5-Bromo-4-(trifluoromethyl)-2-pyridinamine

To a solution of compound 28 (500mg, 3.1 mmol) in DCM (40 mL) was added NBS (600mg, 3.3 mmol). The solution was stirred in the dark for 2 hours at rt. Then the reaction was quenched with iN NaOH (50 mL) and extracted with DCM (50 mL). The organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified with silica gel column chromatography using Petroleum ether : Ethyl acetate (10:1) affording to compound 29 (700 mg, 94percent) as a light yellow solid. ‘H NIVIR (CDC13): 8.28(s, 1H), 6.77(s, 1H), 4.78(bs, 2H).N-bromo succinimide (20.83g, 117 . 0mmol) was added to thf (100 ml), the 2-amino-4 - (trifluoromethyl) pyridine (18.07g, 111 . 5mmol) dissolved in tetrahydrofuran (250 ml) was slowly added to the above-mentioned solution, keeping the temperature at 0 °C, after dripping slowly to room temperature, the reaction was stirred at room temperature for 1 hour. adding sodium thiosulfate (4.65g) aqueous solution (90 ml) quenching, concentrated, crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) purified title compound (24.4g, yield 91percent).4-trifluoromethyl-2-aminopyridine (10g, 61.69mmol) was dissolved in CH4-Trifluoromethyl-2-aminopyridine (10 g, 61.69 mmol) was dissolved in CHStep 1: 5-Bromo-4-(trifluoromethyI)pyridin-2-amineTo a stirred solution of 4-(trifuioromethyl)pyridine-2amine (2.5 g, 0.01542 mol) in dichloromethane (250 mL) was added N-bromosuccinimide (2.74 g, 0.01542 mol) in portions under dark conditions at room temperature and stirring was continued at room temperature for 6 h. The reaction mixture was diluted with IN NaOH solution (20 mL) and extracted with DCM (2x100 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure to afford the title compound (3.2 g, 86percent). *H NMR (400 MHz, CDCITo a solution of 2-amino-4-trifluoromethyl pyridine (5, 15.0 g, 93 mmol) in chloroform (300 mL) was added N-bromosuccinimide (18.0 g, 99 mmol) at 0 °C. Weighing N-bromo succinimide (1.12g, 6 . 3mmol) is added to thf (7.25 ml) in, cooling to 0 °C, the 4 - (trifluoromethyl) pyridin-2-amine (0.97g, 6mmol) dissolved in tetrahydrofuran (5.75 ml) in, dropping slowly added to the above-mentioned solution, keeping the temperature at 0 °C, after dripping, slowly to room temperature, stirring 0.5 hours, adding sodium thiosulfate (0.25g) aqueous solution (4.75 ml) quenching, concentrated, crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) purification, to obtain the title compound (1.2g, yield 83.3percent).Method 7; Synthesis of 5-bromo-4-(trifluoromethvl)-2-pvridylamine; [0247] To a solution of 2-amino-4-trifluoromethylpyridine (10.0 g, 62.1 mmol) in chloroform (200 mL) was added NBS (12.0 g, 67.4 mmol). The solution was stirred in the dark for 2 hours, at which time it was added to DCM (200 mL) and IN NaOH (200 mL). Upon mixing, the layers were separated and the organic layer was washed with NaCl(sat) (10O mL), dried over Na0246] To a solution of 2-amino-4-trifluoromethylpyridine (10.0 g, 62.1 rnrnol) in chloroform (200 mL) was added N-bromosuccinimide (12.0 g, 67.4 mmol). The solution was stirred in the dark for 2 hours, at which time it was added to CH[0087] Synthesis -bromo-4-(trifluoromethyl)-2-pyridylamine[0088] To a solution of 2-amino-4-trifluoromethylpyridine (10.0 g, 62.1 mmol) in chloroform (200 mL) was added N-bromosuccinimide (12.0 g, 67.4 mmol). The solution was stirred in the dark for 2 hours, at which time it was added to CH5-Bromo-4-(trifluoromethyl)pyridin-2-amine (4a); 4b 4aCharge a nitrogen-flushed 3 L reactor that equipped with an overhead stirrer, condenser, nitrogen inlet/outlet and rubber septum with 112.14 g (0.63 mol) of N-bromosuccinimide (NBS) and 645 g (725 mL) of tetrahydrofuran. Stir and cool the slurry to -5 +/- 3 °C. Charge a nitrogen- flushed 1 L round bottom 4-neck flask that equipped with a thermocouple, mechanical stirrer and nitrogen inlet / outlet with 97.26 g (0.6 mol) of 2-amino-4-(trifluoromethyl)pyridine, 4b and 511 g (575 mL) of tetrahydrofuran. Stir to dissolve the 4b. Transfer the 4b solution to the addition funnel on the reactor and add the solution to the NBS slurry over 2 h maintaining an internal temperature of 0 +/- 3 °C throughout the addition. Rinse the 1 L flask and addition funnel with 44 g (50 mL) of tetrahydrofuran and add the wash to the reaction mixture. Warm the solution to 20 + 3 °C over 30 minutes. Check for completeness of the reaction. Quench by charging a solution of 24.6 g of sodium thiosulfate pentahydrate dissolved in 475 mL of water over 10 minutes, maintaining a batch temperature of 20 +/- 3 °C throughout the addition. Stir for 1 h after the quench. Concentrate (internal temp = 25 °C, 50 mbar) to remove tetrahydrofuran. Add 379 g (500 mL) of fert-butyl methyl ether. Stir and warm the resulting solution/suspension to 30 +/- 3 °C and stir for 15 minutes. Separate the phases. Wash the extract four times with a solution of 32 g of sodium chloride dissolved in 768 g (768 mL) of water (4 x 200 mL per wash), separating the phases after each wash. Finally, wash the extract with 150 g (150 mL) of water. Separate the phases. Charge 152 g (200 mL) of terf-butyl methyl ether. Partially concentrate (57 +/- 3 °C) to a volume of 350 mL. Cool to 50 °C and add 265 g (350 mL) of ferf-butyl methyl ether. Resume the concentration (57 +/- 3 °C) until a batch volume of 350 mL is reached. Cool to 50 °C and add 265 g (350 mL) of fe/f-butyl methyl ether. Again, resume the concentration (57 +/- 3 °C) until a batch volume of 350 mL is reached. Cool to 50 °C and add 103 g (150 mL) of terf-butyl methyl ether to raise the batch volume to 500 mL. Charge 1026 g (1500 mL) of heptane over 15 minutes maintaining 45 +/- 3 °C throughout the addition. Slowly increase the vacuum and concentrate (internal temp = 40 °C to 50 °C) to a batch volume of 1000 mL. Release the vacuum and seed the batch. Resume the distillation, further increase the vacuum (slowly) and concentrate (internal temp = 25 °C to 40 °C) to a batch volume of 500 mL. Stir the resulting suspension at 0 °C for 30 min. Filter the solids. Wash the filter cake with 68 g (100 mL) of cold (0 °C) heptane (containing 30 ppm Octastat). Dry the solids (40 °C, 50 mbar) for 16 h to afford 109.8 g (78.0percent yield) 4a as an orange solid.Step l : To a solution of compound [78] (3.5 g, 21.6 mmol, 1 eq) in chloroform (50 ml) was slowly added NBS (4.6 g, 25.9 mmol, 1.2eq) at 0°C temperature. The reaction mass was stirred at room temperature for 3 hrs. Reaction mass was diluted with 50 ml of chloroform and washed with water and brine, dried over anhydrous sodium sulphate, and then evaporated to obtain a brown solid as a crude material. Purification of the solid residue was done by column chromatography with silica gel ( 100: 200 mesh) in solvent system 5percent EtOAc in cyclohexane to get compound [79] as brown solid (4 g, 77 percent). ESIMS: 241 (MExample 27: Preparation of 5-bromo-4-(trifluoromethyl)pyridin-2-amine To a stirred solution of 4-(trifluoromethyl)pyridin-2-amine (5.00 g, 30.8 mmol) in dichloromethane (80 mL) added N-bromosuccinimide (5.55 g, 30.8 mmol). The solution stirred at ambient temperature for 2 hours. 1 M aqueous sodium hydroxide and dichloromethane were added and the layers separated. The aqueous layer was extracted three times with dichloromethane. The combined organics washed with water, dried over MgS0To a stirred solution of 4-(trifluoromethyl)pyridin-2-amine (5.00 g, 30.8 mmol) in dichloromethane (80 mL) N-bromosuccinimide (5.55 g, 30.8 mmol) was added. The solution was stirred at ambient temperature for 2 hours.1M aqueous sodium hydroxide and dichloromethane were added and the layers separated. Theaqueous layer was extracted three times with dichloromethane. The combined organics werewashed with water, dried over Mg504 and concentrated in vacuo to orange oil. Chromatographyon silica gel gave an orange solid (5.682 g, 76percent)1H NMR CDCI3 ö 8.29 (s, 1H), 6.78 (s, 1H), 4.74 (br. s, 2H)2-amino-4-trifluoromethylpyridine (5 g, 30.8 mmol, Langfang Beixin Chemical Co., Hebei) was dissolved in 100 mL of chloroform and N-bromosuccinimide (5.92 g, 33.3 mmol) was added in batches. 2-amino-4-trifluoromethylpyridine (5 g, 30.8 mmol, Langfang Beixin Chemical Co., Hebei) was dissolved in 100 mL of chloroform and N-bromosuccinimide (5.92 g, 33.3 mmol) was added in batches. The mixture was stirred in darkness or away from light at room temperature for 3 hours. The reaction mixture was concentrated and purified by column chromatography with gradient elution (petroleum ether: ethyl acetate=10:1 and dichloromethane), so as to give 4.33 g of red solid. Yield: 58.2percent. LC-MS: 240 (M+1), 242 (M+2+1).To a solution of 4-(trifluoromethyl)pyridine-2-amine (6.50 kg, 40.1 mol, 1 Eq) in 2- methyltetrahydrofuran (78 L) was added at 0 °C in ten equal portions N-bromosuccinimide (7.49 kg, 42.1 mol, 1 .05 Eq) during 50 min. The resulting suspension was stirred at 0 °C for 1 h. The solids were removed by filtration. The filter cake was washed with 2-methyl- tetrahydrofuran (10 L). The combined filtrates were mixed with 4percent aqueous sodium carbonate (65 L). The phases were separated and the organic phase was extracted with 2N hydrochloric acid (3 x 20 L and 3 x 10L). The combined aqueous extracts were mixed with 2-methyl-tetrahydrofuran (5 L), deionized water (3 L) and an aqueous sodium hydroxide solution (30percent w/v, 19 L) at such a rate that the temperature did not exceed 20 °C. The pH of the resulting biphasic mixture was adjusted to 8 by addition of a saturated aqueous sodium bicarbonate solution (8percent w/v, 3.4 L). The phases were separated and the slightly turbid brown organic phase was dried over anhydrous sodium sulfate (3.2 kg). The solids were removed by filtration and the filter cake was washed with 2-methyl- tetrahydrofuran (5 L). The solvent was evaporated under reduced pressure. The resulting brown oil (8.35 kg) was dissolved in 2-methyltetrahydrofuran (94 L) at 60 °C and 1 , 1 - dimethoxy-N, N'-dimethylmethanamine (6.8 L, 51.2 mol, 1 .28 Eq) was added during 10 min. The resulting brown solution was stirred at 60 °C for 3 h cooled to 20 °C and mixed with a saturated aqueous sodium bicarbonate solution (8percent w/v, 33 L). The phases were separated and the organic phase was washed twice with an aqueous sodium chloride solution (5percent w/v, 32 L). The organic phase was dried over anhydrous sodium sulfate (3.2 kg). The solids were removed by filtration and the filtercake was washed with 2-methyl- tetrahydrofuran (1 1 L). The combined filtrates were mixed with heptane (39 L) and the mixture was concentrated under reduced pressure. The residue was mixed with heptane (39 L) and the mixture was concentrated under reduced pressure whereby a suspension formed. The suspension was stirred at 0 °C. The solid was collected by filtration and washed with heptane (8 L) to yield the title compound (8.20 kg, 27.7 mol, 69percent, purity 98.0percent a/a) as yellow-brownish solid.

Molecular Weight:241.01
XLogP3:2.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Exact Mass:239.95100
Monoisotopic Mass:239.95100
Topological Polar Surface Area:38.9
Heavy Atom Count:12
Complexity:161
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes