1-Boc-4-iodomethyl-piperidine

To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate 22 (2.25 g, 10.5 mmol, 1.0 eq.), imidazole (858 mg, 12.6 mmol, 1.2 eq.) and triphenylphosphine (3.30 g, 12.6 mmol, 1.2 eq.) in dry THF (30 mL) was added drop-wise a solution of iodine (3.20 g, 12.6 mmol, 1.2 eq.) in dry THF (30 mL) at 0°C. The reaction mixture was stirred at room temperature for 14h. The mixture was quenched with a saturated NaTo a solution 1 , 1-dimethylethyl 4-(hydroxymethyl)-1-piperidinecarboxylate (10 g, 46.4 mmol), triphenylphosphine (15 g, 55.7 mmol) and imidazole (4 g, 55.7 mmol) in tetrahydrofuran (25 ml_) at 0 A 250 mL round bottom flask was charged with 5.8 g (27 mmol) of 22, 8.5 g (32.37 mmol) of triphenylphosphine, and 2.2 g (32.37 mmol) of imidazole. One hundred milliliters of methylene chloride were added, and the resulting solution was stirred at 0° C. for about 5 minutes. Finally, 8.2 g (32.37 mmol) of iodine were added and the solution was stirred at 0° C. for 5 minutes and at room temp for about 1 hour. The reaction mixture was diluted with 200 mL of hexane, and the triphenylphosphine oxide precipitate was filtered off (this was repeated until all precipitate was removed). The crude mixture was purified by flash chromatography using a 5percent-10percent ethyl acetate/hexane solvent system. A Phosphomolybdic acid stain (PMA), was used to see the product on the TLC plate. The resulting yield of pure 23 as an oil was 2.6 g (30percent). 1H NMR in CDCl3: 2H quartet at 1.1 ppm (J=12 Hz), a 9H singlet at 1.4 ppm, a 1H broad signal at 1.55 ppm, a 2H doublet at 1.75 (J=12 Hz), a 2H broad signal at 2.65 ppm, a 2H doublet at 3.05 ppm (J=6 Hz), and a 2H broad signal at 4.1 ppm. The Rf=0.13 using a 5percent ethyl acetate/hexane solvent systemTo tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (2.57 g, 8.8 mmol) in acetone (60 mL) was added sodium iodide (2.63 g, 17.5 mmol). The yellow solution formed was heated at reflux overnight. The resulting orange suspension formed was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue partitionedbetween DCM (100 ml) and water (20 ml). The organic portion was dried (MgSO4) and treated with silica (10 g). This was filtered and the filtrate concentrated to give the title compound as an orange oil (2.19 g);1H NMR (400MHz, ODd3) o 1.14 (2H, dq), 1.48 (9H, 5), 1.57-1.70 (1H, m), 1.82-1.90 (2H, m), 2.73 (2H, t), 3.12 (2H, d), 4.10-4.20 (2H, m).To a solution of iPr2NH (6.42 ml, 45.8 mmol) in THF (15 ml) at 0 C. was added nBuLi (1.6 M, 28 ml, 45 mmol). After stirring at room temperature for 1 hour, the reaction mixture was cooled to -78 C. and treated dropwise over 5 minutes with a solution of X (5 g, 21.8 mmol in 15 ml THF). The reaction mixture was then warmed to -20 C. and a slurry formed. THF (15 ml) was added to loosen the slurry and the slurry was stirred vigorously for 2.5 hour at -20 C. A solution of N-Boc-4-(iodomethyl)piperidine (10.63 g, 32.7 mmol in 15 ml THF) was added dropwise over 3 minutes and the resulting solution was stirred at -20 C. for 18 hours. The reaction mixture was partitioned between EtOAc (200 ml) and water (200 ml). After mixing and separation, the organic phase was extracted once more with water (150 ml). The combined water layers were then washed with EtOAc (2×200 ml). The aqueous phase was diluted with EtOAc (200 ml) and with rapid stirring brought to pH 2-3 with portionwise addition of solid KHSO4. The EtOAc layer was removed and the aqueous layer was extracted with EtOAc (3×200 ml). The EtOAc extracts from the acidified aqueous layer were combined, dried over Na2SO4, filtered and concentrated. [0330] The residue was taken up in THF (30 ml), treated with TBAF (1.0 M THF, 22 ml) and stirred at room temperature for 2 hours. The reaction mixture was partitioned between EtOAc and 0.5N KHSO4. The aqueous phase was then extracted with EtOAc (4×). The combined EtOAc extracts were dried over MgSO4, filtered and concentrated to give Part A compound (2.8 g, 42%). [0331] 1H-NMR (400 MHz, CDCl3) delta 8-9 (bs, 1H), 6.82 (s, 1H), 4.1 (m, 2H), 3.88 (d, 1H, j=2.47), 3.36 (m, 1H), 2.67 (m, 2H), 1.6-1.9 (m, 6H), 1.43 (s, 9H), 1.1 (m, 1H).437 mg of K2CO3(3.16 mmol) and 617 mg of A solution of chlorotrimethylsilane (1.25 mL, 9.85 mmol) and l-bromo-2-chloroethane (0.2 mL, 2.41 mmol) in THF (10 mL) was prepared under N2 atmosphere in a dried flask and was passed through a column containing Zn (10 g) using a syringe pump at 40C and at a flow rate of lmL/min. A solution of l-Boc-4-iodomethylpiperidine (CAS: 145508- 94-7; 1.00 g, 3.08 mmol) in THF (10 mL) was passed through the column containing activated Zn using a syringe pump at 40 C and at a flow rate of 0.5 mL/min. The outcoming solution was collected in a closed flask under N2 atmosphere. Titration with I2 revealed that a 0.2M solution was obtained which was used as such in the next step.In a round bottom flask, compound 3 (198mg, 0.47mmol) was dissolved in acetonitrile (20mL), triethylamine (0.14mL, 0.96mmol) and

Molecular Weight:325.19
XLogP3:3.1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:3
Exact Mass:325.05388
Monoisotopic Mass:325.05388
Topological Polar Surface Area:29.5
Heavy Atom Count:15
Complexity:217
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes