5-(BROMOMETHYL)-2-METHOXYPYRIDINE

(6-Methoxypyridin-3-yl)methanol (250 mg, 1.797 mmol, commercially available from, forexample, Fluorochem) was dissolved in chloroform (20 mL) in a 50 mL round-bottomed flask, opento the atmosphere and phosphorus tribromide (0.188 mL, 1.989 mmol) was added slowly at 0 °C. The reaction mixture was stirred at rt for 1 h. The aqueous layer was extracted with DCM (3 x 30 mL) and the organic layers were combined, washed with brine (30 mL), passed through a hydrophobic frit and evaporated under vacuum. The resulting oil was loaded in DCM and purified byBiotage Isolera SNAP 25 g silica chromatography using a gradient of O-4Opercent cyclohexane/ethyl acetate. The product containing fractions were combined to give the title compound (160 mg, 0.792 mmol, 44.lpercent yield) as a colourless oil.LCMS (2 mm Formic):Rt = 0.93 mi [MH] = 202.To a stirred solution of 5-iodo-1H-indazole (0.49 g, 1.990 mmol, 0.8 eq) in DMF (20 mL), was added NaH (50%, 0.14 g, 2.985 mmol, 1.2 eq) at 0 C., followed by the addition of General procedure: Concentrated hydrochloric acid solution (14 mL) was added to asolution of 6 (430 mg, 0.97 mmol, 1 eq.) in MeOH (15 mL) and thereaction mixture was left under magnetic stirrer at room temperaturefor 15 min until TLC showed total removal of the protecting group. The solution was then concentrated under reduced pressureto provide 7 (348 mg, 100%) as white solid. Finally, the correspondingbromomethyl pyridine hydrobromide or chlorometyl pyridinehydrochloride derivatives or bromomethyl 4-substitited pyridinederivatives (1.5 eq.) was added to a solution of 7 (from 61 mg to177 mg, 1 eq.) in DMF (8 mL) in the presence of K2CO3 (3 eq.).The reaction mixture was stirred at 50 C under N2 atmospherefor 16 h. The reaction was quenched by addition of water (20 mL)and subsequently extracted with EtOAc (3 20 mL). The collectedorganic phases were washed with brine (3 15 mL), dried onMgSO4, filtered and concentrated under reduced pressure. Thecrude product was purified by column chromatography on silicagel (mobile phase: from 98:2, v/v, DCM-MeOH to 95:5, v/v, DCMMeOH)obtaining the final products 8a-e.5-(Bromomethyl)-2-methoxypyridine (144 mg, 0.714 mmol) was added to a solution of 5- bromo-N-methyl-2-oxo-1, 2-dihydropyridine-3-carboxamide (165 mg, 0.714 mmol) and potassium carbonate (197 mg, 1.428 mmol), in DMF (5 mL). The reaction mixture was left to stir at rt overnight. The reaction mixture was concentrated under vacuum and partitioned between DCM (20 mL) and water (20 mL). The organic solution was concentrated under vacuum, loaded in DCM (3mL) and purified by Biotage Isolera SNAP 25g silica flash chromatography using a gradient of 0-100% cyclohexane/ethyl acetate. The appropriate fractions were combined and concentrated under vacuum to give the product (152 mg) as a white solid.LCMS (2 mm Formic): Rt = 0.83 mi [MH] = 352.0 & 353.9.Compound 63 reacts with aldehyde 6 in the presence of MgSO4 to form imine, which is reduced with sodium cyanoborohydride to generate compound 64. Compound 65 is prepared from 2-hydroxy-5-bromopyridine by alkylation. J. Med. Chem. 1992, 35, 3525.

Molecular Weight:202.05
XLogP3:1.7
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:2
Exact Mass:200.97893
Monoisotopic Mass:200.97893
Topological Polar Surface Area:22.1
Heavy Atom Count:10
Complexity:99.6
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes