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Stage 3: 2-amino-4,6-difluorobenzoic acid First sodium hydroxide (6.70 g, 167 mmol) and then 30% hydrogen peroxide (6.7 ml) in water (60 ml) were added to a suspension of the product from stage 2 (4.58 g, 25 mmol) in water (125 ml) at 0 C. The mixture was stirred at room temperature for 20 h and then brought to pH 3 with formic acid (approx. 11 ml, severe foaming), during which the title compound precipitated out. The mixture was then filtered and product was dried over phosphorus pentoxide in a desiccator. Yield: 3.72 g (86%), white solid. Melting point: 198-202 C.
A portion (0.5 g) of the 2: 1 mixture of 2-amino-4,6-difluorobenzonitrile and 4-amino-2,6-difluorobenzonitrile described in Example 1 was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained 2-amino-4,6-difluorobenzonitrile (0.15 g). A mixture of the material so obtained, concentrated aqueous sulphuric acid (80%; 4 ml) and water (1 ml) was heated to30 1000C for 15 hours. The resultant solution was cooled to ambient temperature, diluted with water and basified by the addition of 1OM aqueous sodium hydroxide solution and washed with ethyl acetate (10 ml). The resultant aqueous solution was neutralised by the addition of dilute aqueous hydrochloric acid solution and extracted with ethyl acetate (20 ml). The EPO <DP n="54"/>organic layer was dried over magnesium sulphate and evaporated. There was thus obtained 2-amino-4,6-difluorobenzoic acid as a colourless solid (0.11 g; 97% HPLC purity using Method B, retention time 6.87 minutes); NMR Spectrum: (DMSOd6) 6.25 (m, IH), 6.4 (m, IH). A mixture of the material so obtained, 1,3,5-triazene (0.044 g), methanol (4 ml) and piperidine (0.038 ml) was heated to 7O0C for 24 hours. The resultant mixture was cooled to ambient temperature and evaporated. Diethyl ether (3 ml) and ethyl acetate (1 ml) were added and the resultant solid was isolated and washed with diethyl ether (1 ml). There was thus obtained 5,7-difluoro-3,4-dihydroquinazolin-4-one (0.048 g).
With piperidine; In methanol; at 70℃; for 24h;Product distribution / selectivity;
A portion (0.5 g) of the 2: 1 mixture of 2-amino-4,6-difluorobenzonitrile and 4-amino-2,6-difluorobenzonitrile described in Example 1 was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained 2-amino-4,6-difluorobenzonitrile (0.15 g). A mixture of the material so obtained, concentrated aqueous sulphuric acid (80%; 4 ml) and water (1 ml) was heated to30 1000C for 15 hours. The resultant solution was cooled to ambient temperature, diluted with water and basified by the addition of 1OM aqueous sodium hydroxide solution and washed with ethyl acetate (10 ml). The resultant aqueous solution was neutralised by the addition of dilute aqueous hydrochloric acid solution and extracted with ethyl acetate (20 ml). The EPO <DP n="54"/>organic layer was dried over magnesium sulphate and evaporated. There was thus obtained <strong>[126674-77-9]2-amino-4,6-difluorobenzoic acid</strong> as a colourless solid (0.11 g; 97% HPLC purity using Method B, retention time 6.87 minutes); NMR Spectrum: (DMSOd6) 6.25 (m, IH), 6.4 (m, IH). A mixture of the material so obtained, 1,3,5-triazene (0.044 g), methanol (4 ml) and piperidine (0.038 ml) was heated to 7O0C for 24 hours. The resultant mixture was cooled to ambient temperature and evaporated. Diethyl ether (3 ml) and ethyl acetate (1 ml) were added and the resultant solid was isolated and washed with diethyl ether (1 ml). There was thus obtained 5,7-difluoro-3,4-dihydroquinazolin-4-one (0.048 g).
Example 131 (5R)-12-(3,5-difluorophenyl)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3',4':6,7]indolizino [1,2-b]quinoline-3,15-dione <strong>[126674-77-9]2-amino-4,6-difluorobenzoic acid</strong> is treated according to a procedure similar to Stages 93a to 93c using 3,5-difluorophenylmagnesium bromide of Stage 93b, and the resulting amino-ketone is treated according to a procedure similar to Stage 86b. Stages 83f to 83h of the operating method of Example 83 above are applied to the quinolone obtained.
EXAMPLE 131 (5R)-12-(3,5-difluorophenyl)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3',4':6,7]indolizino [1,2-b]quinoline-3,15-dione <strong>[126674-77-9]2-amino-4,6-difluorobenzoic acid</strong> is treated according to a procedure similar to Stages 93a to 93c using 3,5-difluorophenylmagnesium bromide of Stage 93b, and the resulting amino-ketone is treated according to a procedure similar to Stage 86b. Stages 83f to 83h of the operating method of Example 83 above are applied to the quinolone obtained.
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