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ChemicalBook CAS DataBase List 2-BROMO-4-FLUORO-6-METHYLANILINE
202865-77-8

2-BROMO-4-FLUORO-6-METHYLANILINE synthesis

1synthesis methods
4-Fluoro-2-methylaniline

452-71-1

2-BROMO-4-FLUORO-6-METHYLANILINE

202865-77-8

Example 1 Step a: Synthesis of 2-bromo-4-fluoro-6-methylaniline N-Bromosuccinimide (18.7 g, 0.105 mol) was dissolved in 70 mL of N,N-dimethylformamide, and the solution was added slowly and dropwise to a solution containing 4-fluoro-2-methylaniline (dissolved in 70 mL of N,N-dimethylformamide) at a reaction temperature of 20 °C. The reaction mixture was stirred overnight. The dark colored reaction solution was poured into a mixture consisting of water (1000 mL), brine (50 mL) and ethyl acetate (300 mL). The mixture was transferred to a dispensing funnel, shaken well and separated. The aqueous phase was extracted with ethyl acetate (4 x 150 mL). The organic layers were combined, washed sequentially with water (5 x 100 mL) and brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The purity of the raw material was shown to be ≥95% by 1H NMR analysis. The product was further purified by silica gel column chromatography (elution system: ethyl acetate/hexane, 1:8). The pure fractions were combined and evaporated to give 14.9 g of product. The impure fractions were combined, concentrated and redissolved in ether (30 mL) and extracted with 5% hydrochloric acid (5 x 10 mL). The acidic aqueous phase was alkalized with aqueous potassium hydroxide and then extracted with ether to give 0.8 g of the target compound. The total yield was 15.7 g (77% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.16 (dd, 3JH-F = 8.3 Hz, 4JH-H = 2.9 Hz, 1H, Ar), 6.91 (dd, 3JH-F = 9.3 Hz, 4JH-H = 2.9 Hz, 1H, Ar), 4.83 (br.s, 2H, NH2), 2.16 (s 3H, CH3).

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Yield: 92%

Reaction Conditions:

with N-Bromosuccinimide in N,N-dimethyl-formamide at -10 - 20; for 16 h;

Steps:

1 Step 1:
To a solution of 4-fluoro-2-methyl-phenylamine (30 g, 0.239 mol) in DMF (450 ml) was added NBS (44.81 g, 0.251 mol) portionwise at -10 °C. The resulting reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with water (1000 ml) and extracted with ethyl acetate (2 x 500 ml). The combined organic layers were washed with water (2 x 500 ml) and brine (250 ml), dried over anhydrous Na2SO4and concentrated to afford the crude compound, which was purified by column chromatography (100-200 mesh silica gel; 10% ethyl acetate/hexane) to afford 2-bromo-4-fluoro-6-methyl- phenylamine (45 g, 92%) as a white solid

References:

GRüNENTHAL GMBH WO2021/144440, 2021, A1 Location in patent:Page/Page column 29-30

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