[ CAS No. 39945-51-2 ] {[proInfo.proName]}

Name: 39945-51-2|Benzyl 3-(hydroxymethyl)piperidine-1-carboxylate|96%
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Quality Control of [ 39945-51-2 ]

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Product Details of [ 39945-51-2 ]

CAS No. :	39945-51-2	MDL No. :	MFCD03407298
Formula :	C₁₄H₁₉NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XLWOOUZKMJBINO-UHFFFAOYSA-N
M.W :	249.31	Pubchem ID :	2776577
Synonyms :

Safety of [ 39945-51-2 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 39945-51-2 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 39945-51-2 ]
Downstream synthetic route of [ 39945-51-2 ]

[ 39945-51-2 ] Synthesis Path-Upstream 1~7

1
[ 4606-65-9 ]
[ 501-53-1 ]
[ 39945-51-2 ]

Yield	Reaction Conditions	Operation in experiment
96%	With triethylamine In dichloromethane at 20℃; Cooling	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 NaHCO₃ (20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate. The drying agent was filtered off and the solvent was removed. The crude product was purified using flash chromatography (silica gel/ethyl acetate/hexanes) to give compound 7 as a colorless oil (1.21 g; 96percent yield). ¹H NMR (CDCl₃): δ 1.20-1.83 (m, 5H), 2.78-3.20 (m, 2H), 3.50 (s, 2H), 3.69-4.05 (m, 2H), 5.14 (s, 2H), 7.25-7.40 (m, 5H).
94%	With triethylamine In dichloromethane at 0 - 20℃;	To 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.
94%	With triethylamine In dichloromethane at 0 - 20℃;	3-Hydroxymethylpiperidine-1-carboxylic acid benzyl ester (a): To a stirred solution of 3-hydroxymethylpiperidine (1 g, 8.7 mmol) in CH₂Cl₂ (50 mL) and Et₃N (1.12 mml) at 0° C. 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 Na₂SO₄, and concentrated. The residue was purified by chromatography with hexane-EtOAc (2:1) to give colorless oil (2 g, 94percent). ¹H NMR (CDCl₃, 400 MHz) δ 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, 100 MHz) δ 155.55, 136.73, 128.38, 127.85, 127.69, 66.96, 64.31, 46.74, 44.71, 38.01, 26.77, 24.05.

85%

With sodium carbonate In tetrahydrofuran; water at 0 - 20℃; for 8 h;

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. ¹H NMR (400 MHz, DMSO-d₆) δ 1.09 (1H, qd, J = 12.2, 3.1 Hz), 1.33 (1H, qt, J = 11.6, 3.7 Hz), 1.45-1.55 (1H, m), 1.59-1.64 (1H, m), 1.64-1.69 (1H, m), 2.42-2.65 (1H, m), 2.70-2.86 (1H, m), 3.16-3.22 (1H, m), 3.27-3.31 (1H, m), 3.86-3.93 (1H, m), 4.04 (1H, dd, J = 12.8, 2.4 Hz), 4.55 (1H, t, J = 5.5 Hz), 5.03-5.10 (2H, m), 7.29-7.39 (5H, m).

Reference： [1] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 20, p. 5975 - 5983
[2] Journal of Medicinal Chemistry, 2006, vol. 49, # 9, p. 2673 - 2676
[3] Patent: WO2005/806, 2005, A2, . Location in patent: Page 85
[4] Patent: US2010/48606, 2010, A1, . Location in patent: Page/Page column 32
[5] Patent: EP1780210, 2007, A1, . Location in patent: Page/Page column 51
[6] Archiv der Pharmazie, 1990, vol. 323, # 1, p. 9 - 12
[7] Tetrahedron, 2005, vol. 61, # 50, p. 11986 - 11990
[8] Patent: US6610707, 2003, B1,
[9] Synthesis, 2011, # 22, p. 3669 - 3674

2
[ 310454-53-6 ]
[ 39945-51-2 ]

Yield	Reaction Conditions	Operation in experiment
92%	Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at -10℃; for 1 h; Stage #2: With sodium hydroxide In tetrahydrofuran; water	Step 2. Benzyl 3-(hydroxymethyl)piperidine-1-carboxylate; A 250-mL 3-necked round-bottomed flask was charged with a solution of LiAlH₄(2.96 g, 77.83 mmol, 2.00 equiv) in THF (150 mL). To this solution was added 1-benzyl 3-ethyl piperidine-1,3-dicarboxylate (11.4 g, 39.16 mmol, 1.00 equiv) in THF (50 mL) drop wise with stirring at -10° C. The resulting mixture was allowed to stir about 1 hour at -10° C. The progress was monitored by TLC (DCM: MeOH=10:1). The resulting solution was diluted with 10 mL of NaOH/H₂O. The solids were filtered out. The resulting mixture was concentrated on a rotary evaporator to afford benzyl 3-(hydroxymethyl)piperidine-1-carboxylate as pale yellow oil in (8.94 g, (92percent).

Reference： [1] Patent: US8080566, 2011, B1, . Location in patent: Page/Page column 44

3
[ 435275-85-7 ]
[ 105706-76-1 ]
[ 39945-51-2 ]

Yield	Reaction Conditions	Operation in experiment
66%	With sodium hydroxide In tetrahydrofuran; hexane; water	Example 3 Synthesis of 3-hydroxymethyl-piperidine-1-carboxylic acid benzyl ester (8) Piperidine-1,3-dicarboxylic acid 1-benzyl ester 3-ethyl ester (7) (1.5 g, 5.83 mmol) was dissolved in 5.8 mL of anhydrous THF, and the reaction was stirred under N₂ at -5° C. while lithium aluminum hydride dissolved in THF (7.0 mL, 1.0M) was added dropwise by addition funnel over 30 minutes. When the reaction was complete by TLC (10 min.), H₂O (0.6 mL), then 10percent NaOH (1.5 mL), then H₂O (0.6 mL) were added, and the reaction was stirred for about 45 minutes. The salts were removed by filtration and the solution was dried with sodium sulfate, filtered, and concentrated. The crude material was purified using an ISCO CombiFlash flash column (silica, 80:20 Hexane: EtOAc to 40:60 Hexane: EtOAc) to achieve 1.24 g of pure 8 (66percent yield).

Reference： [1] Patent: US2002/177721, 2002, A1,

4
[ 4606-65-9 ]
[ 42116-21-2 ]
[ 39945-51-2 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 1997, vol. 5, # 11, p. 2089 - 2094

5
[ 4606-65-9 ]
[ 144-55-8 ]
[ 501-53-1 ]
[ 39945-51-2 ]

Reference： [1] Patent: US6329380, 2001, B1,

6
[ 501-53-1 ]
[ 39945-51-2 ]

Reference： [1] Patent: US8080566, 2011, B1,

7
[ 71962-74-8 ]
[ 39945-51-2 ]

Reference： [1] Patent: US8080566, 2011, B1,

[ 39945-51-2 ] Synthesis Path-Downstream 1~40

1
[ 4606-65-9 ]
[ 501-53-1 ]
[ 39945-51-2 ]

Yield	Reaction Conditions	Operation in experiment
96%	With triethylamine; In dichloromethane; at 20℃;Cooling;	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 5% HCl (2 × 20 mL), saturated NaHCO3 (20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate. The drying agent was filtered off and the solvent was removed. The crude product was purified using flash chromatography (silica gel/ethyl acetate/hexanes) to give compound 7 as a colorless oil (1.21 g; 96% yield). 1H NMR (CDCl3): delta 1.20-1.83 (m, 5H), 2.78-3.20 (m, 2H), 3.50 (s, 2H), 3.69-4.05 (m, 2H), 5.14 (s, 2H), 7.25-7.40 (m, 5H).
94%	With triethylamine; In dichloromethane; at 0 - 20℃;	To 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, 94%). 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.
94%	With triethylamine; In dichloromethane; at 0 - 20℃;	3-Hydroxymethylpiperidine-1-carboxylic acid benzyl ester (a): To a stirred solution of 3-hydroxymethylpiperidine (1 g, 8.7 mmol) in CH2Cl2 (50 mL) and Et3N (1.12 mml) at 0 C. 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 Na2SO4, and concentrated. The residue was purified by chromatography with hexane-EtOAc (2:1) to give colorless oil (2 g, 94%). 1H NMR (CDCl3, 400 MHz) delta 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, 100 MHz) delta 155.55, 136.73, 128.38, 127.85, 127.69, 66.96, 64.31, 46.74, 44.71, 38.01, 26.77, 24.05.

91%	With sodium hydroxide; In 1,4-dioxane; at 0 - 20℃; for 0.5h;	To a solution of piperidin-3-ylmethanol (1.2 g, 10.4 mmol) and 1 NNaOH (14.5 mE, 14.5 mmol) in 1,4-dioxane(14 mE) was added benzylchloroformate (CbzCl) (2.1 mE,14.5 mmol) dropwise (using dropping thnnel) at 00 C. After stirring for 30 mm at room temperature, the mixture was diluted with H20, acidified with 10% HC1 to pH 1 and extracted with ethyl acetate (15 mLx3). The organic layer was washed with brine, dried over MgSO4, and evaporated. The residue was purified with flash column chromatography (Hexanes/EtOAc=1/1) to afford benzyl 3-(hydroxymethyl) piperidine-1-carboxylate (2.37 g, yield 91%) as a colorless oil.
85%	With sodium carbonate; In tetrahydrofuran; water; at 0 - 20℃; for 8h;	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 (85%) of the desired compound as a colorless powder. 1H NMR (400 MHz, DMSO-d6) delta 1.09 (1H, qd, J = 12.2, 3.1 Hz), 1.33 (1H, qt, J = 11.6, 3.7 Hz), 1.45-1.55 (1H, m), 1.59-1.64 (1H, m), 1.64-1.69 (1H, m), 2.42-2.65 (1H, m), 2.70-2.86 (1H, m), 3.16-3.22 (1H, m), 3.27-3.31 (1H, m), 3.86-3.93 (1H, m), 4.04 (1H, dd, J = 12.8, 2.4 Hz), 4.55 (1H, t, J = 5.5 Hz), 5.03-5.10 (2H, m), 7.29-7.39 (5H, m).
	With N-ethyl-N,N-diisopropylamine; In dichloromethane;	PREPARATION 59 Benzyl 3-(Hydroxymethyl)-1-piperidinecarboxylate Benzyl chloroformate (7.88 ml) was added over ten minutes to an ice-cold solution of 3-hydroxymethyl piperidine (5.76 g) and ethyldiisopropylamine (9.58 ml) in dichloromethane (300 ml). The reaction mixture was allowed to warm to room temperature and stirred for 1 hr. The reaction was then diluted with dichloromethane (500 ml), washed with 1N aqueous hydrochloric acid (200 ml), dried over magnesium sulphate, and evaporated to afford benzyl 3-(hydroxymethyl)-1-piperidinecarboxylate as an oil (12.4 g). 1H-NMR (d6-DMSO) delta: 7.30 (5H, m), 5.00 (2H, s), 4.45 (1H, t), 4.00 (1H, d), 3.85 (1H, d), 3.25 (2H, m), 3.15 (1H, m), 2.75 (1H, bs), 1.60 (2H, m), 1.50 (1H, m), 1.30 (1H, m), 1.10 (1H, m).

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 5975 - 5983
[2]Journal of Medicinal Chemistry,2006,vol. 49,p. 2673 - 2676
[3]Patent: WO2005/806,2005,A2 .Location in patent: Page 85
[4]Patent: US2010/48606,2010,A1 .Location in patent: Page/Page column 32
[5]Patent: US10259800,2019,B2 .Location in patent: Page/Page column 60-61
[6]Patent: EP1780210,2007,A1 .Location in patent: Page/Page column 51
[7]Archiv der Pharmazie,1990,vol. 323,p. 9 - 12
[8]Tetrahedron,2005,vol. 61,p. 11986 - 11990
[9]Patent: US6610707,2003,B1
[10]Synthesis,2011,p. 3669 - 3674

2
[ 39945-51-2 ]
[ 110521-96-5 ]
[ 128014-65-3 ]

Reference： [1]Archiv der Pharmazie,1990,vol. 323,p. 9 - 12

3
[ 4606-65-9 ]
[ 42116-21-2 ]
[ 39945-51-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry,1997,vol. 5,p. 2089 - 2094

4
[ 39945-51-2 ]
[ 201478-72-0 ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; potassium bromide; In dichloromethane; water; at 0℃; for 0.25h;	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).
90%	With pyridinium chlorochromate; In dichloromethane; at 20℃; for 2h;	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).
70%	With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; In dichloromethane; water; at 20℃; for 18h;	Step 3. Benzyl 3-formylpiperidine-1-carboxylate; A 500-mL round-bottomed flask was charged a solution of <strong>[39945-51-2]benzyl 3-(hydroxymethyl)piperidine-1-carboxylate</strong> (8.94 g, 35.90 mmol, 1.00 equiv) in DCM (200 mL), NaHCO3 (9.05 g, 107.74 mmol, 3.00 equiv) in H2O (80 mL), I2 (18.24 g, 71.81 mmol, 2.00 equiv) and TEMPO (570 mg, 3.65 mmol, 0.10 equiv). The resulting mixture was stirred for 18 hours at room temperature. The reaction progress was monitored by TLC (DCM:MeOH=20:1). Upon completion, the reaction was then quenched by the addition of 10 mL of NaHSO3/H2O. The pH was adjusted to 8 with NaHCO3. The resulting solution was extracted with dichloromethane (3×50 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator to afford benzyl 3-formylpiperidine-1-carboxylate as brown oil (6.2 g, (70%).

Reference： [1]Patent: EP1780210,2007,A1 .Location in patent: Page/Page column 55
[2]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 5975 - 5983
[3]Patent: US8080566,2011,B1 .Location in patent: Page/Page column 44-45
[4]Bioorganic and Medicinal Chemistry,1997,vol. 5,p. 2089 - 2094
[5]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 5440 - 5443

5
[ 39945-51-2 ]
[ 405090-65-5 ]

Yield	Reaction Conditions	Operation in experiment
97%	With 1H-imidazole; iodine; triphenylphosphine; In dichloromethane; at 20℃; for 4.25h;	To a stirred solution of PPh3 (3.5 g) in dry CH2Cl2 (60 mL) was added 12 (3.34 g) under N2. After stirred for 15 min, imidazole (1.03 g) was added in one portion, followed by addition of 3- HYDROXYMETHYLPIPERIDINE-L-CARBOXYLIC acid b enzyl ester (1.5 g, 6.02 mmol) in CH2C12 (5 mL). The reaction mixture was stirred at room temperature for 4 h, washed with 5% aqueous NAHS03 and brine, dried, and concentrated. The residue was purified by chromatography with hexane-EtOAc (4: 1) to give a viscous oil (2.1 g, 97%). 1H NMR (CDC13) 8 7.35 (M, 5H), 5.13 (s, 2H), 4. 15 (br s, 1H), 3.96 (dt, 1H, J= 13.2, 3.9 Hz), 3.07 (d, 2H, J= 6.3 Hz), 2.85 (M, 1H), 2.66 (br s, 1H), 1.94 (M, 1H), 1.74-1. 38 (M, 3H), 1.33- 1.17 (M, 1H) ; 13C NMR (CDC13) 8 155.10, 136.71, 128. 40,127. 89, 127.75, 67.02, 49.71, 44.31, 37.90, 31.21, 24.18, 9.52.
97%	With 1H-imidazole; iodine; triphenylphosphine; In dichloromethane; at 20℃; for 4h;Inert atmosphere;	3-Iodomethylpiperidine-1-carboxylic acid benzyl ester (b): To a stirred solution of PPh3 (3.5 g) in dry CH2Cl2 (60 mL) was added I2 (3.34 g) under N2. After stirred for 15 min, imidazole (1.03 g) was added in one portion, followed by addition of <strong>[39945-51-2]3-hydroxymethylpiperidine-1-carboxylic acid benzyl ester</strong> (1.5 g, 6.02 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred at room temperature for 4 h, washed with 5% aqueous NaHSO3 and brine, dried, and concentrated. The residue was purified by chromatography with hexane-EtOAc (4:1) to give viscous oil (2.1 g, 97%). 1H NMR (CDCl3, 400 MHz) delta 7.35 (m, 5H), 5.13 (s, 2H), 4.15 (br s, 1H), 3.96 (dt, 1H, J=13.2, 3.9 Hz), 3.07 (d, 2H, J=6.3 Hz), 2.85 (m, 1H), 2.66 (br s, 1H), 1.94 (m, 1H), 1.74-1.38 (m, 3H), 1.33-1.17 (m, 1H). 13C NMR (CDCl3, 100 MHz) delta 155.10, 136.71, 128.40, 127.89, 127.75, 67.02, 49.71, 44.31, 37.90, 31.21, 24.18, 9.52.

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 2673 - 2676
[2]Patent: WO2005/806,2005,A2 .Location in patent: Page 85
[3]Patent: US2010/48606,2010,A1 .Location in patent: Page/Page column 32

6
[ 39945-51-2 ]
1-(piperidin-3-ylmethyl)pyridin-2(1H)-one [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 2673 - 2676

7
[ 39945-51-2 ]
[ 820231-91-2 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 2673 - 2676

8
[ 39945-51-2 ]
[ 128014-66-4 ]

Reference： [1]Archiv der Pharmazie,1990,vol. 323,p. 9 - 12

9
[ 39945-51-2 ]
[ 87413-09-0 ]
[ 201478-72-0 ]

Yield	Reaction Conditions	Operation in experiment
	In diethyl ether; hexane; dichloromethane;	Example 8 Synthesis of 3-formyl-piperidine-1-carboxylic acid benzyl ester (9) To a stirring, 0 C. solution of 0.303 g (1.20 mmol) of <strong>[39945-51-2]3-hydroxymethyl-piperidine-1-carboxylic acid benzyl ester</strong> (8) in CH2Cl2 (4.0 mL) was added 0.630g (1.44 mmol) of Dess-Martin periodinane, and the solution was stirred under N2. When the reaction was complete by TLC (about 30 min.), the reaction was concentrated, and then Et2O was added. After standing for about 15 min., the reaction was filtered through Celite wet with Et2O, rinsed with Et2O, and concentrated. The crude reaction was purified by column chromatography (florisil, 100-200 mesh, 2:1 Hexane: EtOAc) to achieve pure 9.

Reference： [1]Patent: US2002/177721,2002,A1

10
[ 435275-85-7 ]
[ 105706-76-1 ]
[ 39945-51-2 ]

Yield	Reaction Conditions	Operation in experiment
66%	With sodium hydroxide; In tetrahydrofuran; hexane; water;	Example 3 Synthesis of 3-hydroxymethyl-piperidine-1-carboxylic acid benzyl ester (8) Piperidine-1,3-dicarboxylic acid 1-benzyl ester 3-ethyl ester (7) (1.5 g, 5.83 mmol) was dissolved in 5.8 mL of anhydrous THF, and the reaction was stirred under N2 at -5 C. while lithium aluminum hydride dissolved in THF (7.0 mL, 1.0M) was added dropwise by addition funnel over 30 minutes. When the reaction was complete by TLC (10 min.), H2O (0.6 mL), then 10% NaOH (1.5 mL), then H2O (0.6 mL) were added, and the reaction was stirred for about 45 minutes. The salts were removed by filtration and the solution was dried with sodium sulfate, filtered, and concentrated. The crude material was purified using an ISCO CombiFlash flash column (silica, 80:20 Hexane: EtOAc to 40:60 Hexane: EtOAc) to achieve 1.24 g of pure 8 (66% yield).

Reference： [1]Patent: US2002/177721,2002,A1

Yield	Reaction Conditions	Operation in experiment
		Step A: 1-Benzyloxycarbonyl-3-piperidinemethanol The title compound was prepared from 3-piperidinemethanol according to the procedure described in EXAMPLE 199, Step A.
		A. N-Carbobenzyloxy-3-piperidinemethanol To a solution of 3(R)-N-carbobenzyloxy-3-carboxypiperidine (2.0 g, 7.6 mmol) in 15 mL THF was added BH3.Me2 S dropwise at 0 C. and the ice bath was removed. The reaction was stirred at room temperature for 2 hrs. The reaction mixture was quenched with HOAc, MeOH, then 1N 7.6 mL NaOH and was stirred at room temperature for 2 hrs. The reaction mixture was concentrated in vacuo and extracted with EtOAc. The EtOAc layer was washed with 1N NaOH and concentrated in vacuo to give N-carbobenzyloxy-3-piperidinemethanol. STR123

12
[ 558-13-4 ]
[ 39945-51-2 ]
[ 242459-81-0 ]

Yield	Reaction Conditions	Operation in experiment
		PREPARATION 60 Benzyl 3-(Bromomethyl)-1-piperidinecarboxylate The title compound was prepared by the method of Preparation 9 from <strong>[39945-51-2]benzyl 3-(hydroxymethyl)-1-piperidinecarboxylate</strong> [Preparation 59] and carbon tetrabromide. The crude product was purified by column chromatography on silica gel eluding with a solvent gradient of 0:100 changing to 80:20, by volume ethyl acetate:hexane, in 10% increments, to afford benzyl 3-(bromomethyl)-1-piperidinecarboxylate as an oil. 1H-NMR (d6-DMSO) delta: 7.30 (5H, m), 5.00 (2H, s), 4.05 (1H, d), 3.80 (1H, d), 3.40 (2H, m), 2.80-2.60 (2H, m), 1.80 (1H, m), 1.75 (1H, m), 1.60 (1H, m), 1.40 (1H, m), 1.20 (1H, m).

Reference： [1]Patent: US6610707,2003,B1

13
2-(1H-indol-5-yl)-5-[[(4S)-4-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl]carbonyl]phenol [ No CAS ]
[ 39945-51-2 ]
C₃₉H₄₀N₄O₄ [ No CAS ]

Reference： [1]Patent: WO2006/51851,2006,A1 .Location in patent: Page/Page column 162; 218

14
[ 4606-65-9 ]
[ 144-55-8 ]
[ 501-53-1 ]
[ 39945-51-2 ]

Yield	Reaction Conditions	Operation in experiment
	In chloroform;	Step A 1-Benzyloxycarbonyl-3-hydroxymethylpiperidine To a stirred solution of 3-hydroxymethylpiperidine (5 g, 43.4 mmol, 1 eq) in CHCl3 (150 mL) was added saturated aqueous NaHCO3 (150 mL). To the vigorously stirred mixture was added benzyl-chloroformate (6.8 mnL, 47.74 mmol, 1.1 eq) via syringe. The mixture was stirred 5 h. The layers were separated and the aqueous layer was extracted 2* with CH2Cl2. The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated. The material was used crude.

Reference： [1]Patent: US6329380,2001,B1

15
[ 39945-51-2 ]
[ 124-63-0 ]
[ 315717-74-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane;	Step B 1-Benzyloxycarbonyl-3-methanesulfonyloxymethylpiperidine To a stirred solution of 1-benzyloxycarbonyl-3-hydroxymethyl-piperidine (1.29 g, 5.24 mmol, 1 eq) in CH2Cl2 (50 mL) at 0 C. was added diisopropylethylamine (2.7 mL, 15.72 mmol, 3 eq) followed by methanesulfonylchloride (0.61 mL, 7.86 mmol, 1.5 eq) via syringe. Let stir 10 minutes and removed the cooling bath. After 30 minutes the reaction was complete by thin layer chromatography analysis. Removed the CH2Cl2 under reduced pressure and used material crude in the next step.

Reference： [1]Synthesis,2011,p. 3669 - 3674
[2]Patent: US6329380,2001,B1
[3]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 5440 - 5443

16
[ 39945-51-2 ]
[ 18162-48-6 ]
[ 876147-49-8 ]

Yield	Reaction Conditions	Operation in experiment
99%	With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 6h;	Imidazole (3.00 g, 44.0 mmol) and tert-butyldimethylsilyl chloride (6.63 g, 44.0 mmol) were added to 1-(benzyloxycarbonyl)piperidin-3-yl methanol (9.15 g, 36.7 mmol) in N,N-dimethylformamide (40 mL). The solution was stirred at room temperature for 6 hours. Subsequently, water was added and the mixture was extracted with ethyl acetate. The extract was washed with brine and was dried over magnesium sulfate, followed by evaporation of the solvent. Purification of the residue by silica gel column chromatography (hexane: ethyl acetate = 20:1 -> 5:1) gave 13.2 g (99%) of the desired compound as a colorless oil. 1H NMR (400 MHz, CDCl3) delta 0.02 (6H, s), 0.88 (9H, s), 1.11-1.25 (1H, m), 1. 40-1. 53 (1H, m), 1. 61-1.71 (2H, m), 1. 72-1. 80 (1H, m), 2.54-2.66 (1H, m), 2.79 (1H, td, J = 11. 6, 3.1 Hz), 3.34-3.51 (2H, m), 3.99-4.09 (1H, m), 4.12-4.19 (1H, m), 5.12 (2H, s), 7.29-7.39 (5H, m).

