2-Pyridinecarboxylic acid, 6-methyl-, methyl ester

Steps 2 : - 10 °C low temperature and the stirring to 100 ml methanol adding dropwisely SOClTo a suspension of 6-methyl-pyridine-2-carboxylic Acid (10 g, 72.9 mmol) in CH2C12 (200 mL) cooled to 0 °C is added MeOH (10 mL), 4-dimethylaminopyridine (11.6 g, 94.8 mmol), and EDC (18.2 g, 94.8 mmol). The mixture is stirred at RT for 6 h, washed with water and brine, and dried over NA2SO4. The mixture is filtered and concentrated in vacuo and the residue is chromatographed on silica gel (50percent EtOAc/ Hexanes) to yield the title compound, 9. 66 g (92percent), as a colorless liquid. 'H NMR (CDC13) 8 7.93-7. 88 (M, 1H), 7.75-7. 7 (M, 1H), 7.35-7. 3 (M, 1H), 4.00 (s, 3H), 2.60 (s, 3H).Suspend 6-methyl-pyridine-2-carboxylic acid (10 g, 72.9 mmol) in methylene chloride (200 mL). Cool to 0 °C. Add methanol (10 mL), 4-dimethylaminopyridine (11.6 g, 94.8 mmol), and 1- (3-DIMETHYLAMINOPROPYL)-3-ETHYLCARBODIIMIDE HYDROCHLORIDE (EDC) (18.2 g, 94.8 mmol). Stir the mixture at room temperature for 6 hours, wash with water and brine, and dry over sodium sulfate. Filter the mixture and concentrate in vacuo. Chromatograph the residue on Si02 (50percent ethyl acetate/hexanes) to obtain the desired subtitled intermediate, 9.66 g (92percent), as a colorless liquid. 1H NMR (CDC13) 8 7.93-7. 88 (m, 1H), 7.75-7. 7 (m, 1H), 7.35-7. 3 (m, 1H), 4.00 (s, 3H), 2.60 (s, 3H).[0349j Methyl 6-methylpicolinate 3.41: To a 250-mL round-bottomed flask was added 6-methylpicolinic acid (TCI, 5.35 g, 39.0 mmol) and MeOH (100 mL). Concentrated sulfuric acid (3.12 mL, 58.5 mmol) was added dropwise. The reaction was heated at reflux for 48 h. After cooling to RT, most of the solvent was evaporated. The resulting residue was diluted with saturated aqueous NaHCO3 and extracted with DCM (2 x 100 mL). The organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give 6-methylpicolinate (5.33 g, 35.3 mmol, 90percent yield) as a light-yellow oil. MS (M--H) 152.0.INTERMEDIATE 87 - PREPARATION of Methyl 6-methylpicolinate. Concentrated sulfuric acid (2 mL) was added to a solution of 6-methylpicolinic acid (1.97 g; 13.65 mmol) in methanol (50 mL). The resulting mixture was heated at reflux for 22 hours. After cooling to room temperature, the solution was made alkaline by addition of an aqueous solution of sodium carbonate. The methanol was evaporated under reduced pressure, water was added and the mixture was extracted three times with dichloromethane. Combined organic layers were dried over magnesium sulfate, and concentrated under reduced pressure to give 1.81 g (88percent) of methyl 6-methylpicolinate as an oil.ESI/APCI : 152 (M +H), 174 (M+Na).Concentrated sulfuric acid (2 mL) was added to a solution of 6-methylpicolinic acid (1.97 g; 13.65 mmol) in methanol (50 mL). The resulting mixture was heated at reflux for 22 hours. After cooling to room temperature, the solution was made alkaline by addition of an aqueous solution of sodium carbonate. The methanol was evaporated under reduced pressure, water was added and the mixture was extracted three times with dichloromethane. Combined organic layers were dried over magnesium sulfate, and concentrated under reduced pressure to give 1.81 g (88percent) of methyl 6-methylpicolinate as an oil. [0714] ESI/APCI: 152 (M+H), 174 (M+Na).A mixture of 6-methyl-pyridine-2-carboxylic acid (10 g, 72.9 mmol) and concentrated sulfuric acid (3.5 mL) in methanol (300 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was poured into saturated aqueous sodium hydrogen carbonate (250 mL), and extracted with ethyl acetate (3.x.100 mL). The combined organic layers were dried (magnesium sulfate), filtered, and evaporated to give 6-methyl-pyridine-2-carboxylic acid methyl ester (6.5 g, 59percent) as a colorless oil. 1HNMR (CDCl3): δ 7.97 (d, J=7.6 Hz, 1H), 7.73 (dd, J=7.6 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 4.01 (s, 3H), 2.67 (s, 3H).Step 1: Step 1: Synthesis of methyl 6-methylpicolinate 2.2r To a solution of 6-methylpicolinic acid 2.1r (3 g, 21.88 mmol) in anhydrous MeOH (70 niL) at RT under NSynthesis of RDI-2 (KG-3-275) [00142] Methyl-6-methyl-pyridine-2-carboxylate (4). To a solution of 0.9 g (6.6 mmol) of 6-methylpicolinic acid in 7 mL of methanol and 3 mL of dichloromethane was added 6.6 mL (13.2 mmol) of a 2.0 M solution of trimethylsilyldiazomethane in ether. The reaction was allowed to stir at room temperature for 30 minutes. The solvent was then removed under reduced pressure and the remaining residue was taken up in ethyl acetate. The solution was washed with saturated sodium bicarbonate (2 x 10 mL), dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (1:5 ethyl acetate-hexanes) to provide 0.9 g (91percent) of the methyl ester. A solution of A1 (200 mg, 1.38 mmol) and methyl 6-methylpicolinate (209 mg, 1.38 mmol) in anhydrous THF (10ml) was placed under N2 atmosphere and cooled to -78 C. Potassium bis (trimethylsilyl) amide (0.5 M in toluene, 6.9 ml, 3.47 mmol) was added drop wise over a period of 5 min. The reaction mixture was stirred at -78 C for 1 h and then warmed to approximately 21 C and maintained for 20 h. After completion of the reaction (as measured by TLC), the reaction mixture was quenched with saturated ammonium chloride solution (20 ml). The aqueous layer was extracted with EtOAc (2 x 20 ml). The combined organic extracts were washed with water (100 ml), dried over Na2SC>4 and evaporated to give the crude compound A2. The crude material was purified by column chromatography (1 % MeOH /CH2CI2) to afford compound A2 as an orange yellow solid (110 mg, 30.5%).1H NMR (400 MHz, CDCI3: Enol form)6 15.74 (brs, -OH), 8.69 (t, J = 3.6, 1 H), 8.12 (d, J = 9.2 Hz, 1 H), 8.06 (dd, J = 8.4, 4.4 Hz, 2H), 7.82 (t, J = 7.6 Hz, 1 H), 7.55 (dd, J= 8.4, 4.8 Hz, 1 H) 7.45 (d, J= 9.6 Hz, 1 H), 7.3 (dd, J= 7.6, 4.0 Hz, 1 H), 7.16 ( s, 1 H), 2.75(s, 3H) LC-MS (ESI): m/z 264 [M+H]+

Molecular Weight:151.16
XLogP3:1.4
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:151.063328530
Monoisotopic Mass:151.063328530
Topological Polar Surface Area:39.2
Heavy Atom Count:11
Complexity:147
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes