6-CHLORO-2-FLUORO-3-METHYLANILINE synthesis

Yield:-

Reaction Conditions:

with sodium hydroxide;water in methanol; for 72 h;Heating / reflux;

Steps:

1.M M. 2-CHLORO-4-CYCLOPROPYL-5-METHYL-6-FLUOROANILINE

M. 2-CHLORO-4-CYCLOPROPYL-5-METHYL-6-FLUOROANILINE 2-Chloro-5-methyl-6-fluorobenzoic acid (43 g, 0.25 mol) is suspended in CH2CI2 (500 mL) and treated with thionyl chloride (36 mL, 0.49 mol) by dropwise addition, immediately followed by the addition of several drops (0.1 mL) of DMF. The mixture is heated to reflux temperature and stirred for 12 hours during which time the solid completely dissolves and a clear solution is obtained. After cooling to room temperature, most of the solvent is removed by rotary evaporator and toluene (500 mL) is added. The solution is again concentrated by rotary evaporator to remove residual thionyl chloride. The light yellow oil that results is filtered through a plug of cotton and dissolved in CH2CI2 (1000 mL). The organic layer is washed with brine (500 mL), dried (MGS04) and concentrated by rotary evaporator. The white solid, which results, is triturated with hexanes/Et20 (4: 1,500 mL) and collected to provide 2-chloro-5-methyl-6-fluorobenzamide as a white solid (m. p. 151-153°C). A solution of sodium methoxide is generated by treating metallic sodium (29 g, 1.26 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-methyl-6- FLUOROBENZAMIDE (42 g, 0.22 mol) is added and stirring continued for an additional 30 minutes at room temperature. N-Bromosuccinimide (78 g, 0.44 mol) is then slowly added via a powder additional funnel. The reaction mixture is warmed to 60°C for 3 hours 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 (500 mL) and then brine (2 x 500 mL). The organic layer is dried (MGS04), filtered and concentrated by rotary evaporator. the crude product is then purified using flash chromatography, eluting with 4: 1 hexanes/EtOAc to give N- (2-chloro-5-methyl-6- fluorophenyl)-carbamic acid methyl ester as a white solid (m. p. 109-112°C). N-(2-chloro-5-methyl-6-fluorophenyl)-carbamic acid methyl ester (39 g, 0.18 MMOL) is dissolved in MeOH (150 mL), water (150 mL) and 30% NaOH solution (150 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 (500 mL) and water (500 mL). The aqueous phase is extracted again with ET20 (250 mL) and the combined organic layers washed with brine (500 mL), dried and concentrated by rotary evaporator. The crude product is purified by bulb-to-bulb distillation to give 2-chloro-5-methyl-6-fluoroaniline as a colorless oil (b. p. 120-131 °C AT-20 mm of Hg), which forms a white crystalline solid upon storage at 4°C. 2-Chloro-5-methyl-6-fluoroaniline (23 g, 0.14 mol) and N-bromosuccinimide (25 g, 0.14 mol) are dissolved with stirring in 200 mL of anhydrous DMF. The reaction mixture is stirred overnight and then most of the DMF is removed by rotary evaporator under high vacuum. The dark brown residue is partitioned between 1: 1 ET2O/HEXANE (500 mL) and water (500 mL). The organic layer is washed with brine (5 x 250 mL), dried (MGS04) and concentrated by rotary evaporator. The crude material is purified using flash chromatography (20% CH2CI2/hexanes) and then further purified by bulb-to-bulb distillation (b. p. 155-165°C at-20 mm of Hg) to give 2-chloro-4-bromo-5-methyl-6-fluoroaniline as a peach-colored solid which is RE-C-RYSTALLIZED from ice-cold hexanes (m. p. 67-71 °C). 2-Chloro-4-bromo-5-methyl-6-fluoroaniline (6.5 g, 27 MMOL), cyclopropylboronic acid (2.8 g, 33 MMOL), tetrakis (triphenylphosphine) palladium (0) (1.4 g, 1.3 MMOL), potassium phosphate (20.2 g, 95 MMOL) and tricyclohexylphosphine (0.77 g, 2.7 MMOL) are combined and stirred in 200 mL of a 4: 1 DME/water solution. The mixture is degassed by repeated alternating application of vacuum and positive nitrogen pressure (10 x). The mixture is heated to reflux temperature for 2 days and then cooled to room temperature. Most of the DME is removed by rotary evaporator and the residual mixture is partitioned between Et2O (250 mL) and water (250 mL). The organic phase is washed with brine (3 x 250 mL), dried (MGS04) and concentrated by rotary evaporator. The crude product is purified using flash chromatography (8% CH2CI2/HEXANES) to give 2-chloro-4-cyclopropyl-5-methyl-6- FLUOROANILINE as a tan oil.

References:

WO2004/48314,2004,A1 Location in patent:Page 32-33