5-Bromo-3-methoxy-2-methylpyridine synthesis

Yield: 71%

Reaction Conditions:

Stage #1:2,5-dibromo-3-methoxy-pyridine;methylmagnesium bromide;tetrakis(triphenylphosphine) palladium⁽⁰⁾ in tetrahydrofuran;tolueneCooling with ice;Reflux;
Stage #2: with hydrogenchloride in tetrahydrofuran;diethyl ether;water;toluene

Steps:

6.iv
[00111] As shown in step 6-iv of Scheme 6, Compound 1020 (5 g, 18.73 mmol) was dissolved in dry THF (94 mL) and Pd(PPh₃)₄ (2.16 g, 1.873 mmol) was added. The reaction mixture was cooled in an ice bath, and methylmagnesium bromide in 3/1 THF/toluene (17.4 mL, 1.4 M, 24.35 mmol) was slowly added. The ice bath was removed, and the reaction was heated to reflux. The reaction was stirred at reflux for 1 h and 3 mL of the methylmagnesium bromide solution were added. The reaction was stirred at reflux for another 20 min and 2 mL of the methylmagnesium bromide solution were added. The reaction was stirred at reflux for 1 h and cooled to RT. Ethyl ether and 1 N HCl were added, and the organic layer was separated and washed with 1 N HCl. The aqueous extracts were washed with ethyl ether three times. The aqueous layer was made basic with 2 N NaOH and extracted with ethyl acetate three times. The ethyl acetate extracts were combined and dried over Na₂SO₄, then concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-25% ethyl acetate/hexanes) to afford 5-bromo-3-methoxy-2-methylpyridine (Compound 1021, 2.7 g, 71% yield): ESMS (M+H) 202, 204. 5-Bromo-2-ethyl-3-methoxypyridine was made by an analogous procedure: ESMS (M+H) 216, 218; IH NMR (CDCl₃) δ 8.2 (d, IH), 7.2 (d, IH), 3.8 (s, 3H), 2.8 (q, 2H), 1.2 (t, 3H).

References:

VERTEX PHARMACEUTICALS INCORPORATED;ARONOV, Alex;BANDARAGE, Upul, Keerthi;COTTRELL, Kevin;DAVIES, Robert;KRUEGER, Elaine;LEDEBOER, Mark;LEDFORD, Brian;LE TIRAN, Arnaud;LIAO, Yusheng;MESSERSMITH, David;WANG, Tiansheng;XU, Jinwang WO2010/96389, 2010, A1 Location in patent:Page/Page column 46; 48