4-Bromo-3-(trifluoromethyl)aniline

White to off-white crystalline

To 1 L high pressure hydrogenation reactor followed by adding 300 mL of methanol, 284 g step nitro product, Raney Ni 20 g, piperazine 1.0 g. The hydrogen in the kettle was replaced with hydrogen for 3-4 times, then at a pressure of 0.8-1.0 MPa, 80-90°C until the reaction is no longer hydrogen. The reaction solution is cooled to remove the catalyst, remove the methanol, remove the moisture, Simple distillation of light yellow liquid amino 4-bromo-3-trifluoromethyl aniline 250 g, GC content: 95percent yield of 98.8percent. Raney Ni and solvent methanol can be recycled.General procedure: To a solution of substituted aniline 2a or 2b in DMF 100 ml was added to a solution of NBS (92 mmol, 1.0 eq) in DMF 100 ml dropwise. The reaction mixture was stirred at room temperature for 3 h, then diluted with ethyl acetate 500 ml and washed with brine 2 x 150 ml. The organic phase was dried Na2SO4, filtered and concentrated to give the title compound 3a or 3b as brownish solid, 90–92 percent yield. To a solution of 2a or 2b (0.8 mmol) in the selected solvent (1 ml), a solution of NBS (0.8 mmol) in the same solvent (1 ml) was added batch wise at room temperature, and the reaction was monitored by LC–MS/MS. Mixtures were obtained with traces of dibrominated products. 4-Bromo-3-(trifluoromethyl) aniline (3a) Yield: 92 percent; mp 48–50 °C; brownish powder; IR (KBr) ν max: 3485–3362 (N–Hstretch), 2219 (C:N), 1627 (N–Hbend), 1615 1566, 1509, 1467 (C=Carom), 1361, 1185, 1121, 1044 (C–Hbend), 1276, 550 (CF3) cm-1; 1H NMR (CDCl3, 400 MHz, ppm): δ 7.38 (d, 1H, J = 8.8 Hz, C5-H), 6.95 (d, 1H, J = 2.8 Hz, C2–H), 6.63 (dd, 1H, J = 2 Hz, J = 8.4 Hz, C6-H), 3.84 (br s, 2H, –NH2); 13C NMR (100 MHz, CDCl3, ppm): δ 145.7 (C1), 135.5 (C5), 130.6 (C3), 124.3 (C6), 121.6 (CF3), 119.07 (C2), 114.1 (C4); HRMS (ESI): m/z calculated for C7H5 79BrF3N [M–H]-: 237.94847; Found: 237.94478; Calculated for C7H5 81BrF3N [M–H]-: 239.94620; Found: 239. 94250.General procedure: A mixture of 1100 g of 5-acetamido-2-bromotrifluorotoluene (HPLC purity ≥ 96percent) and a mass percentage of 48percent of the liquid caustic soda was added to the four-necked flask (the mass percentage means that the amount The mass of sodium is the percentage of the total mass of sodium hydroxide aqueous solution), the temperature of methanol is 148.5g, the temperature is 90 ° C, the temperature is stirred for 5 hours and then cooled to 65 ° C. The organic layer is washed with water and then layered. Fluoromethyl-4-bromoaniline, the reaction conversion was 99.5percent and the yield was 98.2percent.Charged 4-Bromo-3-(Trifluoromethyl phenyl) acetamide (lOOgm., 0.35 moles) and 14.7percent aqueous solution of hydrochloric acid (224gm., 0.88 moles) at RT to a reaction flask. The temperature of the reaction mixture is raised to 90°C and maintained for 5-6 hrs. Monitor the reaction by HPLC. After complete conversion, the reaction mixture is cooled to 60-65°C. Charged 40percent aqueous solution of NaOH (142gm., 1.42moles) to neutralize the reaction mass. The organic phase was separated and title compound was isolated. Yield (percent): 94percentA solution of Step 1) N- (4-bromo-3- (trifluoromethyl) phenyl) methanesulfonamide To a solution of 4-bromo-3- (trifluoromethyl) aniline (4.8 g, 20 mmol) and pyridine (3.32 g, 42 mmol) in THF (50 mL) at 0 was added methylsulfonyl chloride (2.4 g, 21 mmol) dropwise. After the addition, the mixture was continued to stir for 3 hours. The reaction mixture was quenched with water (10 mL) at a low termperature, and the mixture was stirred for 10 min. The THF was removed in vavuo and the resulting mixture was extracted with EtOAc (50 mL) . The organic layer was washed with water (20 mL × 2) and saturated aqueous NaCl (20 mL) , dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE : EtOAc (V : V) 3 : 1) to give N- (4-bromo-3- (trifluoromethyl) phenyl) methanesulfonamide as a puce solid (5.6 g, 89) . MS (ESI, pos. ion) m/z: 319.2 [M+H]+.Example 249 1-[4-(6-(Methylamino)purin-9-yl)phenyl]-3-(4-pyridin-4-ylmethyl-3-(trifluoromethyl)phenyl)urea (Table 3, Compound No. 52) Step A Preparation of 1-(4-bromo-3-trifluoromethyl-phenyl)-2, 5-dimethyl-1H-pyrrole [Show Image] [Show Image] In 50 mL of toluene, 3.6 g (15 mmol) of A solution prepared by the addition of 4-bromo-3- (trifluoromethyl)aniline (500 mg, 2.08 mmol) to a warmed mixture of concentrated H2SO4 