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b. Preparation of 3,5-dichloro-2,4-difluoroaniline 38.5 g of 3,5-difluoro-2,4-difluoronitrobenzene (0.169 mol) and 1.49 g of Pd/C were introduced into a 100 ml autoclave. Hydrogen gas was introduced into the autoclave under 3 Mpa of hydrogen pressure at 60 C. for three hours. The reactant was cooled to room temperature. The catalyst was filtered off, and the resulting mixture was distilled to give 31.8 g of 3,5-dichloro-2,4-difluoroaniline (0.161 mol) in 95.1% yield.
With hydrogenchloride; sodium hydroxide; sulfuric acid; sodium nitrite;copper(l) chloride; In water;
c. Preparation of 2,4-difluoro-1,3,5-trichlorobenzene 31.1 g of <strong>[83121-15-7]3,5-dichloro-2,4-difluoroaniline</strong> (0.157 mol) was added to 100 ml of a solution of concentrated hydrochloric acid and water (1:1) at 70 C. The resulting mixture was stirred to be a slurry and cooled to 0-5 C. To the mixture was added 11.6 g of aqueous solution of sodium nitrite (0.165 mol) over 30 minutes. The resulting solution was added to a solution of CuCl (0.188 mol) and hydrochloric acid (100 ml). The reaction mixture was stirred for 2 hours and kept overnight. Fractions obtained by wet-distillation were extracted with toluene. The extract was washed successively with 10% aqueous solution of NaOH, concentrated sulfuric acid and water, dried over sodium sulfate and evaporated. The residue was recrystallized from toluene to give 27.7 g of 2,4-difluoro-1,3,5-trichlorobenzene (0.127 mol) in 81.1% yield.
EXAMPLE 3 2,4-Difluoro-3,5-dichlorophenyl isocyanate Hydrogen chloride was passed into a well-stirred solution of 39.6 gm (0.20 mol) of <strong>[83121-15-7]2,4-difluoro-3,5-dichloroaniline</strong> in 400 ml of toluene until a precipitate no longer separated out. The heterogeneous mixture thus obtained was cooled to 5 to 10 C. At this temperature, 40 gm (0.4 mol) of phosgene were passed in, with stirring. The mixture was then heated slowly, with stirring, so that after about two hours a temperature of 100 to 105 C. was reached. Stirring was then continued for seven hours at this temperature. During this time, a clear solution was formed, and hydrogen chloride was liberated. Nitrogen was then passed into the mixture for one hour at the same temperature to drive off the excess phosgene. Thereafter the solvent was distilled off, in vacuo at the end. The crude product which remained was distilled in a water pump vacuum. Yield: 35.4 gm (0.158 mol; 79% of theory), B.p.: 100-104 C./20 mbar.
In water; toluene;
Example 3 2,4-Difluoro-3,5-dichlorophenyl isocyanate Hydrogen chloride was passed into a well-stirred solution of 39.6 gm (0.20 mol) of <strong>[83121-15-7]2,4-difluoro-3,5-dichloroaniline</strong> in 400 ml of toluene until a precipitate no longer separated out. The heterogeneous mixture thus obtained was cooled to 5 to 10 C. At this temperature, 40 gm (0.4 mol) of phosgene were passed in, with stirring. The mixture was then heated slowly, with stirring, so that after about two hours a temperature of 100 to 105 C. was reached. Stirring was then continued for seven hours at this temperature. During this time, a clear solution was formed, and hydrogen chloride was liberated. Nitrogen was then passed into the mixture for one hour at the same temperature to drive off the excess phosgene. Thereafter the solvent was distilled off, in vacuo at the end. The crude product which remained was distilled in a water pump vacuum. Yield: 35.4 gm (0.158 mol; 79% of theory), B.p.: 100-104 C./20 mbar.
