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With palladium on activated charcoal; hydrogen; In methanol; at 25℃; under 775.743 Torr; for 2.0h;
<strong>[159768-50-0]methyl 4-fluoro-5-methoxy-2-nitrobenzoate</strong> (800 mg, 3.49 mmol) and Pd/C (111.5 mg, 10% purity) in MeOH (10 mL) was stirred at 25C under (15 psi) for 2 hours. The reaction mixture was filtered, and the filtrate evaporated to dryness in vacuo. The residue was purified by prep- TLC (petroleumether/EtOAc; 5:1) to afford the title compound as a yellow solid (392 mg, 56%). 1HNMR (500 MHz, CDCI3) d: 7.44 (d, 7=9.5 Hz, 1H), 6.42 (d, 7=12.5 Hz, 1H), 3.87 (s, 3H), 3.83 (s, 3H).
Concentrated nitric acid (70%, 4.8 ml) was added dropwise during 20 minutes to a stirred mixture of methyl 4-fluoro-3-methoxybenzoate (14 g) and concentrated sulphuric acid (140 ml) which had been cooled to -10 C. The mixture was allowed to warm to 5 C. and was stirred at that temperature for 15 minutes. The mixture was poured onto ice and extracted with ethyl acetate. The organic phase was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and methylene chloride as eluent. There was thus obtained methyl 4-fluoro-5-methoxy-2-nitrobenzoate (11.8 g). A mixture of a portion (10.3 g) of the material so obtained, 10% palladium-on-charcoal catalyst (1 g) and ethanol (500 ml) was stirred under an atmosphere pressure of hydrogen for 3 hours. The mixture was filtered and the filtrate was evaporated. There was thus obtained 4-fluoro-5-methoxyanthranilic acid methyl ester (9 g).
The 4-chloro-7-fluoro-6-methoxyquinazoline used as a starting material was obtained as follows: Concentrated nitric acid (70%, 4.8 ml) was added dropwise during 20 minutes to a stirred mixture of methyl 4-fluoro-3-methoxybenzoate (14 g) and concentrated sulphuric acid (140 ml) which had been cooled to -10 C. The mixture was allowed to warm to 5 C. and was stirred at that temperature for 15 minutes. The mixture was poured onto ice and extracted with ethyl acetate. The organic phase was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and methylene chloride as eluent. There was thus obtained methyl 4-fluoro-5-methoxy-2-nitrobenzoate (11.8 g). A mixture of a portion (10.3 g) of the material so obtained, 10% palladium-on-charcoal catalyst (1 g) and ethanol (500 ml) was stirred under an atmosphere pressure of hydrogen for 3 hours. The mixture was filtered and the filtrate was evaporated. There was thus obtained 4-fluoro-5-methoxyanthranilic acid methyl ester (9 g).
With nitric acid;
The 4-chloro-7-fluoro-6-methoxyquinazoline used as a starting material was obtained as follows:- Concentrated nitric acid (70%, 4.8 ml) was added dropwise during 20 minutes to a stirred mixture of methyl 4-fluoro-3-methoxybenzoate (14 g) and concentrated sulphuric acid (140 ml) which had been cooled to -10C. The mixture was allowed to warm to 5C and was stirred at that temperature for 15 minutes. The mixture was poured onto ice and extracted with ethyl acetate. The organic phase was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and methylene chloride as eluent. There was thus obtained methyl 4-fluoro-5-methoxy-2-nitrobenzoate (11.8 g). A mixture of a portion (10.3 g) of the material so obtained, 10% palladium-on-charcoal catalyst (1 g) and ethanol (500 ml) was stirred under an atmosphere pressure of hydrogen for 3 hours. The mixture was filtered and the filtrate was evaporated. There was thus obtained 4-fluoro-5-methoxyanthranilic acid methyl ester (9 g).
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