4-BROMOMETHYL-PIPERIDINE-1-CARBOXYLIC ACID TERT-BUTYL ESTER

Compound 14; EPO To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (2.0 g, 9.29 mmol) in DCM (30 mL) was added CBr4 (5.1 g, 15.51 mmol) in one portion. The resultingcolorless solution was cooled to 0°C and PPh3 (4.1 g, 15.51 mmol) was added in one portion. The resulting dark orange solution was first stirred at 0°C for 1 h and then warmed to rt and stirred overnight. The mixture was washed by H20 (20 mL x 2) and the organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel columnchromatography (petroleum ether: EtOAc = 20: 1) to give tert-butyl 4- (bromomethyl)piperidine-1-carboxylate (1.6 g, 61.9percent yield) as a yellow oil. LC-MS m/z: 263 [M+H- 15j.4-N-Boc-piperidine-methanol (200 mg, 0.93 mmol) was dissolved in diethyl ether (9 mL) and carbon tetrabromide (370 mg, 1.1 mmol) and PPhA solution of 1 g (4.41 mmol) of tert-butyl 4-hydroxymethylpiperidine-1-carboxylate in 25 mL of THF is cooled to 0°C. 1.34 g (5.07 mmol) of triphenylphosphine and 2.02 g (5.96 mmol) of carbon tetrabromide are then added. The reaction mixture is stirred at room temperature over the weekend. The solution is taken up in ethyl ether, the insoluble matter is filtered off and the organic phase is evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 80/20 EtOAc/heptane) to give 960 mg of tert-butyl 4- bromomethylpiperidine-1-carboxylate, the characteristics of which are as follows: LC/MS (method G): ESI+ [M+H]+: m/z 279. tr (min) = 2.13. A solution of 1 g (4.41 mmol) of tert-butyl 4-hydroxymethylpiperidine-1-carboxylate in 25 mL of THF is cooled to 0° C. 1.34 g (5.07 mmol) of triphenylphosphine and 2.02 g (5.96 mmol) of carbon tetrabromide are then added. Amixture of 2 (1eq, 11.72 g, 40 mmol) and lithium bromide (5eq, 17.20 g, 200 mmol) in acetone (80 mL) was heated to reflux overnight.The mixture was evaporated, then the residue was partitionedbetween EtOAc and water. The organic layer was washedwith s brine, dried over Na2SO4, filtered, and evaporated to offer the title product 3 as pale yellow oil (9.46 g, 85.40percent yield).