2-BROMO-5-CHLORO-3-NITROPYRIDINE

Hoar or pale yellow solid

To a solution of intermediate 32a (10.0 g, 57.6 mmol) in HBr [(31 .0 mL (100percent), 286.4 mmol)] at 0 00 sodium nitrite (13.8 g, 199.9 mmol) was added drop wise. To the stirred solution Br2 (10.0 mL, 197.1 mmol) was added in water and stirred at room temperature for 1 h. The reaction mixture was basified with NaHCO3 solution (pH=7) and extracted with ethyl acetate, washed with water, and dried over anhydrousNa2SO4 The solvent was removed under vacuo to yield the title product (10.0 g, 73.0percent) as a yellow solid.To a solution of intermediate 32a (10.0 g, 57.6 mmol) in HBr [(31.0 mL (100percent), 286.4 mmol)] at 0 00, sodium nitrite (13.8 g, 199.9 mmol) was added drop wise. To the stirred solution Br2 (10.0 mL, 197.1 mmol)in water was added and stirred at roomtemperature for 1 h. The reaction mixture was basified with NaHCO3 solution (PH=7) and extracted with ethyl acetate, washed with water, and dried over anhydrous Na2SO4 The solvent was removed under vacuo to yield the title product (10.0 g, 73.0percent) as a yellow solid.2-Bromo-5-chloro-3-nitropyridine (103) To a solution of intermediate 32a (10.0 g, 57.6 mmol) in HBr [(31 .0 mL (100%), 286.4 mmol)] at 0 00 sodium nitrite (13.8 g, 199.9 mmol) was added drop wise. To the stirred solution Br2 (10.0 mL, 197.1 mmol) was added in water and stirred at room temperature for 1 h. The reaction mixture was basified with NaHCO3 solution (pH=7) and extracted with ethyl acetate, washed with water, and dried over anhydrousNa2SO4 The solvent was removed under vacuo to yield the title product (10.0 g, 73.0%) as a yellow solid.To a solution of intermediate 32a (10.0 g, 57.6 mmol) in HBr [(31.0 mL (100%), 286.4 mmol)] at 0 00, sodium nitrite (13.8 g, 199.9 mmol) was added drop wise. To the stirred solution Br2 (10.0 mL, 197.1 mmol)in water was added and stirred at roomtemperature for 1 h. The reaction mixture was basified with NaHCO3 solution (PH=7) and extracted with ethyl acetate, washed with water, and dried over anhydrous Na2SO4 The solvent was removed under vacuo to yield the title product (10.0 g, 73.0%) as a yellow solid.2-Bromo-5-chloro-3-nitropyridine (103) To a stirred, ice bath cooled solution of HBr (48%, 214 mL, d=1.49, 1.89 mol) was added 2-amino-5-chloro-3-nitropyridine (2) (66.0 g, 376 mmol). The mixture was stirred until the internal temperature was less than 0 C., and then bromine (65 mL, d=3.102, 1.3 mol) was added dropwise. The resulting orange mixture was stirred at a temperature below 0 C. A solution of NaNO2 (91.3 g, 1.32 mol, used as received) in water (125 mL) was added slowly to the mixture so as to maintain the internal temperature below 0 C. The mixture was stirred for an additional 45 min at below 0 C., and then NaOH (139.3 g, 3.482 mol) in water (200 mL) was slowly added to the mixture to maintain the internal temperature below 20 C. The mixture was stirred at below 20 C. for an additional hour, and then gravity filtered. The recovered brown solid was dried at 25 C. under vacuum for 6 h. It was purified by recrystalization from 95% ethanol to obtain 103 as a yellow solid (46.0 g, 51.5%), mp 68-73 C. (Lit., 75 C., Berrie et al., J. Chem. Soc. 2042 (1952)); 1 H NMR (CDCl3): delta8.15 (d, J=2.1 Hz, 1H), 8, 57 (d, J=2.1 Hz, 1H).Example 121 : 5-Chloro-3-(4-chloro-3- (trifluoromethyl)phenylsulfonamido)picolinic acid; [00525] Step 1 : A dry 250 mL flask was charged with 2-bromo-5-chloro-3- nitropyridine (24 g, 10 mmol), CuCN (19 g, 20 mmol) and DMF (100 mL). The resultant mixture was stirred at 110 C for 2 h and then concentrated under reduced pressure. Water (100 mL) was added and the aqueous layer was extracted with EtOAc (250 mL X 3). The combined organic layer was washed with brine, dried (MgSO4), and evaporated in vacuo to afford a light yellow solid (15 g) which was used directly for the next step.A dry 250 mL flask was charged with 2-bromo-5-chloro- 3-niotatropyriotadiotane (24 g, 101 mmol), CuCN (19 g, 212 mmol) and DMF (100 mL) The resultant mixture was stirred at 1 10 0C for 2 hours The mixture was concentrated under reduced pressure Water (100 mL) was added and extracted with EtOAc (3 X 250 mL) The combined organic layer was washed with brine, dried (MgSO4) and filtered The solvent was evaporated the solvent in vacuo to afford a light yellow solid (15 g) which was used directly for the next stepA mixture of 2- bromo-5-chloro-3-nitropyridine (1.00 g, 4.21 mmol), methyl 2, 2-difluoro-2- (fluorosulfonyl)acetate (0.971 g, 5.05 mmol), and copper(I) iodide (0.963 g, 5.05 mmol) in DMF (10 mL) was heated at 85 oC for 16 h. Upon cooling to rt, the mixture was diluted with ethyl acetate (20 mL) and filtered through Celite. The filtrate was concentrated under vacuum to almost dryness. The residue was diluted with ethyl acetate (180 mL), washed with water (3 x 40 mL) and brine (30 mL), and dried over anhydrous MgSO4. The desired product, 5-chloro-3-nitro-2-(trifluoromethyl)pyridine (0.578 g, 2.55 mmol, 60.6% yield), was isolated as a light yellow oil by flash chromatography (80 g silica gel, solid loading, 5-20% ethyl acetate/hexane).1H NMR (500 MHz, CHLOROFORM-d) delta 8.89 (d, J=2.2 Hz, 1H), 8.25 (d, J=1.7 Hz, 1H).A mixture of

Molecular Weight:237.44
XLogP3:2.3
Hydrogen Bond Acceptor Count:3
Exact Mass:235.89882
Monoisotopic Mass:235.89882
Topological Polar Surface Area:58.7
Heavy Atom Count:11
Complexity:163
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes