1-(6-chloro-pyridin-3-yl)cyclopentanol synthesis

Yield:1011473-96-3 76%

Reaction Conditions:

Stage #1: 5-bromo-2-chloropyridinewith n-butyllithium in diethyl ether;hexane; for 1 h;Cooling with acetone-dry ice;
Stage #2: cyclopentanone in diethyl ether;hexane at -20;

Steps:

III.A

(A) 5-Bromo-2-chloropyridine (3.0 g, 15.6 mmol) was dissolved in diethyl ether (100 mL) in an oven-dried, nitrogen-flushed 250 mL round bottomed flask and cooled in a dry ice/acetone bath under nitrogen. n-BuLi (1.05 g, 16.4 mmol, 6.6 mL of a 2.5 M solution in hexanes) was added via syringe and the orange heterogenous mixture allowed to stir for 1 hour. Cyclopentanone (1.3 g, 15.6 mmol) was added via syringe and the mixture allowed to warm to -20° C. before being quenched with 1N HCl. The mixture was extracted with EtOAc and the organic extract washed with sat. NaHCO₃. The NaHCO₃ wash was used to neutralize the first aqueous layer and the combined aqueous layers were extracted with additional EtOAc and the combined organic layers dried (Na₂SO₄), filtered, concentrated and purified by flash silica gel chromatography (hexanes:EtOAc; 2:1) to give 1-(6-chloro-pyridin-3-yl)cyclopentanol (2.33 g, 76%) as an off white solid: mp 92-93° C., LC/MS (ESI) m/z 197, ¹H NMR (300 MHz, CDCl₃) δ 8.50 (d, 1H, J=2.4 Hz), 7.77 (dd, 1H, J=8.4, 2.4 Hz), 7.28 (d, 1H, J=8.4 Hz), 2.05-1.80 (m, 8H), 1.60 (s, 1H, OH).

References:

US2008/108666,2008,A1 Location in patent:Page/Page column 10