Reference： [1]Patent: EP1780210,2007,A1 .Location in patent: Page/Page column 51-52

17
[ 19099-93-5 ]
[ 39945-51-2 ]
[ 124-63-0 ]
3-azidomethylpiperidin-1-ylcarboxylic acid benzyl ester [ No CAS ]

Reference： [1]Patent: WO2004/35569,2004,A2 .Location in patent: Page/Page column 16-17

18
[ 39945-51-2 ]
[ 1341126-88-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 5975 - 5983

19
[ 39945-51-2 ]
[ 1341126-87-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 5975 - 5983

20
[ 39945-51-2 ]
[ 1341126-86-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 5975 - 5983

21
[ 39945-51-2 ]
[ 1341126-85-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 5975 - 5983

22
[ 1717-59-5 ]
[ 39945-51-2 ]
[ 1235382-52-1 ]

Yield	Reaction Conditions	Operation in experiment
61%		Benzyl 3-(hydroxymethyl)piperzdine-1-carboxylate (2.49 g, 10.0 mmol) was dissolved in acetonitrile (100 mL), to which copper iodide (1) (2.86 g, 15.0 mmol) and 2,2-difluoro-2-(fluorosulfonyl)acetic acid (2.66 g, 15.0 mmol) were added, followed by stirring at 80C for 20 minutes. The mixture was brought down to room temperature, to which adequate amounts of hexane and ethyl acetate were added, followed by neutralization with a 2M ammonia/methanol solution. Impurities were filtered off, and the solvent was distilled off under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography (hexane: ethyl acetate, 100 : 0 - 0 : 100, V/V) to give the desired title compound (1.82 g, yield 61%). 1H-NMR (CDCl3 delta: 1.22-1.34 (1H, m), 1.41-1.55 (1H, m), 1.64-1.73 (1H, m), 1.76-1.92 (2H, m), 2.59-2.97 (2H, m), 3.64-3.77 (2H, m), 3.93-4.21 (2H, m), 5.13 (2H, s), 6.18 (1H, t, J = 74.5 Hz), 7.28-7.41 (5H, m).

Reference： [1]Patent: EP2380878,2011,A1 .Location in patent: Page/Page column 42; 43

23
[ 39945-51-2 ]
[ 1355455-36-5 ]

Reference： [1]Synthesis,2011,p. 3669 - 3674

24
[ 39945-51-2 ]
[ 242459-83-2 ]

Reference： [1]Synthesis,2011,p. 3669 - 3674

25
[ 310454-53-6 ]
[ 39945-51-2 ]

Yield	Reaction Conditions	Operation in experiment
92%		Step 2. Benzyl 3-(hydroxymethyl)piperidine-1-carboxylate; A 250-mL 3-necked round-bottomed flask was charged with a solution of LiAlH4 (2.96 g, 77.83 mmol, 2.00 equiv) in THF (150 mL). To this solution was added 1-benzyl 3-ethyl piperidine-1,3-dicarboxylate (11.4 g, 39.16 mmol, 1.00 equiv) in THF (50 mL) drop wise with stirring at -10 C. The resulting mixture was allowed to stir about 1 hour at -10 C. The progress was monitored by TLC (DCM: MeOH=10:1). The resulting solution was diluted with 10 mL of NaOH/H2O. The solids were filtered out. The resulting mixture was concentrated on a rotary evaporator to afford benzyl 3-(hydroxymethyl)piperidine-1-carboxylate as pale yellow oil in (8.94 g, (92%).

Reference： [1]Patent: US8080566,2011,B1 .Location in patent: Page/Page column 44

26
[ 501-53-1 ]
[ 39945-51-2 ]