2-Pyridinecarboxylic acid, 5-bromo-, methyl ester

2, 5-Dibromopyridine (9.5 g, 40. 10MMOL), PDCL2 (PPH3) 2 (844 mg), triethylamine (8. 36 mL), methanol (38 mL), and acetonitrile (114 mL) were combined, heated under carbon monoxide atmosphere (75 psi) at 60oC for 16 hours and concentrated. The residue was purified by flash chromatography eluting with 25percent ethyl acetate in hexane. The title compound (5.02 g) was obtained at 58percent yield. MS (DCI/MH3) M/Z : 215.95 (M+H) +. LH NMR (500 MHz, DMSO- D6) 8 ppm 3.91 (s, 3 H) 8.00 (d, J=8.11 Hz, 1 H) 8. 27 (dd, J=8.42, 2.49 Hz, 1 H) 8.86 (d, J=1.56 Hz, 1 H)To a solution of 5-bromopicolinic acid (12.6, 6.0 g, 29.9 mmol) in methanol (60 mL), sulfuric acid (3.0 mL) was added at 0 °C and the reaction mixture was heated at 70 °C for 6 h. After completion, cooled the mixture to room temperature and methanol was removed under reduced pressure. To the mixture, water (50 mL) was added and pH was adjusted to 6 by a solution of sodium bicarbonate .The product was extracted with ethyl acetate (200 mL), the organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by washings with diethyl ether and pentane to afford methyl 5-bromopicolinate (12.5) as white solid. Yield: 6.0 g, 92.0percent.(a) Preparation of methyl 5-bromopicolinate 2:To a 100 mL round bottle flask with 5-bromopicolinic acid (7.0 g, 35 mmol) in methanol (80 mL) was added dropwise thionyl chloride (3.0 mL) at ambient temperature. After addition the reaction mixture was heated to reflux for 3 h. Methanol was removed and ethyl acetate (100 mL) was added to the residue and was adjusted pH to 7.0 by addition of sodium bicarbonate solution. The organic phase was separated and dried over sodium sulfate. The organic solvent was removed and methyl 5-bromopicolinate 2 was obtained as white solid which was used for the next step of the reaction without further purification. Yield: 6.57 g, 86.9percentExample 89 - Preparation of Intermediate 25 [ 00379 ] The synthesis of Intermediate 25 followed General Procedure 1 following. Intermediate 25 [ 00380 ] To a cooled solution (0°C) of 5-bromopyridine-2-carboxylic acid (50.0 g, 0.247 mol, 1.0 eq) in anhydrous methanol (400 mL) was added thionyl chloride (107.0 mL, 2.47 mol, 10.0 eq) dropwise. The reaction mixture was slowly brought to ambient temperature and then heated at 50°C for 12 hours. The reaction was monitored by TLC and LC-MS. After completion, the reaction mixture was concentrated under reduced pressure to obtain a white solid residue, which was slowly quenched with saturated sodium bicarbonate. The white solid was filtered to give desired product methyl-5-bromopyridine-2-carboxylate (43.0 g, yield-80percent) m/z 216.14; 1H NMR (400 MHz, DMSO) δ 8.86 (d, J = 1.9 Hz, 1H), 8.28 (dd, J = 8.4, 2.4 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H) ppm.5-bromo-2-pyridinecarboxylic acid (1.65 g, 8.19 mmol) was dissolved in a methanol solution (30 ml) at room temperature, concentrated sulfuric acid (2.5 ml) was added dropwise, heated, condensed and refluxed for 12 hours, The reaction solution was slowly added dropwise to a saturated sodium bicarbonate solution (200 ml), extracted with ethyl acetate (100 ml * 3) and washed with a saturated sodium chloride solution (100 ml * 2). The organic phase was dried over anhydrous magnesium sulfate Filtered and concentrated under reduced pressure to give methyl 5-bromo-2-pyridinecarboxylate (white solid, 1.39 g), yield: 79percentExample 53; 3-(3, 4-Dichloro-phenoxy)-6-(4-isopropyl-piperazine-1-carbonyl)-pyridine-2-carbonitrile trifluoroacetic acid salt Step A; 5-Bromo-pyridine-2-carboxylic acid methyl ester. A mixture of 5-bromo-2-pyridine carboxylic acid (26.2 g, 0.124 mol) and conc. HExample 29(i) (TMS)CHNGeneral procedure: N, N-Dimethylaminoethanol (0.85 ml, 8.5 mmol, 1 equiv.) and(trimethylsilyl)methyllithium 1 M (25.3 ml, 25.3 mmol, 3 equiv.)was added dropwise to 25 ml of dry toluene at 0 °C and the solutionwas stirred for 30 min to form TMSCH2Li-LiDMAE (in situ). Then, Asolution of 2, 5-dibromopyridine 1 (2 g, 8.5 mmol, 1 equiv.) in 9 mlof dry toluene was added dropwise. The reaction mixture wasstirred for 30 min, cooled to 78 °C and added methyl formate(5.2 ml, 85 mmol, 10 equiv.) or ethyl formate (6.9 ml, 85 mmol, 10 equiv.) in 10 ml of toluene. The reaction mixture stirred for 3 h, and I2 (6.4 g, 25.5 mmol, 3 equiv.), K2CO3 (5.8 g, 42.5 mmol, 5 equiv.)and 20 ml methanol or ethanol were added. The mixture wasstirred at room temperature for 18 h and added 10 ml of a sat.aqueous Na2SO3 solution.Water (10 ml)was added and the mixtureextracted with dichloromethane (3x40 ml), washed with water(1 x 25 ml) and brine (1 x 25 ml). The residue was purified bysilica-gel flash column chromatography (eluent: heptane/diethylether 2: 1) to obtain 2a-b.4.2.2.1. Methyl 5-bromopicolinate (2a). From 1 (2 g) gave 2a(997 mg, 55percent); white solid; >99percent purity; mp 103-104 °C (reported98.0-102.0 °C [30a]); 1H NMR (600 MHz, CDCl3)δ 8.77 (dd, J = 2.2, 0.71 Hz, 1H, H2), 8.01 (dd, J = 8.3, 0.8 Hz, 1H, H5), 7.98 (dd, J = 2.3, 2.2 Hz, 1H, H6), 3.99 (s, 1H, CH3);13C NMR (100 MHz, CDCl3):δ 165.0(C]O, C-7), 151.0(C-2), 146.3(C-4), 139.7(C-6), 126.3(C-5), 125.1(C-1); HRMS (ESI) m/z [M+H]+ calcd for C7H7BrNO2 +215.9660, found 215.9659. Data was in accordance with those reported [30a].To a solution of 5-bromo picolinic acid (0.20 g, 0.99 mmol) in MeOH (5 mL) was added TMSCl (0.50 mL, 3.96 mmol). The reaction mixture was left to stir at room temperature overnight. Water (20 mL) was added to quench the reaction and extracted three times with DCM (50 mL). Organic layer was combined, dried over Na

Molecular Weight:216.03
XLogP3:1.1
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