2,5-Dichloro-4-iodopyridine synthesis

Yield:796851-03-1 53%

Reaction Conditions:

Stage #1:2,5 dichloropyridine with n-butyllithium;diisopropylamine in tetrahydrofuran;2-Methylpentane at -78; for 1.5 h;Inert atmosphere;
Stage #2: with iodine in tetrahydrofuran;2-Methylpentane at -78;Inert atmosphere;

Steps:

3.01.a
a) A solution of 2,5-dichloropyridine (10 g, 67.57 mmol) in THF (17 mL) was added dropwise to a stirred solution of n-BuLi in isohexane (33.8 mL, 67.57 mmol) and diisopropylamine (9.63 mL, 67.57 mmol) in THF (68.0 mL) cooled to -78⁰C, over a period of 1 hour under a nitrogen atmosphere. The resulting mixture was stirred at -78⁰C for 30 minutes and then a solution of I₂ (17.49 g, 68.92 mmol) in THF (17.0 mL) was added dropwise. The resulting solution was stirred at -78 ⁰C for 1 hour and then quenched with water (75 mL) and allowed to warm to room temperature. The mixture was extracted with Et₂O (3x 100 mL) and the combined organic layers were dried over MgSO₄, and then evaporated. The residue was triturated with CH₂Cl₂ to give a solid which was dried under vacuum to afford 2,5-dichloro-4-iodopyridine (9.72 g, 53% yield). The filtrate was evaporated and the residue purified by chromatography on silica, eluting with a gradient of 50-100% CH₂Cl₂ in isohexane. Fractions containing product were combined and evaporated and the residue triturated with MeOH to leave a second crop of 2,5-dichloro-4- iodopyridine (5.74 g, 31% yield); ¹H NMR spectrum: (300 MHz, DMSO) δ 7.85 (IH, s), 8.34 (IH, s).

References:

ASTRAZENECA AB;ASTRAZENECA UK LIMITED WO2009/153589, 2009, A1 Location in patent:Page/Page column 117

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