37% w/w (0.51 mL, 4.6 eq) and water (2.3 mL, C=3.4M) was cooled with vigourous stirring to -10C (ice-salt bath). A slurry of the aniline hydrogen sulfate precipitated. Then, a solution of NaNO2 (158 mg, 1.1 eq) in 1.06 mL (C=2.15M) of water was added dropwise. The mixture was stirred for 40 min at -8C before a solution of KI (495 mg, 1.43 eq) in water (0.4 mL, C=8M) and copper powder (4 mg) were added. The brown reaction mixture was allowed to warm to r.t. by removal of the ice bath, stirred for 30 min, and then, the reactants were heated at reflux (102C) for an additional lh. After cooling to r.t. and diluting with water, the aqueous layer was extracted with DCM (3><20mL). Extracts were washed with a saturated Na2S2O3 solution (20mL), with brine (20mL), dried over MgSO4, filtered and evaporated in vacuo. The crude residue was chromatographed (hexane) to afford theiodinated compound in 93% yield (679 mg) as an orange solid. 1H NMR (300 MHz, CDC13) delta 7.98 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 8.4, 2.1 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H); 13C NMR (75 MHz, CDC13) delta 142.1 (CH), 136.7 (q, J = 5.6 Hz, CH), 136.6 (CH), 132.0 (q, J = 31.7 Hz, C), 121.9 (q, J = 274.2 Hz, C), 120.0 (q, J = 1.7 Hz, C), 91.8 (C)Charged 35% aqueous hydrochloric acid solution (47gm., 0.44 moles), water (95gm) and 5-amino-2-bromo-benzotrifluoride (20gm., O.083moles) in the reaction flask. Cooled reaction mass to 5C and charged chilled 15% aqueous solution of sodium nitrite (40gm., 0.09moles) in small portions maintaining 0C. After complete addition of sodium nitrite, stirred the reaction mass at 0C to 5C for 1.0 hour to get diazonium salt solution. Then charged an aqueous solution of potassium iodide (14gm., 0.08 moles) and further heated the reaction mixture to reflux point using a reflux condenser until no more gas is evolved then allowed to cool and stand undisturbed until the heavy organic layer has settled. The title compound was isolated. Yield (%): 75%A solution prepared by the addition of 4-bromo-3- (trifluoromethyl)aniline (500 mg, 2.08 mmol) to a warmed mixture of concentrated H2SO4 37% w/w (0.51 mL, 4.6 eq) and water (2.3 mL, C=3.4M) was cooled with vigourous stirring to -10C (ice-salt bath). A slurry of the aniline hydrogen sulfate precipitated. Then, a solution of NaNO2 (158 mg, 1.1 eq) in 1.06 mL (C=2.15M) of water was added dropwise. The mixture was stirred for 40 min at -8C before a solution of KI (495 mg, 1.43 eq) in water (0.4 mL, C=8M) and copper powder (4 mg) were added. The brown reaction mixture was allowed to warm to r.t. by removal of the ice bath, stirred for 30 min, and then, the reactants were heated at reflux (102C) for an additional lh. After cooling to r.t. and diluting with water, the aqueous layer was extracted with DCM (3><20mL). Extracts were washed with a saturated Na2S2O3 solution (20mL), with brine (20mL), dried over MgSO4, filtered and evaporated in vacuo. The crude residue was chromatographed (hexane) to afford theiodinated compound in 93% yield (679 mg) as an orange solid. 1H NMR (300 MHz, CDC13) delta 7.98 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 8.4, 2.1 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H); 13C NMR (75 MHz, CDC13) delta 142.1 (CH), 136.7 (q, J = 5.6 Hz, CH), 136.6 (CH), 132.0 (q, J = 31.7 Hz, C), 121.9 (q, J = 274.2 Hz, C), 120.0 (q, J = 1.7 Hz, C), 91.8 (C)Charged 35% aqueous hydrochloric acid solution (47gm., 0.44 moles), water (95gm) and 5-amino-2-bromo-benzotrifluoride (20gm., O.083moles) in the reaction flask. Cooled reaction mass to 5C and charged chilled 15% aqueous solution of sodium nitrite (40gm., 0.09moles) in small portions maintaining 0C. After complete addition of sodium nitrite, stirred the reaction mass at 0C to 5C for 1.0 hour to get diazonium salt solution. Then charged an aqueous solution of potassium iodide (14gm., 0.08 moles) and further heated the reaction mixture to reflux point using a reflux condenser until no more gas is evolved then allowed to cool and stand undisturbed until the heavy organic layer has settled. The title compound was isolated. Yield (%): 75%

Used as medicine and pesticide intermediate

Molecular Weight:240.02
XLogP3:2.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Exact Mass:238.95575
Monoisotopic Mass:238.95575
Topological Polar Surface Area:26
Heavy Atom Count:12
Complexity:159
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes