1-Cbz-4-hydroxymethylpiperidine

N-Benzyloxycarbonyl-4- (hydroxymethyl) piperidine (E-12);. A stirred solution of 4-hydroxymethylpiperidine (2.0 g, 17.4 mmol) in dry dichloromethane (DCM, 100 mL) was cooled to 0°C, treated with triethylamine (4.8 mL, 34.8 mmol) followed by benzyl chloroformate (3.7 mL, 34.8 mmol), allowed to warm to room temperature and stirred for two hours. The mixture was partitioned between DCM (50 mL) and water (30 mL). The layers were separated and the aqueous phase was extracted with DCM (2 x 50 mL). The combined organic phases were washed with brine (1 x 30 mL), dried over Na2S04 and evaporated to a residue, that was purified by column chromatography using a gradient of 70 to 100 percent EtOAc in hexanes as eluant to give 3.85 g (89 percent) of E-12 as clear oil : 1H NMR (CDC13) S 1. 17 (m, 2H), 1.72 (m, 3H), 2.15 (br s, 1H), 2. 78 (t, 2H, J=12. 24), 3.47 (d, 2H, J=6. 04), 4.20 (d, 2H, J=11. 68), 5.12 (s, 2H), 7.33 (m, 5H).To a stirred solution of 4-hydroxymethylpiperidine (1.0 g, 8.7 mmol, 1.0 equiv) in dry CHStep B 4-Hydroxymethyl-piperidine-1-carboxylic acid benzyl ester (2); Piperidine-1 , 4-dicarboxylic acid 1 -benzyl ester 4-ethyl ester (1 ) (165 g, 567. mmol) was dissolved in tetrahydrofuran (1500 ml_) and cooled to 0Piperidin-4-ylmethanol (5.2 g, 45.1 mmol) was dissolved in 60 mE of THF and 60 mE of saturated NaHCO3 aq and then benzyl (2, 5-dioxopyrrolidin- 1 -yl) carbonate (11.25 g, 45.1 mmol) added portionwise. The mixture was stirred for 1 h at RT, partitioned between AcOEt and water, washed twice with 1M HClaq and saturated NaClaq. Organic layer was dried over Na2504, evaporated under reduced pressure to afford the title compound (10.77 g, 43.2 mmol, 96percent yield). The product obtained was used in the following steps without thrther purifications. UPLC-MS: 0.80 mm, 250.2 [M+H]+, method 1.a) Preparation 29 To a 500 ml three neck round bottomed flask under nitrogen atmosphere, benzyl 4- (hydroxymethyl) piperidine- l-carboxylate (10 g, 40.1 1 mmol) was dissolved in CH2CI2 (100 ml) and cooled to 0 C. Triphenyl phosphine (13.7 g, 52.14 mmol) in CH2CI2 (50 ml) was added to the reaction mixture and stirred at 0 C for 20 minutes. Carbon tetra bromide (16 g, 48.13 mmol) in CH2CI2 (50 ml) was added to reaction mixture which was stirred at rt for 3 h. The reaction mixture was diluted with CH2CI2 and washed with water. Organic layer was dried over sodium sulfate and concentrated under vacuum and purified by column chromatography to give 10 g of benzyl 4-(bromomethyl) piperidine- l-carboxylate.4-Formyl-piperidine-1-carboxylic acid benzyl ester (3); Oxalyl chloride (59.1 ml_, 674 mmol) was dissolved in dichloromethane (500 ml_) and cooled to -78C. Dimethylsulfoxide (68.3 ml_, 963 mmol) was added and the mixture was stirred for 15 min. 4-Hydroxymethyl-piperidine-1-carboxylic acid benzyl ester (2) (120 g, 481 mmol) dissolved in dichloromethane (500 ml_) was added. The mixture was allowed to warm to -55C for 15 min. The mixture was again cooled to -78C and triethylamine (205 ml_, 1443 mmol) in dichloromethane (250 ml_) was added. The suspension was allowed to warm to room temperature and quenched with glacial acetic acid (100 ml_). The solution was washed with water and the aqueous phase extracted with dichloromethane (2 x 200 ml_). The combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated to give 4- formyl-piperidine-1-carboxylic acid benzyl ester (119 g, 100%).To oxalyl chloride (10.3 mL, 0.120 mol) in 150 mL of DCM and at -78 C, a solution of DMSO (17.1 mL, 0.241 mol) in DCM (25 mL) was added dropwisely. After 30 min, benzyl 4- (hydroxymethyl)-piperidine-l-carboxylate (20 g, 0.080 mol) in DCM (25 mL) was added dropwisely. After 30 min, Et3N (44.7 mL, 0.321 mol) was added. The resulting solution was stirred for 30 min at -78 C. The reaction was diluted with water, extracted with DCM (3 x). Combined organic layers were washed with water (3 x 500 mL), dried over Na2S04, filtered and concentrated to give Intermediate 6C (18.5 g, 93.0%). MS (ESI) m/z 247 (M+H)+.Example 25;. N-Benzyloxycarbonyl-4- (formyl)-piperidine (E-13).; A stirred suspension of N-(benzyloxycarbonyl)-4-hydroxymethyl)-piperidine (E-12, 2 g, 8 mmol) and CeliteTM (4 g) in dry DCM (120 mL) at room temperature was treated with pyridinium chlorochromate (3.5 g, 16.0 mmol), stirred for 3 hours, and filtered on Celte. The filtrate was evaporated to a dark residue which was purified by column chromatography using a gradient of 25 to 50 % EtOAc in hexane as eluant to give 1.5 g (75 %) of aldehyde E-13 as a clear oil which was immediately used in the next step : 1H NMR (CDC13) 8 1.43 (dd, 2H, J=10), 1.78 (m, 2H), 2.31 (m, 1H), 2.91 (t, 2H, J=10. 6), 3.96 (m, 2H), 5.05 (s, 2H), 7.24 (m, 5H), 9.52 (s, 1H).Step 2:Oxalyl chloride (9.4 g; 74 mmol) is dissolved in DCM (55 ml) and cooled to -78C. DMSO (7.5ml; 106 mmol) is added dropwise and the mixture is stirred for 15 min at -78C. In a separateflask, 4a3 (13 g; 53 mmol) is dissolved in DCM (55 ml) and added dropwise to the first flask viacannula. Once the addition is finished, the mixture is stirred at -55C for 15 min. The reactionmixture is cooled to -78C and a solution of triethylamine (22 ml; 158 mmol) in DCM (28 ml) isadded dropwise to the reation mixture via cannula. The mixture is stirred for 1 hat -78C then15 min at ooc and 30 min at RT. The reaction is neutralized with 11 ml of AcOH and dilutedwith 100 ml of DCM and 100 ml of water. The layers are separated and the aqueous layer isextracted with DCM (2 x 100 ml). The combined organic layers are washed with brine, driedover MgS04, filtered and concentrated. Purification by Combiflash (120 g column, 0-50%EtOAc/Hex) gives 4a4.Reaction step 2: Synthesis of benzyl 4-formylpiperidine-1-carboxylate To a stirred solution of Reaction Step 2 Synthesis of benzyl 4-formylpiperidine-1-carboxylate To a stirred solution of 4-Hydroxymethyl-piperidine-1-carboxylic acid benzyl ester (2); Piperidine-1 , 4-dicarboxylic acid 1 -benzyl ester 4-ethyl ester (1 ) (165 g, 567. mmol) was dissolved in tetrahydrofuran (1500 ml_) and cooled to 00C. Lithium aluminium hydride (311 ml_, 1 M in THF) was added dropwise maintaining the temperature below 5C. The reaction mixture was stirred for one hour and aqueous sodium hydroxide (4 N) was added dropwise. The mixture was filtered and the filtercake was washed with diethyl ether. The organic layer was concentrated and dissolved in ethyl acetate, washed with water and brine, dried over sodium sulphate, filtered and concentrated to give 4-hydroxymethyl-piperidine-1-carboxylic acid benzyl ester (120 g, 85%) as a yellow oil.A solution of benzyl 4-(hydroxymethyl) piperidine-1-carboxylate (15.0 g, 60.2 mmol, CAS122860-33-7) in DCM (15 mL) was added diacetoxyrhodium (1.33 g, 3.01 mmol, CAS623-73-4). The mixture was stirred at 25 C. for 0.5 hour. Then ethyl 2-diazoacetate (13.7 g, 120 mmol) in DCM (15 mL) was added dropwise slowly to the solution. The mixture was stirred at 25 C. for 12 hours. On completion, the reaction mixture was quenched by water (10 mL), and extracted with DCM (3×20 mL). The combined organic layers dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (16.8 g, 83% yield) as yellow oil. LC-MS (ESI+) m/z 336.2 (M+H)+.

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:256
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes