4-(3-Hydroxy-prop-1-ynyl)-piperidine-1-carboxylic acid tert-butyl ester synthesis

Yield:403802-41-5 74%

Reaction Conditions:

Stage #1: tert-butyl 4-(2,2-dibromovinyl)piperidine-1-carboxylatewith n-butyllithium in tetrahydrofuran;hexane at -45; for 0.75 h;
Stage #2: formaldehyd in tetrahydrofuran;hexane at -45 - 20;

Steps:

[00231] Step 2: tert-butyl 4-(3-hydroxyprop-1-yn-1-yl)piperidine-1-carboxylate

[00232] To a solution of tert-butyl 4-(2,2-dibromovinyl)piperidine-1-carboxylate (7.84 g, 21.2 mmol) in THF (100 mL) cooled at -45oC was added n-butyl lithium (17.4 m of a 2.5M soln in Hexanes, 43.5 mmol) slowly over 10 mins. After complete addition mixture stirred at -45oC for 45 minutes then paraformaldehyde (1.91 g, 63.6 mmol) added and mixture allowed to warm slowly to warm to room temperature and stirred overnight. Mixture quenched by the addition of sat.NH4Cl (200 mL) and extracted with EtOAc (300 mL); organic layer washed with water (200 mL), sat. NaCl (100 mL), dried over MgSO4, filtered and evaporated. The residue was purified by silica gel column chromatography (Teledyne Isco: SNAP 80g GOLD) eluent: gradient 0-100% EtOAc in Heptane (7cv) to give tert-butyl 4-(3-hydroxyprop-1-yn-1-yl)piperidine-1-carboxylate (3.77 g, 74%) as a light yellow oil..1H NMR (500 MHz, Chloroform-d) δ 4.27 (dd, J = 6.0, 2.0 Hz, 2H), 3.75 - 3.66 (m, 2H), 3.14 (ddd, J = 13.5, 8.8, 3.4 Hz, 2H), 2.60 (ttq, J = 8.2, 4.0, 2.0 Hz, 1H), 1.77 (ddt, J = 13.7, 6.3, 3.5 Hz, 2H), 1.56 (dtt, J = 12.7, 8.6, 3.7 Hz, 2H), 1.45 (s, 9H).

References:

WO2021/71837,2021,A1 Location in patent:Paragraph 00231-00232