tert-Butyl 4-(cyanomethyl)-4-hydroxypiperidine-1-carboxylate synthesis

Yield:774609-73-3 58%

Reaction Conditions:

Stage #1: with n-butyllithium;diisopropylamine in tetrahydrofuran;hexane at -78; for 1.16667 h;
Stage #2: N-tert-butyloxycarbonylpiperidin-4-one;cyanomethyl bromidewith N,N,N,N,N,N-hexamethylphosphoric triamide at 20; for 2 h;

Steps:

3.a Preparation 3; Preparation of 2,2,2-trifluoro-N-[2-(4-hydroxy-4-piperidinyl)ethyl]acetamide; a) 4-cyanomethyl-4-hydoxy-piperidine-1-carboxylic acid tert-butyl ester

To an oven-dried flask equipped with a stirring bar and rubber septum was added anhydrous THF (250 mL). Diisopropylamine (7.0 mL, 50.2 mmole) was added and the solution cooled to-78 °C. To the cooled solution was added n-butyllithium (1.6 M in hexanes, 31 mL, 50.2 MMOLE) over 10 minutes. The reaction mixture was stirred for 60 min and N-BOC-4-PIPERIDONE (10.0 g, 50.2 mmole, in 10 mL of anhydrous THF) BROMOACETONITRILE (4.2 mL, 60.2 mmole) and HMPA (20 mL) was added and the mixture stirred for an additional 2 h at RT. The reaction mixture was quenched with brine and concentrated in vacuo. The residue was taken up in ethyl acetate (500 mL) and washed with sat. NAHCO3 (2 x 200 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to obtain the title compound (7.0 g, 58%) as a yellow oil : H NMR (400 MHz, CDCl3) 8 3.90 Hz (bs, 2H), 3.16 Hz (m, 2H), 2.55 Hz (s, 2H), 1.74 Hz (m, 2H), 1.50 (m, 2H), and 1.47 (s, 9H). LC-MS (ES) M/E 241.2 (M + H).

References:

WO2004/87145,2004,A2 Location in patent:Page/Page column 31-32