2-BROMO-ISONICOTINIC ACID METHYL ESTER

Colorless liquid or solid

Into a 250-mL round-bottom flask, was placed a solution of 2-bromopyridine-4- carboxylic acid (10 g, 49.50 mmol, 1.00 equiv) in methanol (100 mL), and sulfuric acid (98percent, 5 mL). The resulting solution was stirred overnight at 70 A solution of 2-bromoisonicotinic acid (5.00 g, 24.8 mmol) in MeOH (50 mL) was treated with sulfuric acid (0.50 mL, 9.4 mmol) and the reaction mixture was stirred at 80 C for 1 hour. The mixture was returned to room temperature and stirred for a further 96 hours before heating to 80 C and stirring for 24 hours. The reaction mixture was cooled to room temperature, and the volatiles were removed in vacuo. An aqueous NaOH solution (2 M, -50 mL) was added to the residue and the aqueous was extracted with EtOAc (3 * 50 mL). The organic layers were combined, washed with brine, dried (MgS0To an ice cooled solution of 2-bromoisonicotinic acid (73 g, 0.361 mol) in dichloromethane (500 mL) and methanol (35 g, 1.08 mol) was added 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (67 g, 0.434 mol) by portions.To an ice cooled solution of 2-bromoisonicotinic acid (73 g, 0.361 mol) in dichloromethane (500 mL) and methanol (35 g, 1.08mol) was added 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (67g, 0.434mol) by portions. The mixture was stirred at ambient temperature overnight. Then 120g silica gel was added and the solvent evaporated. The residue was purified by flashchromatography, eluting with 5percent ethyl acetate in petroleum ether to afford 58 g (75percent) of methyl 2-bromoisonicotinate as a white solid.A mixture of 2-bromoisonicotinic acid, 2, (0.200 g, 0.99 mmol) in acetone and K2-Bromo isonicotinic acid (20.2 g, 100 mmol) was dissolved in DMF (500 mE) at ambient temperature. Cs2CO3 (32.6 g, 100 mmol) was added in one portion, followed by Mel (6.3 mE, 100 mmol). The mixture was stirred at ambient temperature for 15 h, followed by the addition of water (500 mE). The mixture was extracted with EtOAc (500 mE). The organic layer was washed with water (500 mE), brine (500 mE) and then dried over Na2SO4. The organic layer was then filtrated and concentrated to give compound DD as a white solid in 80percent yield (17.4 g, 80.5 mmol). EC-MS: [M+H] 217.0 (C7H5BrNO2+H, calc: 216.1). Compound DD was used directly without further purification.To a solution of 2-bromoisonicotinic acid (Chem. Pharm. Bull., 38:2446(1990)) (2.0 g) in tetrahydrofuran (100 ml) was added excess ethereal diazomethane and the resulting mixture was stirred at room temperature for 1 hour. The mixture was evaporated and the product chromatographed on silica gel eluting with a 1:3 mixture of ethyl acetate and hexane to afford the Methyl 2-bromoisonicotinate ester as a colorless liquid.

Molecular Weight:216.03
XLogP3:1.6
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:214.95819
Monoisotopic Mass:214.95819
Topological Polar Surface Area:39.2
Heavy Atom Count:11
Complexity:151
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes