Reference of 1996-29-8, In the next few decades, the world population will flourish. As the population grows rapidly and people all over the world use more and more resources, all industries must consider their environmental impact. 1996-29-8, name is 1-Bromo-4-chloro-2-fluorobenzene belongs to chlorides-buliding-blocks compound, it is a common compound, a new synthetic route is introduced below.
N. 2-CHLORO-5-CYCLOPROPYL-6-FLUOROANILINE The preparation is an adaptation of a method described in Tetrahedron Lett, Vol. 37, p. 6551 (1996). A solution of lithium DIIOSOPROPYL amide is generated by adding n-BuLi (360 mL of 2 M solution in THF) to diisopropylamine (73 g, 0.722 mol) in 500 mL of anhydrous THF while a reaction temperature OF-60C is maintained by cooling in dry-ice acetone bath. After stirring for 30 minutes, 1-bromo-4-chloro-2-fluorobenzene (75 g, 0.36 mol) is added and stirring maintained AT-70C for 2 hours. The cold solution is then transferred, via a canula, under an inert atmosphere to a suspension of solid C02 (100 g, excess) in anhydrous ET2O. The mixture is allowed to warm to room temperature with stirring and then the solvent removed by rotary evaporator. The residual solid is treated with 1 N HCI solution until PH = 3.0 and the mixture is filtered. The white solid that is obtained is suspended in 1000 mL of 2 N HCI solution and stirred for an additional 1 hour. The suspension is filtered to collect a white solid which is air dried, suspended in 100 mL of hexanes and collected to give 2-CHLORO-5-BROMO-6-FLUOROBENZOIC acid. 2-Chloro-5-bromo-6-fluorobenzoic acid (91 g, 0.36 mol) is suspended in CH2CI2 (200 mL) and treated with oxalyl chloride (51 g, 0.40 mol) by dropwise addition, immediately followed by the addition of several drops (0.1 mL) of DMF. The mixture is stirred at room temperature for 3 hours during which time the solid completely dissolves and a clear solution is obtained. The solvent is removed by rotary evaporator and the residue is added to 1000 mL of ammonium hydroxide while stirring at 0C. The product is collected by filtration and washed with water to give 2-chloro-5-bromo-6-fluorobenzamide as a white solid. A solution of sodium methoxide is generated by treating metallic sodium (18 g, 0.78 mol) with 1000 mL of anhydrous methanol by dropwise addition under an inert atmosphere. After the metal is completely consumed the solution is heated at reflux temperature for 30 minutes and then cooled to room temperature. 2-Chloro-5-bromo-6-fluorobenzamide (65 g, 0.26 mol) is added and stirring continued for an additional 30 minutes at room temperature. N-BROMOSUCCINIMIDE (92 g, 0.52 mol) is then slowly added via a powder addition funnel. The reaction mixture is warmed to 60C for 30 minutes during which time foaming is observed. The reaction mixture is cooled to room temperature and most of the solvent is removed by rotary evaporator. The residue is partitioned between EtOAc (1000 mL) and water (1000 mL). The organic layer is separated and washed with water (5 x 500 mL) and then brine (2 x 500 mL). The organic layer is dried (MGS04), filtered and concentrated by rotary evaporator to GIVE N- (2-CHLORO-5-BROMO-6-FLUOROPHENYL)-CARBAMIC acid methyl ester as a light yellow solid (m. p. 107-112C). N-(2-chloro-5-bromo-6-fluorophenyl)-carbamic ester methyl ester (8.65 g, 30.6 MMOL), cyclopropylboronic acid (3.16 g, 36.7 MMOL), potassium phosphate (22.8 g, 107 MMOL), palladium acetate (343 mg, 1.53 MMOL) and tricyclohexylphosphine (858 mg, 3.06 MMOL) are combined and stirred in a two-phase solution comprised of toluene (350 mL) and water (75 mL). The mixture is degassed by repeated alternating application of vacuum and positive nitrogen pressure (10 x). The mixture is heated to 95C for 4 days and then cooled to room temperature. The reaction mixture is partitioned between EtOAc (500 mL) and water (500 mL). The organic phase is washed with water (2 x 250 mL), brine (500 mL) and then dried (MGS04) and concentrated by rotary evaporator. The crude product is purified using flash chromatography (7-14% EtOAc/hexanes). After evaporation of the appropriate fractions the product is further purified by treating a solution in ET20 (100 mL) with charcoal, followed by filtration through Celite and evaporation. N- (2-chloro-5- cyclopropyl-6-fluorophenyl)-carbamic acid methyl ester is obtained as a white crystalline solid (m. p. 100-102C). N-(2-CHLORO-5-CYCLOPROPYL-6-FLUOROPHENYL)-CARBAMIC acid methyl ester (2.3 g, 9.4 MMOL) is dissolved in MeOH (50 mL), water (50 mL) and 30% NAOH solution (50 mL). The reaction mixture is heated to reflux temperature for 3 days and then cooled to room temperature. The reaction is concentrated by rotary evaporator to remove most of the methanol and then partitioned between ET20 (250 mL) and water (250 mL). The aqueous phase is extracted again with ET20 (150 mL) and the-combined organic layers washed with brine (250 mL), dried and concentrated by rotary evaporator. The crude product is purified by bulb-to-bulb distillation. 2-Chloro-5-cyclopropyl-6-fluoroaniline is isolated as a colorless oil (b. p. 120-135C at-20 mm of Hg).
The synthetic route of 1-Bromo-4-chloro-2-fluorobenzene has been constantly updated, and we look forward to future research findings.
Reference:
Patent; NOVARTIS AG; NOVARTIS PHARMA GMBH; WO2004/48314; (2004); A1;,
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