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a) 29.0 g (0.200 mol) of 6-chloro-2-fluorotoluene are dissolved, with stirring, in 200 ml of dry THF. After cooling to -70° C., 151.0 ml (0.24 mol) of n-butyllithium in solution in hexane are added dropwise. After 2 hours, the reaction mixture maintained at -70° C. is poured onto solid carbon dioxide. After returning to room temperature, an aqueous ammonium chloride solution is added. The aqueous phase is extracted with ether, acidified with 6N hydrochloric acid and extracted with ether. The organic phases are dried over magnesium sulphate and concentrated to dryness. The residue is washed with heptane to give 9.0 g (0.048 mol) of 4-chloro-2-fluoro-3-methylbenzoic acid in the form of a white powder (yield: 24percent; melting point: 198° C.).
24%
With n-butyllithium In tetrahydrofuran; hexane
EXAMPLE 4B (passing from VII to VI) (compound 54) 29.0 g (0.2 mol) of 6-chloro-2-fluorotoluene are dissolved with stirring in 200 ml of dry THF. After cooling to -70° C., 151 ml (0.24 mol) of n-butyllithium in solution in hexane are added dropwise. After two hours, the reaction mixture, maintained at -70° C., is poured on solid carbon dioxide. After returning to room temperature, an aqueous ammonium chloride solution is added. The aqueous phase is extracted with ether, acidified with 6N hydrochloric acid and extracted with ether. The organic phases are dried over magnesium sulphate and concentrated to dryness. The residue is washed with heptane to give 9.0 g (0.048 mol) of 4-chloro-2-fluoro-3-methylbenzoic acid in the form of a white powder (yield: 24percent; melting point: 198°)
Reference：
[1] Patent: US5945382, 1999, A,
[2] Patent: US5945382, 1999, A,
2
[ 124-38-9 ]
[ 443-83-4 ]
[ 153556-55-9 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1996, vol. 133, # 2, p. 133 - 141
a) 29.0 g (0.200 mol) of 6-chloro-2-fluorotoluene are dissolved, with stirring, in 200 ml of dry THF. After cooling to -70 C., 151.0 ml (0.24 mol) of n-butyllithium in solution in hexane are added dropwise. After 2 hours, the reaction mixture maintained at -70 C. is poured onto solid carbon dioxide. After returning to room temperature, an aqueous ammonium chloride solution is added. The aqueous phase is extracted with ether, acidified with 6N hydrochloric acid and extracted with ether. The organic phases are dried over magnesium sulphate and concentrated to dryness. The residue is washed with heptane to give 9.0 g (0.048 mol) of 4-chloro-2-fluoro-3-methylbenzoic acid in the form of a white powder (yield: 24%; melting point: 198 C.).
24%
With n-butyllithium; In tetrahydrofuran; hexane;
EXAMPLE 4B (passing from VII to VI) (compound 54) 29.0 g (0.2 mol) of 6-chloro-2-fluorotoluene are dissolved with stirring in 200 ml of dry THF. After cooling to -70 C., 151 ml (0.24 mol) of n-butyllithium in solution in hexane are added dropwise. After two hours, the reaction mixture, maintained at -70 C., is poured on solid carbon dioxide. After returning to room temperature, an aqueous ammonium chloride solution is added. The aqueous phase is extracted with ether, acidified with 6N hydrochloric acid and extracted with ether. The organic phases are dried over magnesium sulphate and concentrated to dryness. The residue is washed with heptane to give 9.0 g (0.048 mol) of 4-chloro-2-fluoro-3-methylbenzoic acid in the form of a white powder (yield: 24%; melting point: 198)
With ammonium chloride; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2.0h;
A flask was charged with <strong>[153556-55-9]4-chloro-2-fluoro-3-methylbenzoic acid</strong>, (1 equiv), hydroxybenzotriazole (0.2 equiv) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.5 equiv). DMF (0.5 M) was added followed by diisopropylethyl amine (2 equiv). The reaction mixture was stirred for 15 min, followed by addition of ammonium chloride (5 equiv). The reaction mixture was stirred at room temperature for 2 h. The crude reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was washed with 1 N HC1 and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound.
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