5-(3-Methoxyphenyl)pyridin-3-aMine synthesis

Yield:1225523-08-9 91%

Reaction Conditions:

with tetrakis(triphenylphosphine) palladium⁽⁰⁾;potassium carbonate in methanol;water;toluene at 100; for 40 h;

Steps:

Synthesis of N-(5-(3-methoxyphenyl)pyridin-3-yl)cyclopropanecarboxamide 19

The mixture of (3-methoxyphenyl)boronic acid 22 (1.0 g, 6.6 mmol), 5-bromopyridin-3-amine 23 (1.0 g, 5.8 mmol), Pd(PPh₃)₄ (0.2 g, 0.17 mmol) and K₂CO₃ (1.5 g, 10.9 mmol) in toluene (12.0 mL), MeOH (5.0 mL) and water (6.0 mL) was sealed and heat at 100 ^oC for 40 hrs. The mixture was cooled to rt. The catalyst was filter off through a layer of Celite. The filtrate was diluted with ethyl acetate (50.0 mL), washed with water, brine, dried over Na₂SO₄ and concentrated under reduced pressure. The resulting residue was purified by CombiFlash (CH₂Cl₂/MeOH: 100/0 to 95/5 in 20 min) to afford 1.05 g (91%) of 5-(3-methoxyphenyl)pyridin-3-amine 24. ¹H NMR (400 MHz, CDCl₃): δ 8.21 (d, J = 2.1 Hz, 1H), 8.04 (d, J = 3.2 Hz, 1H), 7.32 (t, J = 8.1 Hz, 1H), 7.02-7.10 (m, 3H), 6.87-6.91 (m, 1H), 3.92 (bs, 2H), 3.81 (s, 3H). 5-(3-methoxyphenyl)pyridin-3-amine 24 (0.240 g, 1.20 mmol) was dissolved in CH₂Cl₂ (10.0 mL) and cooled at 0 ^oC. Triethylamine (0.17 mL, 1.20 mmol) was added, followed by the addition of cyclopropanecarbonyl chloride 13 (0.125 g, 1.20 mmol). The mixture was stirred at rt for 2 hrs. The solvent was removed under reduced pressure. The resulting residue was purified with chromatography (CH₂Cl₂/MeOH: 100/0 to 95/5 in 20 min) to afford 0.250 g (78%) of the desired product 19.

References:

Li, Guiying;Zhou, Hao;Jiang, Yu;Keim, Holger;Topiol, Sidney W.;Poda, Suresh B.;Ren, Yong;Chandrasena, Gamini;Doller, Darío [Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,# 4,p. 1236 - 1242] Location in patent:supporting information; experimental part