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Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -78℃; Stage #2: at -78 - 25℃; Stage #3: With water; ammonium chloride In tetrahydrofuran
To a stirred solution of diisopropylamine (1.7 g, 16.4 mmol) in THF 2.6 M solution of n-BuLi (1.1 g, 16.4 mmol) was added at -30°C and the mixture was stirred for an hour at the same temperature. To this mixture a solution of 2,4-difluorobenzoic acid (1.0 g, 6.3 mmol) in THF was added slowly at -78°C, followed by methyl iodide (2.2 g, 15.7 mmol) and it was stirred for another 2 h at the same temperature and allowed to attain the room temperature. The reaction mixture was treated with saturated aqueous NH4Cl solution and the aqueous layer extracted with ethylacetate (3 x 25 mL). The organic phases were combined and dried over anhydrous sodium sulfate. After removal of solvent, the residue was purified over a silica gel flash column using a gradient of ethyl acetate in pet. ether to give product as a white solid. Yield: 0.77 g (70percent) MS (ES) MH+: 172 for C8H6F2O2 1H NMR (400 MHz, CDCl3) δ: 2.2 (s, 3H), 7.0 (m, 1H), 7.9 (m, 1H).
With thionyl chloride;N,N-dimethyl-formamide; In dichloromethane; for 70.0833h;Heating / reflux;
25.0 g (145 mmol) of <strong>[112857-68-8]2,4-difluoro-3-methylbenzoic acid</strong> from Example 9 and 2.1 g (29 mmol) of dimethylformamide were initially charged under nitrogen in 300 ml of dichloromethane and 26 g (217 mmol) of thionyl chloride were added dropwise within 5 minutes. The mixture was heated to reflux for 70 hours and then thionyl chloride and dichloromethane were distilled off. 22 g of a colourless solid were obtained.
With hydrogenchloride; sodium hydroxide; bromine; In 1,4-dioxane; water;
STR14 A solution of 30 g of 2,4-difluoro-3-methylacetophenone in 270 ml of dioxane is added dropwise with ice cooling to a bromine lye prepared from 72 g of NaOH, 86.4 g of bromine and 360 ml of water, at 10 C. The mixture is allowed to come to room temperature, a further 80 ml of water are added, and the phases are separated. A solution of 18 g of Na2 S2 O5 in 270 ml of water is added to the aqueous phase. The mixture is then acidified using HCl, the acid precipitating. Yield 24.9 g of 2,4-difluoro-3-methylbenzoic acid. Melting point: 180-81 C.
3-Methyl-2,4-difluorobenzoic acid 3-Methyl-2,4-difluoro-bromobenzene (16.07 g 77.6 mmol) is dissolved in 120 ml anhydrous ether and cooled in a dry ice/acetone bath. A solution of butyllithium (20.5 ml of a 2.5 M solution in hexanes, 76.2 mmol) in 15 ml of ether is added dropwise at a rate to keep the temperature below -65 C. After 45 minutes, CO2 is bubbled through the solution keeping the temperature below -65 C. After the temperature stabilized, CO2 bubbling is continued as the reaction is allowed to warm to room temperature. The mixture is quenched with 30 ml of water and acidified to pH 2 with 1N HCl. The layers are separated and the aqueous layer is extracted with ether. The combined organics are washed with brine and saturated sodium bicarbonate. The bicarbonate layer is then acidified with 1N HCl to pH 3. The resulting solid is filtered, washed with water, and dried under vacuum.
3-Methyl-2,4-difluorobenzoic acid 3-Methyl-2,4-difluoro-bromobenzene (16.07 g 77.6 mmol) is dissolved in 120 ml anhydrous ether and cooled in a dry ice/acetone bath.. A solution of butyllithium (20.5 ml of a 2.5 M solution in hexanes, 76.2 mmol) in 15 ml of ether is added dropwise at a rate to keep the temperature below -65 C. After 45 minutes, CO2 is bubbled through the solution keeping the temperature below -65 C. After the temperature stabilized, CO2 bubbling is continued as the reaction is allowed to warm to room temperature.. The mixture is quenched with 30 ml of water and acidified to PH 2 with 1N HCl.. The layers are separated and the aqueous layer is extracted with ether.. The combined organics are washed with brine and saturated sodium bicarbonate.. The bicarbonate layer is then acidified with 1N HCl to PH3.. The resulting solid is filtered, washed with water, and dried under vacuum.
13 g (534 mmol) of magnesium were initially charged under nitrogen in 600 ml of tetrahydrofuran and stirred slowly with a magnetic stirrer overnight. The stirrer was switched off, an iodine crystal was first added, then approx. 10 g of 3-bromo-2,6-difluorotoluene from Example 8 were added dropwise until the reaction commenced. Subsequently, the remaining 90 g of 3-bromo-2,6-difluorotoluene (a total of 483 mmol) were added dropwise with stirring within 65 min, in such a way that continuous gentle reflux was obtained (intrinsic heat). On completion of addition, stirring was continued until a clear solution was obtained. Subsequently, carbon dioxide was introduced for approx. 35 minutes until exothermicity could no longer be observed. 500 ml of water were cautiously added dropwise. The remaining Mg turnings were filtered off and the filtrate was acidified with approx. 250 ml of concentrated hydrochloric acid (pH 1). The solid which precipitated out was filtered off with suction and dried under reduced pressure. Recrystallization from ethanol afforded 38 g of colourless solid; m.p.: 168-170 C.
To a stirred solution of diisopropylamine (1.7 g, 16.4 mmol) in THF 2.6 M solution of n-BuLi (1.1 g, 16.4 mmol) was added at -30C and the mixture was stirred for an hour at the same temperature. To this mixture a solution of 2,4-difluorobenzoic acid (1.0 g, 6.3 mmol) in THF was added slowly at -78C, followed by methyl iodide (2.2 g, 15.7 mmol) and it was stirred for another 2 h at the same temperature and allowed to attain the room temperature. The reaction mixture was treated with saturated aqueous NH4Cl solution and the aqueous layer extracted with ethylacetate (3 x 25 mL). The organic phases were combined and dried over anhydrous sodium sulfate. After removal of solvent, the residue was purified over a silica gel flash column using a gradient of ethyl acetate in pet. ether to give product as a white solid. Yield: 0.77 g (70%) MS (ES) MH+: 172 for C8H6F2O2 1H NMR (400 MHz, CDCl3) delta: 2.2 (s, 3H), 7.0 (m, 1H), 7.9 (m, 1H).
A solution of 1.9 M n-BuLi (3.8 ml, 7.2 mmol) in hexanes was added at -30C to a stirred solution of 2,2,6,6-tetramethylpiperidine (1.2 g, 9.0 mmol) in THF and the mixture was stirred for an hour at the same temperature. After cooling to -78C, a solution of 2,4-difluoro-3- methylbenzoic acid (Intermediate 46, 0.5 g, 3.0 mmol) in THF was added slowly at and the mixture was stirred for another 2 h at the same temperature. To this mixture, a solution of thiazole-2-carboxaldehyde (0.8 g, 7.2 mmol) in THF was added dropwise over aperiod of 10 mins and the mixture was brought to the room temperature. The reaction mixture was quenched with 1.5N hydrochloric acid and the organic layer was separated, the aqueous layer was extracted with ethyl acetate (3 x 10 mL) and the combined organic layer was dried over sodium sulfate. Removal of solvent afforded the title compound as colorless product. Yield: 0.42 g (51%). MS (ES) MH+: 285 for C12H9F2NO3S
With thionyl chloride; In methanol; at 60℃; for 3h;Cooling with ice;
Step A: Preparation of 2,4-difluoro-3-methyl-benzoic acid methyl ester To a suspension of <strong>[112857-68-8]2,4-difluoro-3-methylbenzoic acid</strong> (950 mg, 5.52 mmol) in methanol (10 mL), cooled using an ice water bath, was added thionyl chloride (1 mL) in a dropwise manner. The solution was heated at 60 C. for three hours. The reaction was returned to ambient temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated to provide the ethyl ester as a yellow oil (1.1 g, 90%). MS (M+H): 187
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