EXAMPLE 10 N-(2,4-Difluoro-3,5-dichlorophenyl)-N'-(2,6-difluorobenzoyl)-urea Three grams (0.016 mol) of 2,6-difluoro-benzoyl isocyanate were added to a solution of 2.95 gm (0.015 mol) of <strong>[83121-15-7]2,4-difluoro-3,5-dichloroaniline</strong> in 50 ml of toluene. The solution thus obtained was stirred for 15 hours at room temperature. Thereafter, the product which precipitated during that time was removed by suction filtration and dried. Yield: 4.2 gm (0.011 mol; 73% of theory), M.p.: 221-224 C.
In toluene;
Example 10 N-(2,4-Difluoro-3,5-dichlorophenyl)-N'-(2,6-difluorobenzoyl)-urea Three grams (0.016 mol) of 2,6-difluoro-benzoyl isocyanate were added to a solution of 2.95 gm (0.015 mol) of <strong>[83121-15-7]2,4-difluoro-3,5-dichloroaniline</strong> in 50 ml of toluene. The solution thus obtained was stirred for 15 hours at room temperature. Thereafter, the product which precipitated during that time was removed by suction filtration and dried. Yield: 4.2 gm (0.011 mol; 73% of theory), M.p.: 221-224 C.
To a mixture of <strong>[83121-15-7]3,5-dichloro-2,4-difluoroaniline</strong> (5.0 g), an aqueous 57% solution of hydroiodic acid (20 ml) and water (20 ml), copper iodide (1.92 g) was added. The reaction liquid was maintained at 30C or less in a water bath.To the reaction mixture was added dropwise a water solution (2 mL) of sodium nitrite ( 1.74 g). The reaction mixture was stirred for 10 minutes, maintained at 30C or less in a water bath. To the reaction mixture was added dropwise a water solution (2 mL) of sodium nitrite (1.74 g), again. The reaction mixture was further stirred for 10 minutes, maintained at 30C or less in a water bath. To the reaction mixture was added dropwise a water solution (2 mL) of sodium nitrite (1.74 g), again. t-Butyl methyl ether was added and the mixture was washed with water and with an aqueous solution of sodium sulfite and brine, and dried over anhydrous magnesium sulfate. The drying agent was filtered off, the solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography (n- hexane) to obtain l,3-dichloro-2,4-difluoro-5-iodobenzene (6.0 g). i-NMR (CDC13) delta: 7.6-7.75 (1H, m).
6 g
With copper(l) iodide; hydrogen iodide; sodium nitrite; In water; at 30℃;
To a mixture of <strong>[83121-15-7]3,5-dichloro-2,4-difluoroaniline</strong> (5.0 g), an aqueous 57% solution of hydroiodic acid (20ml) and water (20 ml), copper iodide (1.92 g) was added. The reaction liquid was maintained at 30 C orless in a water bath. To the reaction mixture was added dropwise a water solution (2 mL) of sodium nitrite (1.74 g). The reaction mixture was stirred for 10 minutes, maintained at 30 C or less in a water bath. To the reaction mixture was added dropwise an aqueous solution (2 mL) of sodium nitrite (1.74 g), again. The reactionmixture was further stirred for 10 minutes, maintained at 30C or less in a water bath. To the reaction mixture was added dropwise a aqueous solution (2 mL) of sodium nitrite (1.74 g), again. t-Butyl methyl ether was added and the mixture was washed with water and with an aqueous solution of sodium sulfite and brine, and dried over anhydrous magnesium sulfate. The drying agent was filtered off, the solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography (n15 hexane) to obtain 1,3-dichloro-2,4-difluoro-5-iodobenzene (6.0 g). 1H-NMR (CDCl3) : 7.6-7.75 (1H, m).
2.7 mmol of 2,4-difluoro-3,5-dichloro-aniline, and 20 ml of 1,2-dichloroethane in a 100 ml round bottom flask and stirred until the 2,4-difluoro-3,5diclofenac was completely dissolved, was added dropwise with stirring 3 mmol of 4-methyl-1,2,3-thiadiazole-5-formylphenyl isocyanate, dropwise over 15 minutes immediatelythereafter precipitation, followed by stirring at room temperature for 8 hours aftercompletion of the reaction, allowed to stand, the solid product was suction filtered,the filtrate solvent was removed by rotary evaporation, ethyl acetate with a volumeratio of 1:3: recrystallized from petroleum ether after the refrigerator to precipitatea solid, the solid product was combined with 1:3 volume ratio of ethyl acetate:petroleum ether, washed and dried to obtain the product; mp: 187-189 C, yield 92%;
Step 1: Preparation of 1-bromo-3,5-dichloro-2,4-difluorobenzene To a solution of <strong>[83121-15-7]3,5-dichloro-2,4-difluorobenzenamine</strong> (9.9 g, 50.0 mmol) in HBr (200 mL) was added a solution of NaNO2 (3.45 g, 50.0 mmol) in H2O (80 mL) slowly under salt ice-bath, then the mixture was stirred for 2 h, and CuBr (7.15 g, 50.0 mmol) was added at 0 C. The mixture was stirred for additional 2 h, and then poured into water (100 mL), extracted with DCM, dried over NaSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by chromatography over silica gel eluted with PE to give compound 1-bromo-3,5-dichloro-2,4-difluorobenzene (6.2 g, yield 48%) as a colorless oil. 1H NMR (400 MHz, CDCl3): delta 7.49 (t, J=7.2 Hz, 1H) ppm.
With iron; ammonium chloride; In water; 1,2-dichloro-ethane; for 2h;Reflux;
In a 500-ml four-necked flask, 8 g of iron powder (0.14 mol), 80 g of dichloroethane, 100 g of water and 2 g of ammonium chloride were added. 3,5-dichloro-2,4-difluoronitrobenzene 11. 4 g (0.55 mol)in 20 g of dichloroethane solution were dropped at reflux. After dropping was completed, the resulting mixture was insulated for 2 hours, and GC analysis was carried out. After completion of the reaction, filtered, the filtrate was washed with water, layered, organic phase was combined and the solvent was evaporated. 9.5 g, yield 96%, GC purity 96%
With phosphoric acid; 3 % platinum on carbon; hydrogen; In methanol; at 75 - 80℃; under 1500.15 - 11251.1 Torr; for 6h;Autoclave;
In a 500ml stainless steel autoclave equipped with a hydrogen port, cooling circulating water, pressure gauge and electric heating device,160 g of methanol and 22.8 g (0.1 mol) of compound (II) 3,5-dichloro-2,4-difluoronitrobenzene were added.0.80 g of 3% platinum carbon and 0.85 g (0.007 mol) of 85% phosphoric acid were added by stirring, and the pipe was rinsed with 20 g of methanol to close the kettle;Wherein the molar amount of platinum carbon is calculated as 0.80*(1-60% aqueous)*3% dry basis platinum content/195.078 platinum molecular weight=0.0000492 mol; First, hydrogen is introduced to the internal pressure of 0.2 to 0.4 MPa for 2 to 3 times, then hydrogen is introduced to the internal pressure of 1.0 to 1.5 MPa, and the temperature is controlled at 75 to 80 C to stir the reaction. During the period, hydrogen is added until the pressure is no longer lowered.HPLC monitoring raw material (II) basically disappeared or the content was less than 0.5%; reaction 6h, the reaction solution was suction filtered, the filter residue was washed twice with methanol, 10ml each time; solid platinum carbon was recovered and applied; The filtrate was vacuum-recovered to recover a large amount of light yellow solids. The mixture was stirred and dripped into 50 g of water, stirred rapidly for 30 minutes, slowly cooled to 0 to 5 C for 1 h, filtered, and dried.The solid was further washed with water to neutrality, rinsed with 10 g of water, and dried at 50 C under normal pressure to obtain a white-white powdery solid. The weight: 19.0 g, content: 97.2%; yield: 96.0%.
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