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[00308] 2 « O-5-FLUORO-4-METHYL-L) ENZOIC ACID. Chloral hydrate (76 g) was dissolved in 1 L water and subsequently 1 kg NA2S04, 94.1 g HXNOH HCL, and 51.3 g 4-fluoro-3-methyl aniline in 250 ml 5% aq. HC1 were added. The suspension was heated to boiling and kept boiling for 1 minute. After cooling down to room temperature, the solid was filtered off and washed twice with warm water (40C). Yield after drying overnight at 60C under vacuum was 275 g, which was used without further purification or drying. The 275 g of crude product was slowly poured in 500 ml of CONCENTRATED H2SO4 at 50C, such that the temperature was kept below 75C. After completion of addition, the dark/purple solution was heated to 85C for 15 minutes. After cooling down to room temperature, the solution was poured in 2 L of ice water and was left standing for an half hour. The red solid was filtered and washed twice with cold water. Subsequently, the solid was dried under vacuum at 70C. Yield: 69.9 g (quantitatively from 4- fluoro-3-methyl aniline) of a mixture of two regio isomers: 5-fluoro and 3-fluoro 3-methyl-isatin in a ratio of about 55: 45. The mixture of isatins (69.4g) was dissolved in 1L 1N aq. NAOH and subsequently 100 ml of 30% aq. H202 was added drop wise, keeping the temperature below 30C. After completion of addition, the mixture was heated to 45C until evolution of gas ceased. The solution was cooled to room temperature, filtered and acidified with glacial acetic acid. The precipitate formed was filtered off, washed twice with water and air-dried 45C. Yield: 29.4 g of 5-FLUORO-4-METHYL-ANTHRANILIC acid iii.
Preparation of 2-amino-4-methyl-5-fluoro-benzoic acid 525 g of 2-nitro-4-methyl-5-fluoro-benzoic acid are hydrogenated in 3 l of dioxane with 50 g of 5% strength Pd-C catalyst at 30-40 under 20-30 bar. The catalyst is filtered off with suction and the solution is poured onto water. The crystals which have precipitated are filtered off with suction and dried. Yield: 357 g (80.1% of theory), melting point: 201-202 C.
N-(4-fluoro-3-methylphenyl)-2-hydroxyiminoacetamide[ No CAS ]
[ 103877-79-8 ]
6-amino-3-fluoro-2-methyl-benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a mixture of 78 mL of concentrated sulfuric acid and 16 mL of water, 25.4 g of N-(4-fluoro-3-methylphenyl)-2-hydroxyiminoacetamide was added. After stirring at 80C for one hour, the reaction solution was poured into 500 mL of ice water and the precipitated solid was collected by filtration to obtain a mixture of 4-methyl-5-fluoroisatin with 6-methyl-5-fluoroisatin. The obtained mixture of 4-methyl-5-fluoroisatin with 6-methyl-5-fluoroisatin is mixed with a mixture of 18.0 g of sodium hydroxide and 80 mL of water, and then 6 mL of 30% hydrogen peroxide solution was added. While maintaining the temperature at 70C, the pH of the reaction solution was adjusted to 4 by adding dropwise acetic acid. The precipitated solid was collected by filtration to obtain 11.5 g of a mixture of 6-amino-3-fluoro-2-methylbenzoic acid and 2-amino-5-fluoro-4-methylbenzoic acid.
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