6-Bromo-2-methyl-3-pyridinamine

crystalline powder

A suspension of 6-bromo-2-methyl-3-nitropyridine (XIV) (250 g, 1.15 mol, 1.00 eq) and NH4C1 (300 g, 5.61 mol, 4.88 eq) in EtOH (3.50 L) and water (150 mL) was heated with stirring to 65°C. To this mixture was added Fe (130 g, 2.33 mol, 2.02 eq) and HC1 (15.3 g, 419 mmol, 0.36 eq). The suspension was then heated to 80°C for another 3 h. The reaction was cooled to 25°C and filtered through a plug of Celite. The filtrate was concentrated under reduced pressure to yield a residue that was taken up in EtOAc (1 L x 3) and washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 6-bromo-2-methylpyridin-3-amine (XV) as brown solid (373 g, 1.99 mol, 86.7percent yield) which was used for the next step without any purification. ‘H NMR (DM50-cl6, 400 MHz) ppm 6.01 (dd, J= 2.3, 7.9 Hz, 2H), 7.03 (d, J= 8.2 Hz, 1H); ESIMS found for C6H7BrN2 mlz 186.8 (M+H).A suspension of 6-bromo-2-methyl-3-nitropyridine (XIV) (250 g, 1.15 mol, 1.00 eq) and NHA suspension of 6-bromo-2-methyl-3-nitropyridine (XIV) (250 g, 1.15 mol, 1.00 eq) and NHA suspension of 6-bromo-2-methyl-3-nitropyridine (XIV) (250 g, 1.15 mol, 1.00 eq) and NHTo a stirred solution of 6-bromo-2-methyl-3-nitropyridine (15 g, 69.12 mmol) in ethanol (280 mL) was added iron powder (57.9 g, 1036 mmol) followed by conc HCl (30 mL). Into a 50-mL seal tube was placed methyl 6-bromo-2-methylpyridin-3 -amine (500 mg, 2.67 mmol) in MeOH (15 mL) and Pd(OAc)2(120 mg, 0.53 mmol), dppf (444 mg, 0.80 mmol), TEA (809 mg, 8.01 mmol). The seal tube was evacuated and flushed three times with CO. The resulting solution was stirred for 5 h at 100C under 10 atm of CO. Then the solution was concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1 : 1).This resulted in 351 mg (79.2 %) of the title compound as a light yellow solid. MS-ESI: 167 (M+l).To a stirring solution of 2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3- (trifluoromethyl)benzoic acid (prepared as described in Example 1, Step 3, 200 mg, 0.479 mmol) in dichloromethane (4 mL) at 0 C was added DMF (6 mu, 0.08 mmol) followed by the dropwise addition of oxalyl chloride (84 mu, 0.96 mmol). The solution was stirred for 10 minutes then removed from the ice bath and allowed to warm to room temperature over 20 minutes. The reaction was concentrated in vacuo and azeotroped with dichloromethane to afford 2-fluoro-6-[2-(trideuteriomethoxy)-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl chloride as a white solid. The solid was redissolved in cold dichloromethane (2 mL) and added dropwise to a stirring solution of 6-bromo-2- methyl-pyridin-3 -amine (99 mg, 0.53 mmol) in NMP (1 mL) and DIEA (250 mu, 1.44 mmol) at 0 C. The reaction was allowed to warm to room temperature and was then diluted with dichloromethane and washed with water and brine, dried over Na2S04, filtered and concentrated in vacuo. Silica gel chromatography (0- 10% methanol/dichloromethane) provided N-(6-bromo-2-methyl-3-pyridyl)-2-fluoro- 6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide (250 mg, 89%). ESI-MS m/z calc. 585.02, found 588.2 (M+l)+; retention time (Method B): 2.07 minutes (3 minute run). 'H NMR (400 MHz, DMSO-d6) delta 10.58 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.79 (t, J = 8.7 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 2.7 Hz, 1H), 7.07 (ddd, J = 8.7, 2.6, 1.3 Hz, 1H), 6.65 (d, J = 8.9 Hz, 1H), 2.44 (s, 3H) ppm.