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2,5-Difluoro-4-nitrobenzonitrile A mixture of 1-bromo-2,5-difluoro-4-nitro-benzene (95 g, 399 mmol) and CuCN (71.8 g, 798 mmol) in NMP (700 ml.) was set to a pre-heated 160 °C oil-base and stirred at 160 °C under N2 over 450 min. The mixture was cooled to RT, charged with Na2S04 (300 g) and MTBE (1 L), and stirred for an additional 15 min. The resulting mixture was filtered and the filtrate was charged with 800 mL of water, then the separated aqueous layer was extracted with MTBE. The combined organic layers were washed with water and brine, dried over Na2S04 andconcentrated. The material was recrystallized from EtOH/water (2/1 ) to yield 2,5-Difluoro-4- nitro-benzonitrile (50 g, 68percent yield) as a pale brown solid. 1H NMR (400 MHz, CDCI3) δ 7.96- 7.95 (dd, 1 H), 7.67-7.64 (dd, 1 H).
2,5-Difluoro-4-nitrobenzonitrileA mixture of 1-bromo-2,5-difluoro-4-nitro-benzene (95 g, 399 mmol) and CuCN (71.8 g, 798 mmol) in NMP (700 mL) was set to a pre-heated 160 °C oil-base and stirred at 160 °C under N2 over 450 min. The mixture was cooled to RT, charged with Na2S04 (300 g) and MTBE (1 L), and stirred for an additional 15 min. The resulting mixture was filtered and the filtrate was charged with 800 mL of water, then the separated aqueous layer was extracted with MTBE. The combined organic layers were washed with water and brine, dried over Na2S04 andconcentrated. The material was recrystallized from EtOH/water (2/1 ) to yield 2,5-Difluoro-4- nitro-benzonitrile (50 g, 68percent yield) as a pale brown solid. H NMR (400 MHz, CDCI3) δ 7.96- 7.95 (dd, 1 H), 7.67-7.64 (dd, 1 H)
Step B 2, 5-difluoro-4-nitrobenzonitrile; A mixture of 1-brom-2, 5-difluoro-4-nitrobenzene (5g, 21 mmol) and 2.44 g (27 mmol) of CuCN in 20 ml of DMF is heated at 160C in a sealed tube, under argon atmosphere overnight. The mixture is washed with 50 ml of water and NH40H (3x20 ml) and then extracted with CH2Cl2 (3 x 100ml). The organic phase is dried over MgS04 and evaporated to give 3.8 g of the title compound, which is used in next step without further purification.
With aluminum oxide; potassium fluoride;18-crown-6 ether; In acetonitrile; at 20℃; for 1.0h;Heating / reflux;
Step C 2- [4- (5-cyano-4-fluoro-2-nitrophenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester; A mixture of 2, 5-difluoro-4-nitrobenzonitrile (1.6 g, 8.7 mmol), 2.1 g (8. 7 mmol) of 2- (4-hydroxy-2-methylphenoxy)-2-methylpropionic acid ethyl ester (WO 2003072102), 5.25 g of 40% w/w potassium fluoride-alumina, 230 mg (0. 87 mmol) of 18-crown-6 in CH3CN is refluxed under argon atmosphere. After 1 hour, the mixture is cooled to rt, partitioned between equal parts of ether and water, and shaked vigorously. The aqueous layer and alumina sediments are separated, and the resulting organic phase is washed once with a saturated potassium chloride solution. The organic phase is dried over MgS04, and concentrated in vacuo. The crude is purificated by silica gel chromatogaphy (hexane/ethyl acetate 15: 1) to yield 2,4 g of the title compound.
In N,N-dimethyl-formamide; at 150 - 155℃;Large scale;
1280 g of 2,5-difluoro-4-nitrobromobenzene was added to the reaction vessel. 6580 mL DMF, temperature control to 150 C, slowly add 728 g of cuprous cyanide solids under stirring. During the addition, the temperature should not exceed 155 C. After the addition, The reaction was stirred and the GC was followed until the reaction was completed. After the reaction is completed, the reaction product is poured into water, a solid is precipitated, suction filtration, and 1,2-dichloroethane is added for extraction. Then suction filtration, liquid separation, rotary steaming, drying, Obtained 688 g of 2,5-difluoro-4-nitrobenzonitrile as a white powdery solid. The content was 97%, and the yield was 69.8%.
68%
In 1-methyl-pyrrolidin-2-one; at 160℃; for 7.5h;Inert atmosphere;
2,5-Difluoro-4-nitrobenzonitrile A mixture of 1-bromo-2,5-difluoro-4-nitro-benzene (95 g, 399 mmol) and CuCN (71.8 g, 798 mmol) in NMP (700 ml.) was set to a pre-heated 160 C oil-base and stirred at 160 C under N2 over 450 min. The mixture was cooled to RT, charged with Na2S04 (300 g) and MTBE (1 L), and stirred for an additional 15 min. The resulting mixture was filtered and the filtrate was charged with 800 mL of water, then the separated aqueous layer was extracted with MTBE. The combined organic layers were washed with water and brine, dried over Na2S04 andconcentrated. The material was recrystallized from EtOH/water (2/1 ) to yield 2,5-Difluoro-4- nitro-benzonitrile (50 g, 68% yield) as a pale brown solid. 1H NMR (400 MHz, CDCI3) delta 7.96- 7.95 (dd, 1 H), 7.67-7.64 (dd, 1 H).
In 1-methyl-pyrrolidin-2-one; at 160℃; for 7.5h;Inert atmosphere;
2,5-Difluoro-4-nitrobenzonitrileA mixture of 1-bromo-2,5-difluoro-4-nitro-benzene (95 g, 399 mmol) and CuCN (71.8 g, 798 mmol) in NMP (700 mL) was set to a pre-heated 160 C oil-base and stirred at 160 C under N2 over 450 min. The mixture was cooled to RT, charged with Na2S04 (300 g) and MTBE (1 L), and stirred for an additional 15 min. The resulting mixture was filtered and the filtrate was charged with 800 mL of water, then the separated aqueous layer was extracted with MTBE. The combined organic layers were washed with water and brine, dried over Na2S04 andconcentrated. The material was recrystallized from EtOH/water (2/1 ) to yield 2,5-Difluoro-4- nitro-benzonitrile (50 g, 68% yield) as a pale brown solid. H NMR (400 MHz, CDCI3) delta 7.96- 7.95 (dd, 1 H), 7.67-7.64 (dd, 1 H)
Add 680 g of cyanide to the reaction vessel. 15% sodium hydroxide solution 340 g, Stir, heat, reflux at around 95, GC tracking until the reaction is over, slightly cold, Add hydrochloric acid under stirring to adjust the pH of the solution to about 1, slightly cold, Pour into ice water to precipitate a solid product, suction filtration, and dry. Obtained 518 g of a white solid. The content is more than 97%, and the yield is 76%.
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