtOH (O 63 vol) is added through a dropping funnel over 1 h At the end of the addition, EtOH (0 63 vol) is added through the dropping funnel into the reaction suspension in order to remove traces of hydrazine hydrate The reaction suspension is heated at approximately 85 0C at slight reflux for 14 h It is cooled to approximately 20 0C and a sample is taken to check the conversion (99percent conversion, HPLC) Acetone (0 35 vol) is added to the reaction mixture over 30 mm (exothermic reaction) The quenched suspension is stirred for at least 1 h and is then cooled to approximately 2 0C over 30 mm and stirred at approximately 2 0C for 1 h The product is isolated by filtration through a suction strainer and is washed with cold EtOH (approximately 0-5 0C, 3 x 1 9 vol) The pale brown solid is completely dried on the suction strainer in vacuo under nitrogen The title compound is obtained as a pale brown solid Yield (corrected for 1H NMR assay) 90-95percent1H MMR (400MHz, DMSO-Cf6), δ 4 30 (s, 2H), 7 35 (m, 4H), 7 88 (m, 3H), 8 26 (d, 1 H), 12 62 (s, 1 H)
With sodium acetate In 1-methyl-pyrrolidin-2-one at 200℃; for 48h;
76.1
Intermediate 76 (Stage 1) (3£)-3-[(4-chlorophenyl) methylidene]-2-benzofuran-1(3H)-one4-Chlorophenylacetic acid (commercially available, for example, from Aldrich) (1.00 eq), phthalic anhydride (commercially available, for example, from Aldrich) (1.10 eq) and sodium acetate (0.04 eq) are mixed in NMP (3 vol). The resulting suspension is heated to approximately 200 0C and the resulting brown solution is stirred over 2 days. During the reaction NMP/ water (0.45 vol) is distilled off at ambient pressure. After checking complete conversion (99%, HPLC) the reaction mixture is cooled to approximately 70 0C over 1 h and EtOH (4.5 vol) is added over 1 h at approximately 70 0C. The resulting brown solution is cooled to approximately 50 0C over 1.5 h during which it turns into a brown suspension. At approximately 50 0C, EtOH (3.8 vol) is added over 1 h and the resulting brown suspension is cooled to approximately 2°C over 1 h and is stirred at approximately 0-5 0C for 1 h. The brown solid is isolated by filtration through a suction strainer, washed with cold aq. EtOH (EtOH/water = 1/1 , vol/vol, approximately 2 °C, 3 x 1 vol) and dried on a suction strainer under nitrogen. The product is obtained as a pale brown and humid solid. The loss on drying is determined and the material is taken into the next stage. Yield (corrected for loss on drying and 1H NMR assay): 80%.1H NMR (400MHz, CDCI3), δ 6.37 (s, 1 H), 7.38 (d, 2H), 7.58 (t, 1 H), 7.77 (m, 4H), 7.95 (d, 1H)
Intermediate 77 (Stage 2) <n="116"/>4-[4-chlorophenyl]methyl}-1(2H)-phthalazinone(3£)-3-[(4-Chlorophenyl)methyhdene]-2-benzofuran-1 (3H)-one (as prepared, for example, in stage 1) (1 0 eq, corrected for loss on drying) is suspended in EtOH (3 7 vol) and heated to approximately 85 0C at slight reflux A solution of hydrazine hydrate (commercially available, for example, from Aldrich) (1 2 eq) in EtOH (O 63 vol) is added through a dropping funnel over 1 h At the end of the addition, EtOH (0 63 vol) is added through the dropping funnel into the reaction suspension in order to remove traces of hydrazine hydrate The reaction suspension is heated at approximately 85 0C at slight reflux for 14 h It is cooled to approximately 20 0C and a sample is taken to check the conversion (99% conversion, HPLC) Acetone (0 35 vol) is added to the reaction mixture over 30 mm (exothermic reaction) The quenched suspension is stirred for at least 1 h and is then cooled to approximately 2 0C over 30 mm and stirred at approximately 2 0C for 1 h The product is isolated by filtration through a suction strainer and is washed with cold EtOH (approximately 0-5 0C, 3 x 1 9 vol) The pale brown solid is completely dried on the suction strainer in vacuo under nitrogen The title compound is obtained as a pale brown solid Yield (corrected for 1H NMR assay) 90-95%1H MMR (400MHz, DMSO-Cf6), delta 4 30 (s, 2H), 7 35 (m, 4H), 7 88 (m, 3H), 8 26 (d, 1 H), 12 62 (s, 1 H)
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