Methyl 2-amino-5-bromonicotinate

To a stirred solution of 2-amino-nicotinic acid methyl ester (2 g, 13.15 mmol) and sodium bicarbonate (2.2 g, 26.31 mmol) in DCM (30 mL) is added a solution of bromine (1.01 mL in DCM (20 mL) drop wise at 0° C. To a solution of 2-amino-5-bromonicotinic acid 22 (1.0 g, 4.6 mmol)in MeOH (10 mL) was added sulphuric acid (2.0 mL, 36.8 mmol)dropwise and the mixture was stirred at 80 °C for 18 h. After completionmonitored by TLC, the solvent was removed under reduced pressure.The residue was neutralised with sat. NaHCO3 (aq.) and extracted withethyl acetate (3×20 mL). The combined organic layers were driedover MgSO4 and concentrated in vacuo to afford the product 23 as awhite powder (1.0 g, 94percent) without further purification. m.p.148–149 °C; Rf (CH2Cl2/MeOH 20:1): 0.55; 1H NMR (400 MHz, d6-DMSO): δ 8.24 (1H, d, J=2.4 Hz), 8.21 (1H, d, J=2.4 Hz), 6.68–6.19(2H, br.s), 3.89 (3H, s); 13C NMR (100 MHz, d6-DMSO): δ 166.6, 158.0, 154.4, 142.0, 107.5, 106.1, 52.4. HRMS (ESI+) Calc. for C7H7N2O2Br [M+H]+ 230.9764/232.9743, found 230.9765/232.9745. IR (neat, cm−1): v 3425, 3131, 2918, 1704, 1620, 1223, 796, 526.Compound 1 (27.40 g, 126.88 mmol) obtained in Step 1 of was placed in a well-dried 1000 mL three-neck round bottom flask and placed in a water bath containing ice water. 250 mL of methanol was added and stirred for 15 minutes. Sulfuric acid (125.80 mL, 2360.00 mmol) was slowly added dropwise thereto. The mixture was stirred for 8 hours at a temperature of 80 ° C under a stream of nitrogen. The product was poured into 1500 mL of ice water and neutralized with NaHCO 3 until the pH reached 7. Extraction with dichloromethane followed by column separation with 100percent dichloromethane. The resulting solid was dried to give compound 2 (18.5 g, 63percent yield).2. To a suspension of 2-amino-5-bromonicotinic acid hydrobromide (18.8 g, 60.0 mmol) in 150 mL of methanol was added cone, sulfuric acid (6 mL). The mixture was heated at 75 °C for 2 days, evaporated, diluted with water (100 mL), basified with solid sodium bicarbonate to pH 7-8, and extracted with ethyl acetate (3 x 100 mL). The extracts were washed with brine (50 mL), dried over sodium sulfate and filtered. The filtrate was dried in vacuo and the residue was purified by flash chromatography eluted with ethyl acetate/hexanes (1/4) to afford methyl 2-amino-5- bromonicotinate as a white solid in 36percent yield (5.0 g). 1H NMR (400 MHz, CDC1To a stirred solution of 2-amino-nicotinic acid methyl ester (2 g, 13.15 mmol) and sodium bicarbonate (2.2 g, 26.31 mmol) in DCM (30 mL) is added a solution of bromine (1.01 mL in DCM (20 mL) drop wise at 0° C. To a solution of 2-amino-5-bromonicotinic acid 22 (1.0 g, 4.6 mmol)in MeOH (10 mL) was added sulphuric acid (2.0 mL, 36.8 mmol)dropwise and the mixture was stirred at 80 °C for 18 h. After completionmonitored by TLC, the solvent was removed under reduced pressure.The residue was neutralised with sat. NaHCO3 (aq.) and extracted withethyl acetate (3×20 mL). The combined organic layers were driedover MgSO4 and concentrated in vacuo to afford the product 23 as awhite powder (1.0 g, 94percent) without further purification. m.p.148–149 °C; Rf (CH2Cl2/MeOH 20:1): 0.55; 1H NMR (400 MHz, d6-DMSO): δ 8.24 (1H, d, J=2.4 Hz), 8.21 (1H, d, J=2.4 Hz), 6.68–6.19(2H, br.s), 3.89 (3H, s); 13C NMR (100 MHz, d6-DMSO): δ 166.6, 158.0, 154.4, 142.0, 107.5, 106.1, 52.4. HRMS (ESI+) Calc. for C7H7N2O2Br [M+H]+ 230.9764/232.9743, found 230.9765/232.9745. IR (neat, cm−1): v 3425, 3131, 2918, 1704, 1620, 1223, 796, 526.Compound 1 (27.40 g, 126.88 mmol) obtained in Step 1 of was placed in a well-dried 1000 mL three-neck round bottom flask and placed in a water bath containing ice water. 250 mL of methanol was added and stirred for 15 minutes. Sulfuric acid (125.80 mL, 2360.00 mmol) was slowly added dropwise thereto. The mixture was stirred for 8 hours at a temperature of 80 ° C under a stream of nitrogen. The product was poured into 1500 mL of ice water and neutralized with NaHCO 3 until the pH reached 7. Extraction with dichloromethane followed by column separation with 100percent dichloromethane. The resulting solid was dried to give compound 2 (18.5 g, 63percent yield).2. To a suspension of 2-amino-5-bromonicotinic acid hydrobromide (18.8 g, 60.0 mmol) in 150 mL of methanol was added cone, sulfuric acid (6 mL). The mixture was heated at 75 °C for 2 days, evaporated, diluted with water (100 mL), basified with solid sodium bicarbonate to pH 7-8, and extracted with ethyl acetate (3 x 100 mL). The extracts were washed with brine (50 mL), dried over sodium sulfate and filtered. The filtrate was dried in vacuo and the residue was purified by flash chromatography eluted with ethyl acetate/hexanes (1/4) to afford methyl 2-amino-5- bromonicotinate as a white solid in 36percent yield (5.0 g). 1H NMR (400 MHz, CDC1A mixture of

Molecular Weight:231.05
XLogP3:1.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:229.96909
Monoisotopic Mass:229.96909
Topological Polar Surface Area:65.2
Heavy Atom Count:12
Complexity:177
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes