tert-butyl 4-(2-iodoethyl)piperidine-1-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 1,1-dimethylethyl 4-(2-iodoethyl)-1-piperidinecarboxylate (Example 101, Step A) (23.6 g, 69.5 mmol) in DMF (100 mL) was added sodium thiomethoxide (5.37 g, 76.4 mmol). The mixture was stirred at 50° C. overnight. The mixture was diluted with EtOAc, washed with H2O (6×), dried (MgSO4), and rotovapped down to provide the title compound of Step A (17.9 g, 68.8 mmol, 99%). 1H NMR (400 MHz, CDCl3) δ 1.09 (dd, 2H), 1.44 (s, 9H), 1.53 (t, J=5.6 Hz, 3H), 1.65 (d, J=12.6 Hz, 2H), 2.08 (s, 3H), 2.51 (t, J=6.9 Hz, 2H), 2.67 (t, J=12.6 Hz, 2H), 4.06 (d, J=13.2 Hz, 2H). washed with H2O (6×) dried (MgSO4)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 1,1-dimethylethyl 4-(2-iodoethyl)-1-piperidinecarboxylate (3.13 g, 9.23 mmol) in DMF (50 mL) was added sodium thiomethoxide (661 mg, 10.4 mmol) in one portion. The reaction was stirred for 3 days. Upon completion by TLC, the reaction was diluted with EtOAc (250 mL), washed with H2O (4 times), dried (MgSO4) and concentrated to provide the title compound of step B (2.37 g, 9.20 mmol, 99%, approximately 93% pure, used without further purification). 1H NMR (400 MHz, CDCl3) δ ppm 1.02-1.13 (m, 2H), 1.42 (s, 9H), 1.48-1.55 (m, 3H), 1.63 (d, J=12.5 Hz, 2H), 2.07 (s, 3H), 2.45-2.53 (m, 2H), 2.65 (td, J=12.8, 2.6 Hz, 2H), 4.02-4.09 (m, 2H). washed with H2O (4 times) dried (MgSO4) concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To N-Boc-4-piperidine-ethanol (5.00 g, 21.8 mmol) in THF (100 mL) was added triphenylphosphine (6.29 g, 24.0 mmol), imidazole (1.64 g, 24.1 mmol) and iodine (6.09 g, 24.0 mmol). The reaction was stirred at rt for 2 h. The mixture was filtered through Celite® purified by flash chromatography to provide the title compound of step A (6.31 g, 18.6 mmol, 85%). 1H NMR (400 MHz, CDCl3) δ ppm 1.07 (dq, J=12.2, 4.3 Hz, 2H), 1.42 (s, 9H), 1.49-1.58 (m, 1H), 1.62 (d, J=13.2 Hz, 2H), 1.75 (q, J=7.1 Hz, 2H), 2.67 (td, J=12.9, 2.5 Hz, 2H), 3.18 (t, J=7.1 Hz, 2H), 4.06 (d, J=13.0 Hz, 2H). The mixture was filtered through Celite® purified by flash chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-11 (10.42 g, 0.048 mol) was dissolved in 400 ml benzene, imidazole (4.66 g, 0.068 mol), triphenylphosphine (15.24 g, 0.05 mol) and iodine (0.048 mol) were added at room temperature. After 6 hours the reaction mixture was filtered and the filtrate was evaporated to give a dark residue. This was purified by flash chromatography on silica gel eluting with 10% EtOAc-hexanes to give 2-12 as a yellow oil. After 6 hours the reaction mixture was filtered the filtrate was evaporated to give a dark residue This was purified by flash chromatography on silica gel eluting with 10% EtOAc-hexanes

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a slurry of sodium hydride (47 mg, 60% in mineral oil, 1.2 mmol) in tetrahydrofuran at 0° C. was added 4-fluorothiophenol (0.1 mL, 0.94 mmol). The reaction mixture was warmed to rt. for 20 min, followed by addition of 4-(2-iodoeth-1-yl)-1-tert-butoxycarbonylpiperidine (265 mg, 0.78 mmol, from Step C). The reaction was then heated to reflux for 10 min, cooled and diluted with ether. The organic layer was washed with 1 N NaOH, dried over magnesium sulfate and concentrated to provide 252 mg (95%) of the title compound. ESI-MS: 340.0 (M+H); HPLC A: 4.07 min. The reaction was then heated to reflux for 10 min cooled The organic layer was washed with 1 N NaOH dried over magnesium sulfate concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a slurry of sodium hydride (47 mg, 60% in mineral oil, 1.2 mmol) in tetrahydrofuran at 0° C. was added 4-fluorothiophenol (0.1 mL, 0.94 mmol). The reaction mixture was warmed to rt. for 20 min, followed by addition of 4-(2-iodoeth-1-yl)-1-tert-butoxycarbonylpiperidine (265 mg, 0.78 mmol, from Step C). The reaction was then heated to reflux for 10 min, cooled and diluted with ether. The organic layer was washed with 1 N NaOH, dried over magnesium sulfate and concentrated to provide 252 mg (95%) of the title compound. ESI-MS: 340.0 (M+H); HPLC A: 4.07 min. The reaction was then heated to reflux for 10 min cooled The organic layer was washed with 1 N NaOH dried over magnesium sulfate concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Combined 4-(2-hydroxyeth-1-yl)-1-tert-butoxylcarbonylpiperidine (37.4 g, 0.16 mol, from Step B), triphenylphosphine (55 g, 0.21 mol) and imidazole (14 g, 0.21 mol) in 800 mL of 33% acetonitrile in ether. Cooled to 0° C. and added iodine (56 g, 0.22 mol) portionwise. The iodine is de-colored until the endpoint of the reaction. Diluted with 1 L of ether. Washed organic layer with 2×500 mL each of sat'd. aq. Na2S2O3, sat. aq. CuSO4 and brine. Dried over magnesium sulfate, filtered and concentrated. Triphenylphosphine oxide precipitates. Added ether and filtered the slurry through a plug of silica gel. Purified a portion of the crude material by flash chromatography (5% ethyl acetate in hexane eluent) to afford the title compound. Dried over magnesium sulfate filtered concentrated Triphenylphosphine oxide precipitates Added ether and filtered the slurry through a plug of silica gel Purified a portion of the crude material by flash chromatography (5% ethyl acetate in hexane eluent)