5-BROMO-2-METHOXY-4-METHYLPYRIDINE

5-Bromo-2-methoxy-4-methylpyridine (B3.1) (0356) Sodium (4.8 g, 0.2 mol) was added to a stirred solution of 80 mL CHSodium (4.8 g, 0.2 mol) was added to a stirred solution of 80 mL CH3OH portion by portion. After addition, 5-bromo-2- fluoro-4-methylpyridine (7.6 g, 40 mmol) was added subsequently by neat. Then theclear solution was stirred at rt overnight. The reaction was quenched by water (400 mL), extracted with dichloromethane (300 mL x 3). The combined organic phase was washed with brine, dried over sodium sulphate, filtered and concentrated to give the title compound (6.95 g, 86percent) as a pale yellow solid. 1H NMR (500 MHz, CDCI3) O 2.31 (5, 3H), 3.87 (5, 3H), 6.61 (5, 1H), 8.15 (5, 1H).Sodium acetate (3.54g. 43.23mmol) was added to a solution of 2-methoxy-4-methylpyridine 54-5-1 (5.0g.3gmmol) in EtOAc (25mL). Br2 (1 .52mL, 58mmol) was added drop wise over 20 mm at 0°C. The RM wasstirred at 50°C for 18 h. The total reaction mass was cooled and after diluting with water, the pH was adjusted to 8 with aq. NaOH. The organic layer was separated and aq. layer extracted with EtOAc (250mL x 3). The combined extract was washed with water (300 mL), brine (200 mL), dried (Na2SO4) and concentrated under reduced pressure to get crude compound. The crude compound was purified by CC(silica gel 100-200mesh, 0-5percent EtOAc in PE) to obtain 5-bromo-2-methoxy-4-methylpyridine (2.82g. 40percent) as liquid.Sodium (143 mg, 6.30 mmol) was dissolved in methanol (1.8 mL) at 80° C. and 5-bromo-2-Chloro-4-methylpyridine (1.00 g, 4.84 mmol) in methanol (1 mL) was added. The mixture was stirred at 80° C. overnight and 1M HCl was added. The mixture was extracted with EtOAc, the combined organic layers were dried and the volatiles were removed under reduced pressure to yield the desired compound (770 mg, 79percent). [0417] [0107] Butyllithium solution (1.6M in hexane, 15.3 ml, 22.27 mmol) was added under argon to a solution of 5-Bromo-2-methoxy-4-methylpyridine (10 g, 49.5 mmol, 1.0 eq) was dissolved in anhydrous under nitrogen.In THF (170 mL), cool to -78 C, A solution of n-butyllithium in THF (2.4 mol/L) was slowly added dropwise. After the drop, Keep warm for 10min, Pass carbon dioxide gas until the system is bright yellowThe reaction was continued at -78 C for 1 hour, and a 1 mol/L hydrochloric acid solution was slowly added dropwise.(25mL). After the drop, slowly return to room temperature. LC-MS detected the reaction completely, The pH was adjusted to 3 with a 6 mol/L hydrochloric acid solution. The system is concentrated under reduced pressure, Most of the organic solvent was removed, the solid was precipitated, suction filtered, and the filter cake was washed with water (100 mL×2), and the filtrate was extracted with DCM (50 mL×3).The organic phases were combined, dried and concentrated to give a product (6.5 g, crude).It was used in the next step without purification.

Molecular Weight:202.05
XLogP3:2.2
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:200.97893
Monoisotopic Mass:200.97893
Topological Polar Surface Area:22.1
Heavy Atom Count:10
Complexity:110
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes