5-Bromo-1,2-dihydro-2-oxo-3-pyridinecarboxylic acid

white to light yellow crystal

This compound was prepared according to the procedure of Y. S. Lo (Synthetic Communications, 1989, 553). Bromine (0.77 eq) was added dropwise at 0°C to a stirred solution of 50percent NAOH (2.4 eq) in water (1 M solution). After 5 min, 50percent NAOH (3 eq) followed by solid 2- hydroxynicotinic acid (1 eq) was added to the mixture and the resulting solution was stirred at 50°C. After 20 h, a solution prepared by adding bromine (0. 38 eq) to 50percent NAOH (1. 2 eq) in water (1 M solution) was added to the reaction mixture and stirring continued for another 24 h at 50°C. After that time the reaction mixture was cooled to 0°C and acidified to pH 2 with concentrated hydrochloric acid to allow the formation of a solid which was isolated by filtration, washed with warm water/isopropanol (3: 1), then with diethyl ether and dried to afford 5-bromo-2- hydroxynicotinic acid (87percent) as an off-white solid. OH (400 MHz; DMSO) 8.25 (1H, d, J 2.7), 8.33 (1H, d, J 2.7), 13.84 (2H, bs) ; BC (400 MHZ ; DMSO) 99.45, 117.97, 142.01, 147.42, 163.22, 163.88 ; M/Z (ES-) 218-216 (M-H)-.(d) Step A. 5-Bromo-2-hydroxypyridine-3 -carboxylic acidTo a solution of 2-hydroxypyridine-3 -carboxylic acid (2 g, 14.3 mmol) in 50percent sodium hydroxide (2.7 g, 67.5 mmol) diluted with water (10 mL) was added sodium hypobromite solution (15 mL). The sodium hypobromite solution was prepared by adding bromine (1.81 g, 11.3 mmol) to a solution of 50percent sodium hydroxide (3.4 g, 84.5 mmol) in water (15 mL) at 0 To a stirred ice-cooled solution of 2-hydroxynicotinic acid (10 g, 71.9 mmol) in DMF (100 mL) was added bromine (5.56 mL, 108 mmol) in DMF (20 mL) slowly for 1 hr. The reaction mixture was allowed to stir at room temperature for 3 hr. After completion of the reaction, the reaction mixture was slowly added to ice water (1.5 L), and the mixture stirred for 15 min. The obtained solid was filtered, washed with water and dried under suction to obtain 5-bromo-2-hydroxynicotinic acid as a white solid. Yield: 10.5 g, (67.17percent). NMR (300 MHz, DMSO-d) δ = 13.68 (bs, 1 H), 8.35 (d, J= 2.7 Hz, 1 H), 8.26 (d, J= 2.7 Hz, 1 H). LCMS: (ES+) m/z observed = 218.2 (M+H)Preparation 49 PREPARATION 49 To a mixture of A63 (2 g, 9.17 mmol, 1 eq) in DMF (20 mL) were added CS2CO3 (7.47 g, 22.9 mmol, 2.5 eq) and 2, 2, 2-trifluoroethyl trifluoromethanesulfonate (4.26 g, 18.3 mmol, 2 eq) at 0C, the mixture was stirred at l5C for 1 hour to give a pale mixture. LCMS showed the desired product was observed. The mixture was poured into ice-water (30 mL). The aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (50 mL x 5), dried with anhydrous Na2S04, filtered and concentrated in vacuum to afford crude product. The crude product was purified by combi flash (PE/EtOAc=l/0 to 3/1) to afford A63 (1.49 g, 42.5% yield) as a white solid.To a solution of compound 2 (22.7 g, 0.104 mol) in sulfoxide chloride (100ml) was added one drop DMF and the mixture was refluxed for 12 h. The reaction mixture was then evaporated in vacuo and diluted with dichloromethane. After that, methanol was dropped into the reaction mixture slowly at ice bath, and stirring for 2h at room temperature. Then, DCM was removed and the resulted precipitate was neutralized with saturated sodium bicarbonate. The whole mixture was extracted ethyl acetate, washed with brine and dried over Na2SO4. The organic layer was evaporated and the resulting precipitate purified with column chromatography to obtain the ethyl 5-bromo-2-chloronicotinate 3 (20 g, 76.9%).

Used as an intermediate for the preparation of antihypertensive drugs, antiviral drugs and anti-resistance amine drugs

Molecular Weight:218.00
XLogP3:0.9
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:216.93746
Monoisotopic Mass:216.93746
Topological Polar Surface Area:66.4
Heavy Atom Count:11
Complexity:280
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes