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With potassium fluoride In N,N-dimethyl-formamide at 140 - 160℃;
In the solution prepared in step (3)29.0 g of KF was charged under stirring,And then incubating the mixture at a temperature of 140-160 DEG C until the content of 2,3,4-trichlorobenzonitrile reaches 2percent(5) under normal pressure to do spin-drying solvent DMF,The resulting brown-yellow granular solid was recrystallized by dissolving 200 mL of toluene,Cooling to about 0 overnight,Filtration,And dried to give 33.8 g of 3-chloro-2,4-difluorobenzonitrile as a pale yellow granular solid in an amount of 98.637percent (GC) in a molar yield of 65.0percent Benzene);
Reference：
[1] Patent: CN106278860, 2017, A, . Location in patent: Paragraph 0023; 0028; 0029
t-Butyl, methyl malonate (7.5 g, 43 mmol) in DMF (50 mL) was cooled in an ice bath before NaH (60percent in mineral oil, 1.0 g, 42 mmol) was added portionwise over 5 minutes with hydrogen evolution. The suspension was allowed to warm to RT for 30 minutes at which time everything was in solution. 3-Chloro-2,4-difluorobenzonitpile (5.0 g, 28.8 mmol) was added as a solid and the reaction was heated to 90 0C for 4 hours and then at RT for 12 hours. TLC (15percent ethyl acetate/hexanes) indicated still some starting material but mostly product at a slightly lower Rf. The reaction was diluted with ether and quenched into water containing 2N HCl. The mixture was extracted twice with ether and the ether layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was taken up in 1 : 1 methanol :dichloromethane (50 mL) and 2M trimethylsilyldiazomethane in ether was added until the yellow color persisted to re-esterify any acid. The excess diazomethane was quenched with acetic acid and the mixture was reconcentrated. The product mixture was separated by flash chromatogrphy (5-10percent ethyl acetate/hexanes, then 10-20percent) to afford first some recovered starting material, then a mixture of product and isomeric t-butyl, methyl (R,S)-2-(2-chloro-6- cyano-3-fluorophenyl)malonate by NMR (900 mg), followed by clean title product isomer. 1H-NMR (400 MHz, CDCl3) delta ppm 1.46(s, 9H), 3.79 (s, 3H)5 5.15 (s, IH), 7.448 (d, J = 8.3 Hz, IH), 7.56 (dd, J = 6.0, 8.2, IH).
tert-Butyl methyl malonate (7.5 g, 43 mmol) in anhydrous DMF (50 mL) under nitrogen was cooled in an ice bath. Sodium hydride (60percent in mineral oil, 1.00 g, 42 mmol) was added portionwise over 5 minutes. The reaction was allowed to warm to room temperature for 30 minutes at which time all was in solution and hydrogen gas had ceased. To the solution was then added 2,4-difluoro-3-chlorobenonitrile (5.0 g, 29 mmol) as a solid in one portion. The reaction was heated in a 90 °C oil bath for 4 hours and then stirred at room temperature for 16 hours. The reaction was quenched by addition of 2N HCl in water. The mixture was partitioned with ether (2x), and the organic layers were washed with brine, dried over sodium sulfate and evaporated in vacuo. TLC (15percent ethyl acetate/hexanes) indicated a small amount of di-fluoro starting material, but mostly the desired product and excess malonate. The crude residue was purified by flash chromatography (5-10percent percent ethyl acetate/hexanes to elute excess malonate and starting material, then 10-20percent ethyl acetate/hexanes for products). The first product fractions were a mixture with some of the minor t-butyl methyl (2-chloro-6-cyano-3-fluorophenyl)malonate side product isomer (900 mg, mostly desired title product by NMR), then later fractions were clean desired title isomer. 1H-NMR (500 MHz, CDCl3) delta ppm 1.464 (s, 9H), 3.793 (s, 3H), 5.145 (s, 1H), 7.448 (d, J = 8.3 Hz, 1H), 7.560 (dd, J = 6.2 and 8.3 Hz, 1H).
Step A: Di-tert-butyl (2-chloro-4-cvano-3-fluorophenyl)propanedioate A dry flask was charged with sodium hydride (60% suspension in mineral oil, 3.8 g, 94 mmol) and 150 ml of dry DMF, and cooled to 0 C followed by dropwise addition of di-tert-butyl malonate via syringe. After 30 min at 0 C, a solution of <strong>[887267-38-1]3-chloro-2,4-difluorobenzonitrile</strong> in DMF (10ml) was added over a period of 15 minutes. The ice bath was removed and the reaction mixture was subjected to heating at 80 C in an oil bath for 12 hrs. The mixture was cooled to RT, quenched with saturated ammonium chloride, and partitioned between water and ethyl acetate. The organic layer was concentrated and the resulting residue purified by flash chromatography (eluted with 2->10% hexanes / ethyl acetate) to provide di-tert-butyl (2-chloro- 4-cyano-3-fiuorophenyl)propanedioate. 1H-NMR (400 MHz, CDC13) delta ppm 7.68 (m, 1H), 7.53 (m, 1H), 5.06 (s, 1H), 1.52 (s, 18H). LC-MS (IE, m/z): 370 [M + 1]+.
[0184] A dry flask was charged with sodium hydride (60% suspension in mineral oil, 3.8 g, 94 mmol) and 150 ml ofdry DMF, and cooled to 0 C followed by dropwise addition of di-tert-butyl malonate via syringe. After 30 min at 0 C, asolution of <strong>[887267-38-1]3-chloro-2,4-difluorobenzonitrile</strong> in DMF (10ml) was added over a period of 15 minutes. The ice bath wasremoved and the reaction mixture was subjected to heating at 80 C in an oil bath for 12 hrs. The mixture was cooledto RT, quenched with saturated ammonium chloride, and partitioned between water and ethyl acetate. The organic layerwas concentrated and the resulting residue purified by flash chromatography (eluted with 2->10% hexanes / ethyl acetate)to provide di-tert-butyl (2-chloro-4-cyano-3-fluorophenyl)propanedioate. 1H-NMR (400 MHz, CDCl3) delta ppm 7.68 (m, 1H),7.53 (m, 1H), 5.06 (s, 1H), 1.52 (s, 18H). LC-MS (IE, m/z): 370 [M + 1]+.
With potassium fluoride; In N,N-dimethyl-formamide; at 140 - 160℃;
In the solution prepared in step (3)29.0 g of KF was charged under stirring,And then incubating the mixture at a temperature of 140-160 DEG C until the content of 2,3,4-trichlorobenzonitrile reaches 2%(5) under normal pressure to do spin-drying solvent DMF,The resulting brown-yellow granular solid was recrystallized by dissolving 200 mL of toluene,Cooling to about 0 overnight,Filtration,And dried to give 33.8 g of 3-chloro-2,4-difluorobenzonitrile as a pale yellow granular solid in an amount of 98.637% (GC) in a molar yield of 65.0% Benzene);
In a 500 mL four-necked flask, 250 mL of 20% (by mass concentration) dilute sulfuric acid was poured,33.8 g of <strong>[887267-38-1]3-chloro-2,4-difluorobenzonitrile</strong> obtained in the step (5) was added portionwise with stirring,Keeping the reaction until the content of <strong>[887267-38-1]3-chloro-2,4-difluorobenzonitrile</strong> is less than or equal to 2% at 100 to 120 DEG C;(7) The oil layer in the solution obtained in step (6) was extracted with 150 mL of toluene,Separate the oil layer,Wash the oil layer with cold water 2 to 3 times,Cooling to about 0 overnight,A yellowish powdery solid precipitated, which was filtered off and dried, yielding 35.5 g of 3-chloro-2,4-difluorobenzoic acid as a pale yellow powder.
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