Phenylmethyl 3-(hydroxymethyl)-1-piperidinecarboxylate

White to off-white crystal powder

To a chilled solution of 3-(hydroxymethyl)piperidine (0.61 g; 5 mmol) in methylene chloride (10 mL) was added triethylamine (0.51 g; 5 mmol), followed by the dropwise addition of benzyl chloroformate (0.88 g; 5 mmol). The resulting reaction mixture was allowed to warm to room temperature and stirred overnight. Methylene chloride (50 mL) was added to the reaction and the organic layer was washed with 5percent HCl (2 .x. 20 mL), saturated NaHCOTo a stirred solution of 3- hydoxymethylpiperidine (lg, 8. 7 mmol) in CH2C12 (50 mL) and Et3N (1.12 MML) at 0 oC was added dropwise CbzCl (1.24 mL, 8.7 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was washed with brine, dried over NA2S04, and concentrated. The residue was purified by chromatography with hexane-EtOAc (2: 1) to give a colorless oil (2 g, 94percent). LH NMR (CDC13) 8 7.35 (M, 5H), 5.12 (M, 2H), 4.20-3. 60 (M, 2H), 3.47 (M, 2H), 3.20-2. 20 (M, 3H), 1.82-1. 10 (M, 5H) ; 13C NMR (CDCl3) 8 155. 55, 136.73, 128.38, 127. 85, 127.69, 66.96, 64.31, 46.74, 44.71, 38.01, 26.77, 24.05.3-Hydroxymethylpiperidine-1-carboxylic acid benzyl ester (a): An aqueous solution (20 mL) of sodium carbonate (6. 90 g, 65.1 mmol) was added to 3-piperidinylmethanol (5.00 g, 43.4 mmol) in tetrahydrofuran (20 mL). While the mixture was chilled in an ice bath, benzyloxycarbonyl chloride (9.36 g, 52.1 mmol) was added and the mixture was stirred for 1 hour and subsequently 7 hours at room temperature. The solvent was then evaporated and ethyl acetate was added to the residue. The mixture was then washed sequentially with water, 0.1 mol/L hydrochloric acid and brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the residue by silica gel column chromatography (hexane : ethyl acetate = 5:1 -> 1:1) gave 9.15 g (85percent) of the desired compound as a colorless powder. Step 2. Benzyl 3-(hydroxymethyl)piperidine-1-carboxylate; A 250-mL 3-necked round-bottomed flask was charged with a solution of LiAlHExample 3 To a solution of benzyl 3-(hydroxymethyl) piperidine-1 - carboxylate (2.37 g, 9.5 mmol), dimethylaminopyridine (58 mg, 0.48 mmol) and triethylamine (2.6 ml, 19.0 mmol) in dichloromethane (50 ml) at 0 C. was added p-toluenesul-fonyl chloride (2.0 g, 10.5 mmol) and the reaction stirred for 18 hours at room temperature. The mixture was diluted with100 ml of dichloromethane and washed saturated sodium bicarbonate (15 mLx3), water (20 mE) and brine (50 mE). The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford benzyl 3-((to- syloxy)methyl)piperidine- 1 -carboxylate (3.7 g, 97%) as a white solid, which was characterized according to a literature procedure (see e.g. Abreu et al., Tetrahedron, 2005, 6 1:11986-11990)An aqueous solution (2 mL) of potassium bromide (983 mg, 8.26 mmol) was added to 1-benzyloxycarbonyl-3-piperidinyl methanol (2.00 g, 8.02 mmol) and 2, 2, 6, 6-tetramethyl piperidine-N-oxyl (12.5 mg, 0.0802 mmol) in dichloromethane (20 mL). The mixture was stirred for 5 min while chilled in an ice bath. A 0.35 mol/L aqueous sodium hypochlorite solution (25.2 mL, 8.82 mmol) and sodium bicarbonate (1.96 g, 23.3 mmol) were added and the mixture was stirred for 10 min. Subsequently, the reaction mixture was extracted with ethyl acetate and the extract was washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the residue by silica gel column chromatography (hexane: ethyl acetate = 10:1 -> 2:1) gave 1.78 g (90%) of the desired compound as a colorless oil. 1H NMR (400 MHz, DMSO-d6) delta 1.36-1.47 (1H, m), 1.52-1.65 (2H, m), 1.86-1.95 (1H, m), 3.10-3.16 (1H, m), 3.27-3.33 (2H, m), 3.51-3.62 (1H, m), 3.83 (1H, dd, J = 13.4, 3.7 Hz), 5.07 (2H, m), 7.30-7.40 (5H, m), 9.59 (1H, s). FAB+(M/Z): 248 (M+H).To a suspension of pyridinium chlorochromate (0.65 g; 3 mmol) in 10 ml methylene chloride was added compound 7 (0.50 g; 2 mmol) in methylene chloride (5 mL). The reaction was stirred at room temperature for 2 h and filtered. The filtrate was evaporated and the residue was treated with diethyl ether (25 mL). The precipitate was filtered off again and the filtrate was evaporated, leaving pure product 8 as a pink oil (0.50 g; 90% yield). 1H NMR (CDCl3): delta 1.42-1.78 (m, 3H), 2.00 (br s, 1H), 2.43 (br s, 1H), 3.08-3.20 (m, 1H), 3.33-3.41 (m, 1H), 3.71-3.82 (m, 1H), 3.92-4.10 (m, 1H), 5.13 (s, 2H), 7.27-7.42 (m, 5H), 9.68 (s, 1H).Step 3. Benzyl 3-formylpiperidine-1-carboxylate; A 500-mL round-bottomed flask was charged a solution of Example 70A Benzyl 3-[(vinyloxy)methyl]piperidine-1-carboxylate At RT, 23 ml (241 mmol) of ethyl vinyl ether were added to 321 mg (0.65 mmol) of chloro(triphenylphosphine)gold(I) and 108 mg of silver(I) acetate. After 10 min of stirring, 6.00 g (24.07 mmol) of

Molecular Weight:249.30
XLogP3:1.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:4
Exact Mass:249.13649347
Monoisotopic Mass:249.13649347
Topological Polar Surface Area:49.8
Heavy Atom Count:18
Complexity:264
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes