1-(5-Bromo-2-fluorophenyl)ethanone

Chromium trioxide (2.6 g, 26.0 mmol) was dissolved in water (3.7 ml) and cooled in an ice bath. Concentrated sulfuric acid (2.2 ml) was added over 5 min, and the solution was diluted with water (7.4 ml). The mixture was then added dropwise to a solution of the product from Step A (5.7 g, 26.0 mmol) in acetone (17 ml) at 0-20° C. over 30 min. The resultant solution was allowed to warm to room temperature over 14 h. It was then partitioned between ether (300 ml) and water (300 ml) and the organic phase removed. The aqueous phase was washed with ether (100 ml) and the combined organic phases were dried over sodium sulfate then concentrated, providing the ketone (5.2 g, 92percent) as a dark liquid: [00200] 1 -(5-Bromo-2-fluro-phenyl)-ethanone: 5-Bromo-2-fluro-phenyl- methanol (50.0g, 228 mmol) along with 300 mL DCM was charged into 2 liter round bottom flask. Crushed pyridinum dichromate (171.Og, 456 mmol) and powdered molecular sieves (10 g) were both added into the flask. The heterogeneous reaction mixture was stirred for 16 hours at 2OCrushed pyridinum dichromate (171.Og, 456 mmol) and powdered molecular sieves (10 g) were both added into the flask. The heterogeneous reaction mixture was stirred for 16 hours at 20 I. 1-(5-bromo-2-fluorophenyl)ethan-1-one. To a solution of 1-(5-bromo-2-fluoro phenyl)ethan-1-ol (8.66 g., 39.54 mmol) in 1, 4-dioxane (175 mL)was added MnOExample 102B To a solution of 1-(5-bromo-2-fluoro-phenyl)-ethanol (37 g, 168mmol) in CHStep 2 [0202] To a solution of Compound 2 (14.01 g) in ethyl acetate (150 ml) was added 2-iodoxybenzoic acid (35.8 g), and the mixture was refluxed for 7 hours. The reaction solution was cooled in an ice bath and the precipitated solid was removed by filtration. The filtrate was evaporated under reduced pressure to afford Compound 3 (13.66 g) [0203] A solution of 5-bromo-2-fluoro-benzoic acid (3.50 g, 16 mmol) in dichloromethane (70 ml) was cooled to 0° C. and treated with triethylamine (1.725 g, 17 mmol), N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (3.032 g, 16 mmol), 4-dimethylamino-pyridine (0.097 g, 0.8 mmol), and N, O-dimethyl-hydroxylamine (1.774 g, 18 mmol). The reaction mixture was left to warm to room temperature and stirred for 16 hours. For the workup, the reaction mixture was diluted with dichloromethane (100 ml) and, consecutively, extracted with water (50 ml), citric acid (10percent, 50 ml), and saturated sodium hydrogen-carbonate solution (50 ml). The organic layer was dried over sodium sulfate, then evaporated. The crude 5-bromo-2-fluoro-N-methoxy-N-methyl-benzamide material (3.73 g, 91percent of theory) was sufficiently pure and was directly engaged in the next step. In a dried flask, a solution of methylmagnesium chloride (3M in tetrahydrofuran, 5.69 ml, 17 mmol) in tetrahydrofuran (24 ml) was treated at 12-16° C. with a solution of 5-bromo-2-fluoro-N-methoxy-N-methyl-benzamide (3.73 g, 14.2 mmol) in tetrahydrofuran (24 ml). After complete addition, the reaction mixture was heated to reflux. After 20 minutes, the white suspension was quenched under ice cooling with a saturated solution of ammonium chloride (25 ml). After dilution with ethyl acetate (50 ml), the aqueous layer was separated and re-extracted with ethyl acetate (50 ml). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate, and evaporated at reduced pressure. 1-(5-bromo-2-fluoro-phenyl)-ethanone was obtained as a light yellow solid (2.6 g, 84percent of theory), which was directly engaged in the next step. RTo a 0° C. stirred solution of 5-bromo-2 fluoro-benzaldehyde (5.00 g, 24.6 mmol) in anhydrous ether (100 mL) under nitrogen gas was added via syringe MeMgBr (3M solution in ether, 10 mL, 30 mmol) over 3 min. After 30 min, TLC showed the reaction completed. The mixture was poured into a saturated solution of sodium bicarbonate (100 mL), the organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give a viscous oil. The oil was mixed with acetone (100 mL) and treated with Jones reagent (1.1 M, 40 mL, 1.79 mmol). The mixture was stirred overnight, acetone was evaporated and the residue was extracted with ethyl acetate (60 mL.x.2). The extracts were washed with water (50 mL) and then a saturated aqueous solution of sodium bicarbonate (50 mL). Evaporation gave the ketone as an oil (4.63 g, 87percent) that was used in the next reaction without further purificationTo a 0° C. stirred solution of 5-bromo-2 fluoro-benzaldehyde (5.00 g, 24.6 mmol) in anhydrous ether (100 mL) under nitrogen gas was added via syringe MeMgBr (3M solution in ether, 10 mL, 30 mmol) over 3 min. The mixture was poured into a saturated solution of sodium bicarbonate (100 mL), the organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give a viscous oil. The oil was mixed with acetone (100 mL) and treated with Jones reagent (1.1 M, 40 mL, 1.79 mmol). The mixture was stirred overnight, acetone was evaporated and the residue was extracted with ethyl acetate (60 mL.x.2). The extracts were washed with water (50 mL) and then a saturated aqueous solution of sodium bicarbonate (50 mL). Evaporation gave the ketone as an oil (4.63 g, 87percent) that was used in the next reaction without further purification.Preparation of 1-(5-Bromo-2-fIuorophenyI)ethanone (15)To a stirred solution of compound 14 (106 g, 404 mmol) in anhydrous THF (1.7 L) was added a solution of methyl magnesium bromide in diethyl ether (3.0 M, 270 mL, 808 mmoi) at 0 °C under nitrogen. After addition was completed, the reaction mixture was stirred at 0 °C for 6.5 h. After this time, the solution was poured to a coid 2 N hydrochloric acid (1 L) and warmed to room temperature. The resulting mixture was extracted with ethyl acetate (2 x 1 L). The combined extracts were washed with saturated aqueous NaHC0Method D Method D 500 ml of dry reaction flask was charged with 26.3 g of compound, 160 g of ether, cooled to -80 to -90 ° C with stirring under nitrogen, and a solution of lithium diisopropylamide (2. Omol / L tetrahydrofuran solution ) 86 ml. After completion of the dropwise addition, the reaction was stirred at -80 to -90 ° C for 1 hour and cooled to -90 to -100 ° C. Take 1 liter of dry reaction flask, add methyl acetate 110 grams, stirring under nitrogen and stirring to -90 ~ -100 ° C, slowly dropping the prepared aryl lithium solution, after the end of the feeding, in -90 ~-100 ° C The reaction was continued for 1 hour. Reaction system back to -50 ° C, add 15 grams of formic acid, continue to warm to 0 ° C, add 150 grams of water, stirring at room temperature for 10 minutes, standing, separating the organic phase, the water phase with 50 grams of ether extraction , The organic phase was combined, dried, concentrated and distilled to give 26.7 g of compound (III) and 99.6percent pure.1 ml of dry reaction flask was added 42.5 g of diisopropylamine and 175 g of anhydrous tetrahydrofuran. The mixture was cooled to -40 to 50 ° C with stirring under nitrogen and a solution of n-butyllithium (2.5 mol / L n-hexane solution ) Was added dropwise, and the mixture was stirred at -40 to -50 ° C for 1 hour, cooled to -70 to -80 ° C, and 70 g of a mixed solution of the compound(I) and 70 g of anhydrous tetrahydrofuran was added dropwise After completion, stir at -70 to -80 ° C for 1 hour and cool to -80 to -90 ° C. Another 1 liter of dry reaction flask, add ethyl acetate 140 grams, stirring under nitrogen and stirring to -80 ~ -90 ° C, slowly dropping the prepared aryl lithium solution, after the end of the additive, in -80 ~ -90 ° C The reaction was continued for 1 hour. The reaction system was warmed to -20 ° C and diluted to 250 g of 15percent sulfuric acid solution. The mixture was stirred at room temperature for 10 minutes. The organic phase was separated and the aqueous phase was extracted with 100 g of ethyl acetate. The organic phase was combined, Dried, concentrated and distilled to give 70.5 g of compound (III), purity of 99.5percent.