Ethyl N-Boc-4-methylpiperidine-4-carboxylate

Ethyl N-Boc-piperidine-4-carboxylate (10.00 g, 36.92 mmol) was dissolved in THF(100 mL) and cooled to -78°C. LDA (47 mmol, 23 mL) was added and the reaction stirred for 1 h. Iodomethane (81.25 mmol, 5.08 mL) was then added and the reaction stirred for a further lh before removing the cold bath and allowing the reaction to warm to r.t. for 30 min. The reaction was quenched with NHEthyl N-Boc-piperidine-4-carboxylate (10.00 g, 36.92 mmol) was dissolved inTHF (100 mL) and cooled to -78°C. LDA (47 mmol, 23 mL) was added and the reactionstirred for 1 h. lodomethane (81.25 mmol, 5.08 mL) was then added and the reaction stirred for a further lh before removing the cold bath and allowing the reaction to warm to r.t. for 30 mm. The reaction was quenched with sat. aq. NH4C1 and partitioned with EtOAc, the organics were extracted and dried (MgSO4) and concentrated in vacuo, (quantitative yield). 1H NMR (400 MHz, DMSO- d6) ö: 4.11 (q, J7.1 Hz, 2 H), 3.61 (dt, J13.4 Hz, J 4.5 Hz, 2 H), 2.95 (d, J 0.3 Hz, 2 H), 1.91 (d, J 13.6 Hz, 2 H), 1.39 (s, 9 H), 1.31 (m, 2 H), 1.19 (m, 3 H), 1.15 (s, 3 H).The compound was prepared following a procedure outlined in PCT Publication No. WO 01/40217. 1-tert-Butyl 4-ethyl piperidine-l, 4-dicarboxylate (7.12 g, 27.7 mmol) was dissolved in THF (30 mL) and cooled to -40 °C. LHMDS (55.3 ml, 55.3 mmol) was added slowly and the solution was stirred at -40 °C for 1 hour. Iodomethane (3.45 ml, 55.3 mmol) was added and the reaction mixture was warmed to ambient temperature and stirred for 14 hours. The reaction was quenched with water and saturated NaHCOTo a mixture of iV, jV-diisopropylamme (6.8ImL, 48.6mmol) in THF (10OmL) at a temperature of Otert-Butyl 4-ethyl 4-methylpiperidine-1, 4-dicarboxylate A solution of O1-tert-butyl O4-ethyl piperidine-1, 4-dicarboxylate (1.5 g, 5.84 mmol) in THF (25 mL) was cooled to -78° C. followed by dropwise addition of LDA (1.80 M in THF, 6.5 mL, 11.68 mmol) at -78° C. The resulting mixture was stirred at the same temperature for 45 minutes followed by addition of MeI (1.2 mL, 17.52 mmol) at -78° C. The temperature of the reaction mixture was slowly raised up to rt and left to stir at rt for 6 h. The reaction mixture was then cooled to 0° C., quenched by dropwise addition of saturated NHA solution of O1-tert-butyl O4-ethyl piperidine-1, 4-dicarboxylate (1.5 g, 5.84 mmol) in THF (25 mL) was cooled to -78° C. followed by dropwise addition of LDA (1.80 M in THF, 6.5 mL, 11.68 mmol) at -78° C. Method V: 1-tert-butyl 4-ethyl 4-methylpiperidine-1, 4-dicarboxylate To a stirred solution ofN-Boc-ethylisonipecotate 17 (503.4 mg, 1.96 mmols) in dry THF(10.0 mL), cooled at -78 °C, freshly prepared solution of lithiumdiisopropyl amide (0.5 M in THF, 4.70 mL) was added. After stirring the reaction mixture for 1 h, methyl iodide(0.2 mL, 2.94 mmols) was added and the stirring continued for another hourbefore the reaction mixture was quenched with saturated aqueous NHTo a -60 °C solution of 1-(tert-butyl) 4-ethyl piperidine-1, 4-dicarboxylate (15.52 g, 60.31 mmol) in THF (100 ml) was added LDA(2 M solution in THF/Hex, 45.00 mL, 90.00 mmol)dropwise under nitrogen atmosphere. The resulting mixture was allowed to warm to -20 °C and stirred for 50 mm. The mixture was cooled to -50 °C, and a solution of CH3I (8.56 g, 60.31 mmol) in THF (20 mL) was added dropwise. The resulting mixture was stirred for 50 mm at this temperature. The reaction mixture was carefully quenched with sat. aq. NH4C1 (80 mL), extractedwith EA (100 mL, 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 1-(tert-butyl) 4-ethyl 4-methylpiperidine-1, 4-dicarboxylate (17.70 g) which was used without any further purification. MS: m/z 216 (M+H-56) .

Replacing the ester functional group with an amino functional group provides a key structural unit for the piperazinyl CCR5 antagonist.