5-bromo-2-pyridinecarboxylic acid ethyl ester

(a) Preparation of ethyl 5-bromopyridine-2-carboxylate 2:To a suspension of 5-bromopyridine-2-carboxylic acid 1 (2.02 g, 10 mmol) in 50 mL of EtOH was added thionyl chloride (5 mL). The mixture was stirred at ambient temperature for 18 h. After removal of all solvent, the residue was purified by column (2: 1 of hexane/ethyl acetate) to give 2.3 g of ethyl 5-bromopyridine-2-carboxylate 2 as an oil. Yield: 2.3g, quantitative yield. Reference Example 255Pyridine (22) is obtained in two steps from 5-bromo-2-methyl-pyridine (20) by oxidation to 5-bromo-2-pyridinecarboxylic acid (21) as described in G. M. Sanders, M. van Dijk and H. C. van der Plas, Heterocycles 1981, 15, 213-223, and chlorination with SOClCompound d-1-1 of 21g was dissolved in EtOH (ethanol) 300ml and 15ml of sulfuric acid was added, and the mixture was stirred for 3 hours at 70 . Then, by cooling the resulting solution, and then was neutralized with aqueous sodium hydrogen carbonate and ethyl acetate was added to extract fractions, it was carried out the concentration of the organic layer. Purification of the resultant concentrate by silica gel column chromatography to obtain 15g of the compound d-1-2.SYNTHESIS OF INTERMEDIATE KETONE B2-(5-Bromopyridin-2-yl)- 1-(2, 4-difluorophenyl)-2, 2-difluoroethanone (B) To a suspension of copper powder (2.68 grams (g), 42.2 millimoles (mmol)) in dimethyl sulfoxide(DMSO; 35 milliliters (mL)) was added ethyl 2-bromo-2, 2-difluoroacetate (2.70 mL, 21.10mmol), and the mixture was stirred for 1 hour (h) at room temperature (RT). 2, 5-Dibromopyridine(2.50 g, 10.55 mmol) was then added, and stirring was continued for 15 h at RT. The reactionmixture was quenched with aqueous (aq) ammonium chloride (NH4C1) and extracted withdichloromethane (CH2C12 3 x 25 mL). The combined organic layers were washed with water (H20), washed with brine, dried over anhydrous sodium sulfate (Na2SO4), and concentrated under reduced pressure to afford the crude product mixture. Purification by column chromatography (eluting with ethyl acetate (EtOAc)/hexane) afforded the ethyl ester intermediate (2.40 g, 8.57mmol, 81percent) as a pale yellow oil. ‘H NMR (500 MHz, CDC13): ö 8.71 (s, 1H), 8.00 (d, J 9.0 Hz, 1H), 7.64 (d, J= 9.0 Hz, 1H), 4.42-4.35 (m, 2H), 1.39-1.3 1 (m, 3H).General 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

Molecular Weight:230.06
XLogP3:1.6
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:228.97384
Monoisotopic Mass:228.97384
Topological Polar Surface Area:39.2
Heavy Atom Count:12
Complexity:163
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes