4-Bromo-2-fluoro-N-methylbenzamide

Compound 9 (2.2 g, 10 mmol) was added to anhydrous ethylene glycol dimethyl ether (20 mL).The solution was cooled to 0 ° C, and thionyl chloride (1.5 g, 13 mmol) was slowly added under stirring. The reaction was mildly exothermic, and the temperature of the solution did not exceed 5 ° C during the addition of thionyl chloride. After reacting at 0 ° C for 1 h, the solution is reacted at 50 ° C for not less than 6 h or TLC monitoring shows that the reaction is complete, the solution temperature is lowered to 25 ° C, and it will be dissolved in ethylene glycol dimethyl ether (5 mL).A solution of methylamine (0.9 g, 30 mmol) was slowly added dropwise thereto, and the mixed solution was reacted at 35 ° C for 0.5 h or TLC monitoring showed that the reaction was completed, the reaction was stopped, and saturated brine (15 mL) was added, and ethyl acetate (2) *15mL), extracted, layered, combined with organic layer, dried over anhydrous sodium sulfate, filtered.Concentration and drying gave a white solid in a yield of 88-93percent.Step 1 : 4-Bromo-2-fluoro-N-methylbenzamide To a 100 niL flask is added 4-bromo-2-fluorobenzonic acid (3.0 g, 13.7 mmol), 2 M methylamine (34.3 mL, 68.5 mmol), EDCI (6.6 g, 34.25 mmol), HOBt (2.8 g, 20.6 mmol), jV, jV-diisopropylethylamine, and DMF (50 mL). The reaction mixture is stirred at room temperature for 16 hrs. Then water (50 mL) is added. The aqueous phase is isolated and extracted with ethyl acetate (3 X 50 mL). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified on a silica gel flash chromatography with ethyl acetate/petroleum ether (1 :3 ) to yield the titled compound as a white solid (2.34 g, 74percent yield). (MS: [M+l] 232)4-Bromo-2-fluoro-N-methyl-benzamide A solution of 4-bromo-2-fluorobenzoic acid (0.8g, 3. 7MMOL), methylamine (3.65mL, 7. 3MMOL), EDC (1.4g, 7. 3MMOL), triethylamine (1. 0ML, 7. 3MMOL) dissolved in CH2CI2 (15ML) was stirred under N2 for 24h. The reaction mixture was partitioned between 1 N HCI and EtOAc. The organic layers were washed with saturated NAHC03, brine, dried over dried over NA2SO4AND concentrated. The residue was purified by silica gel chromatography (40percent EtOAc in hexanes) to give the title compound as a white solid (0.27g, 32percent). H NMR (CDC13) : 5 3.03 (d, 3H, J= 6.0 Hz), 6.68 (BR S, 1H), 7.32 (d, 1H, J= 11.3 Hz), 7.42 (d, 1H, J= 10.2 Hz), 8.01 (t, 1H, J= 8.5 Hz).A solution of 4-bromo-2-fluorobenzoic acid (0.8 g, 3.7 mmol), methylamine (3.65 mL, 7.3 mmol), EDC (1.4 g, 7.3 mmol), triethylamine (1.0 mL, 7.3 mmol) dissolved in CH4-Bromo-2-fluorobenzoic acid (2.Og, 9.1 mmol) was added to DCM, to this was added oxalyl chloride (1.2 ml, 13.7 mmol) and 4 drops of DMF, the reaction was stirred until no gas was liberated (approx 30 mins). To the reaction was added triethylamine (6.3 ml, 46.0mmol) followed by methylamine (10 ml, 2.0N in THF). The reaction was stirred for 10 mins before being quenched with HCl (2.0 N, 50 ml), extracted with DCM (2 x 100 ml), dried and the solvent was removed in vacuo. The obtained solid was purified by passing through a plug of silica eluting with DCM, the obtained yellow solid was added to 20percent ether/isohexane and stirred for 10 minutes before being filtered and dried. A white solid was obtained (1.Ig, 52percent). NMR (299.954 MHz, CDClCompound 49: (4-Bromo-2-fluoro-benzyl)-methyl-amine. (1029) A mixture of 4-bromo-2-fluorobenzoic acid (1.0 equiv.), methylamine hydrochloride (1.1 equiv.), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.1 equiv.) and diisopropylethylamine (3.3 equiv.) in dichloromethane (0.20 mol.LN, N-Dimethylformamide (0.5 mL, 0.006 mol) was added to the suspension of 4-bromo-2- fluorobenzoic acid (10.0 g, 0.045 mol) in dichloromethane (70 mL) at 10 to 15 °C. To the reaction mixture oxalyl chloride (8.0 mL, 0.093 mol) was added drop wise and stirred at 25- 30°C for 2 to 3 hrs. Distill off the solvents to get residue. Methyl tertiary butyl ether (100 mL) was added to the residue and cooled to 10 to 15 °C. To the obtained reaction mixture aqueous methyl amine (40percent) was added drop wise at a pH around 8 to 9. The reaction mixtures was stirred at 25-30°C for 30 min to 1 hr. Add DM water and stir for 30 min and separate the organic layer. The aqueous layer was extracted twice with Dichloromethane (2 x 100 ml) and combined organic layer washed with 5percent citric acid solution (100 mL). The organic layer was washed with 100 ml of 5percent NaHC0200 g of 2-fluoro-4-bromobenzoic acid was dissolved in 1400 mL of ethyl acetate at room temperature and then under nitrogen, To the mixture was added 1 g of N, N-dimethylformamide and 150 g of thionyl chloride, After the addition of the starting material, the reaction was refluxed for 4 hours and concentrated to dryness to give 230 g of crude 4-bromo-2-fluorobenzoyl chloride, Add 1000mL of ethyl acetate to dissolve, The solution was slowly added dropwise to a mixture of 800 mL of methylamine and ethyl acetate (1: 1 by volume)Temperature control at 30 ~ 35°C , continue to stir the reaction 15min, with TLC detection reaction is complete, Add 400 mL of saturated brine to the aqueous layer, add 500 mL of ethyl acetate, layer, combine the organic phase, Dried over anhydrous sodium sulfate, filtered, concentrated and dried to give 195 g of a white solid in 92percent yield.

Molecular Weight:232.05
XLogP3:2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:230.96950
Monoisotopic Mass:230.96950
Topological Polar Surface Area:29.1
Heavy Atom Count:12
Complexity:176
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes