4-BROMO-2-FLUOROACETOPHENONE

Step 2: Intermediate 94Step 2:To a solution of intermediate 19 (step 1) (5.0 g, 22.82 mmol) in DMF (25 ml), pyridinium dichromate (12.8 g, 34.23 mmol) was added at room temperature. After 12h, the reaction mixture was quenched with water, diluted with ethyl acetate and filtered through celite. The organic layer was washed with brine solution and dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as a red colour liquid (4.1 g, 84percent). 'H-NMR (δ ppm, DMSO-dTo a solution of 4-bromo-2-fluoro-N-methoxy-N-methylbenzamide (13 g, 46 mmol) in THF (4.0 mL) was added dropwise methylmagnesium bromide (3M ethyl ether solution, 30 mL, 91 mmol) at 0°C, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a pale yellow oil (10 g, quant.). Preparative Example 46 To a solution of 4-bromo-2-fluoro-N- methoxy-N-methylbenzamide (1.97 g, 7.5 mmol) in dry tetrahydrofuran (50 mL) was added methyl magnesium bromide (3M in diethyl ether, 5.5 mL) at 0 °C. The resulting mixture was allowed to warm to room temperature and then was stirred for 3 h. The reaction mixture was quenched with saturated ammonium chloride, and the organic layer was washed with water and brine, was dried over magnesium sulfate, was filtered and was concentrated to give l-(4- bromo-2-fluorophenyl)ethanone (1.34 g, 83percent yield) as an oil. To a solution of 1 (10 g, 45.7 mmol) in DMF (150 mL) were added HBTU (26 g, 68.5 mmol), dimethylhydroxylamine HCI salt (5.35 g, 54.8 mmol) and DIEA (9.6 mL, 55.0 inmol) at 0°C. After stirring for 2h, the mixture was allowed to warm up to room temperature. Stirring continued for 2 days. The reaction mixture was partitioned between EtOAc (500 mL) and H20 (200 mL). The organic layer was washed with NaOH (2N, 200 mL), HCl (2N, 200 mL), H2O, brine, dried over Na2S04, and concentrated to give 2 (9.6 g), which was used without further purification. LRMS (M+H+) m/z 262.0. [00453] To a solution of 2 (9.6 g, ~36.8 mmol) in Et2O (100 mL) was added MeMgBr (3 M in Et20, 27 ml) at 0°C. The resulting mixture was stirred for 4 h while it was allowed to warm up to room temperature. The reaction mixture was quenched with saturated NH4CI (100 mL). The organic layer was washed with H20, brine, dried over Na2S04, and concentrated to give 3 (7 g, 71 percent from 1), which was characterized by NMR. [00454] To a solution of 3 (6.5 g, 30 mmol) in DCM (200 mL) and MeOH ( 100 mL) was added tetrabutylammonium tribromide (14.5 g, 30 mmol). The reaction mixture was stirred for 14 h. The mixture was concentrated, and dried under high vacuum to give 5 (characterized by NMR), which was used in the next step without further purification. [00455] To a solution of 4 (5 g, ~16.9 mmol) in DCM (50 mL) was added hexamethylenetetramine (2.6 g, 18.5 mmol). The reaction mixture was stirred for 2 h. The mixture was diluted with DCM (500 mL). The precipitate was collected, washed with DCM (500 mL x 2), and dried under high vacuum. To the resulting residue was added EtOH ( 60 mL) and concentrated HCI (30 mL). The reaction mixture was stirred for 2 h. The mixture was concentrated, dried to give 5, which was used without further purification. LRMS (M+H+) m/z 231.9. [00456] To a solution of cmde 5 ((at)16.9 mmol) in dioxane (50 mL) were added NaOAc (6.93 g, 84.5 mmol), HOAc (4.8 mL, 84.5 mmol), and 5.1. (5.93 g, 84.5 mmol). After 1 h, the reaction mixture was warmed up to 80 °C and stirred for 3 h. The reaction mixture was partitioned between EtOAc (500 mL) and saturated NaHC03 (200 mL). The aqueous layer was extracted with EtOAc (300 mL x 2). The combined organic layers were washed with brine, dried over Na2S04, and concentrated. The resulting residue was purified on silica gel (hexane/EtOAc, 1: 0, 1: 2, 1; 1, 0:1) to give 6 (1.2 g, 23percent from 4). LRMS (M+H+) m/z 312.9.[00207] To a solution of 11.2 (9.6 g, -36.8 mmol) in EtTo a solution of 4-bromo-2-fluoro-N-methoxy-N-methylbenzamide (0.8 g, 3.05 mmol) in dry THF (10 mL) at 0 °C was added, MeMgBr (2.0 mL, 6.1 mmol) drop- wise and the reaction was stirred at RT for 3 h. After completion (TLC), it was cooled to 0°C, slowly quenched with aq. NaHC04-Bromo-2-fluoro-thiobenzoic acid S-pyridin-2-yl ester (39 g, 124.94 mmol) from step 1 below was dissolved in THF (500 mL) and cooled to-78 C. MeMgBr 3.0 M solution (45 mL, 137.43 mmol) was added and reaction stirred 1 hour at-78 C. The resulting reaction mixture was poured into NAHC03 (100 mL) and extracted with EtOAC. The combined organics were washed with water (100ML) and brine (100 mL) then dried over NA2SO4, filtered and concentrated. The crude residue was purified by flash chromatography (10percent EtOAc in Hexanes) to yield the intermediate ketone as a colorless oil (20g, 74percent). 1 H NMR (CDCI3) : 8 2.63 (d, 3H, J = 5. 1 Hz, 3H), 7.37 (dd, J = 8.8, 1.9 Hz, 1H), 7.37 (s, 1H), 7.77 (7, J = 8. 8 Hz, 1H). ESIMS (MH+): 218.2.4-Bromo-2-fluoro-thiobenzoic acid S-pyridin-2-yl ester (39 g, 124.94 mmol) from step 1 below was dissolved in THF (500 mL) and cooled to -78° C. MeMgBr 3.0 M solution (45 mL, 137.43 mmol) was added and reaction stirred 1 hour at -78° C. The resulting reaction mixture was poured into NaHCOLithium bis(trimethylsilyl)amide (1.5 M in THF, 50 mL, 75.0 mmol) was added to a mixture of

Molecular Weight:217.03
XLogP3:2.4
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:215.95861
Monoisotopic Mass:215.95861
Topological Polar Surface Area:17.1
Heavy Atom Count:11
Complexity:160
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes