(1-(methylsulfonyl)piperidin-4-yl)methanol synthesis

Yield:241134-34-9 87%

Reaction Conditions:

Stage #1: 1-methanesulfonylpiperidine-4-carboxylic acid ethyl esterwith lithium aluminium tetrahydride in tetrahydrofuran at 0 - 20;
Stage #2: with water in tetrahydrofuran at 0 - 10;
Stage #3: with hydrogenchloride in tetrahydrofuran;water at 0 - 20; pH=< 2; for 0.25 h;

Steps:

2

Preparation 2Preparation of (l-methanesulfonyIpiperidin-4-yl)methanol l-Methanesulfonyl-4-(ethoxycarbonyl)-piperidine (1 mol eq) was charged to a reaction vessel followed by a line wash of THF (6 rel vols). The reaction mixture was cooled to between 0 and 1O⁰C. A solution of lithium aluminium hydride (IM in THF, 0.75mol eq) followed by a line wash of THF (1 rel vol) was added to the vessel, keeping the temperature between 0° and 20⁰C, and then the reaction mixture was warmed to ambient temperature and stirred until the reaction was complete. The reaction mixture was cooled to between 0 and 2°C. Purified water (1 rel vol) was then charged to the vessel maintaining the temperature between 0° to 1O⁰C. The pH of the reaction was adjusted to <2 by charging 5M HCl, maintaining the temperature between 0 and 1O⁰C. The reaction mixture was warmed to room temperature, stirred for at least 15 minutes and then the phases separated. DCM (5 rel vol) was charged to the aqueous phase, stirred for at least 15 minutes and the phases separated. The first organic (THF) phase was concentrated to approximately 3.5 rel vols by vacuum distillation at 40°C. The second organic (DCM) phase was added to the concentrate, the phases separated and the organic phase concentrated to approximately 3.5 rel vol by atmospheric distillation. DIPE (10 rel vol) was added to the residue from the distillation at 40 to 45⁰C. After concentration to approximately 5 rel vol by vacuum distillation more DIPE (5 rel vol) was added and the resulting slurry cooled to ambient temperature and stirred for approximately 60 minutes. The sub-titled compound was isolated by filtration, washed with DIPE (2 x 1 rel vol) and dried at ambient temperature to give the sub-titled compound in approximately 87% yield¹H NMR (400 MHz, CDCl₃) δ 3.84 (dd, J= 9.6, 2.2 Hz, 2H), 3.54 (d, J= 4.9 Hz, 2H), 2.78 (s, 3H), 2.67 (t, J= 12.0 Hz, 2H), 1.70 - 1.56 (m, 2H), 1.54 (s, IH), 1.36 (qd, J= 12.5, 4.2 Hz, 2H).

References:

WO2007/57643,2007,A1 Location in patent:Page/Page column 6-7