1-PYRIMIDIN-2-YL-PIPERIDIN-4-OL synthesis

Yield:893755-98-1 100%

Reaction Conditions:

Stage #1: 1-(2-Pyrimidinyl)-4-piperidinonewith sodium tetrahydroborate in methanol at 20; for 0.166667 h;
Stage #2: with water in methanol;ethyl acetate;

Steps:

6.10

6.10. Preparation of 2-r4-(Biphenyl-4-yloxy)-piperidin-l-yll-pyrimidine; To a solution of l-pyrimidin-2-yl-piperidin-4-one (50 mg, 0.282 mmol) in methanol (0.8 ml), was added sodium borohydride (12.0 mg, 0.282 mmol) at room temperature. After being stirred for 10 minutes, the mixture was treated with EtOAc (10 ml) and water (3 ml). The organic layer was washed with brine (2 ml), dried (MgSO₄), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (20% EtOAc/hexanes) to give the corresponding alcohol (51 mg, 100%) as a white solid. To a mixture of the above alcohol (50 mg, 0.279 mmol), PPh₃ (109.6 mg, 0.418 mmol) and biphenyl-4-ol (57.0 mg, 0.335 mmol) in THF (3 ml), was added DEAD (40% in toluene, 0.152 ml, 0.335 mmol) at O⁰C. After being stirred overnight, the mixture was treated with EtOAc (15 ml) and water (5 ml). The aqueous phase was extracted with EtOAc (2 x 5 ml). The combined organic layers were washed with brine (5 ml), dried (MgSO₄), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (15% EtOAc/hexanes) to give the title compound (81 mg, 88%) as white crystals: ¹U NMR (CDCl₃, 400 MHz) δ 8.38 (d, J = 6.4 Hz, 2 H), 7.59-7.04 (m, 9 H), 6.61 (t, J= 6.4 Hz, 1 H), 4.62 (m, 1 H), 4.21 (m, 2 H), 3.68 (m, 2 H), 2.14 (m, 2 H), 1.83 (m, 2 H); MS calc'd for C₂iH₂₂N₃O [M+H]⁺: 332; Found: 332.

References:

WO2008/67121,2008,A2 Location in patent:Page/Page column 55