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CAS No. : | 67686-01-5 | MDL No. : | MFCD00831014 |
Formula : | C13H19NO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FLQPYEOKVZYXRL-UHFFFAOYSA-N |
M.W : | 205.30 | Pubchem ID : | 736802 |
Synonyms : |
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.54 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 66.11 |
TPSA : | 23.47 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.26 cm/s |
Log Po/w (iLOGP) : | 2.44 |
Log Po/w (XLOGP3) : | 1.82 |
Log Po/w (WLOGP) : | 1.36 |
Log Po/w (MLOGP) : | 2.02 |
Log Po/w (SILICOS-IT) : | 2.34 |
Consensus Log Po/w : | 1.99 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.36 |
Solubility : | 0.901 mg/ml ; 0.00439 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.93 |
Solubility : | 2.4 mg/ml ; 0.0117 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -3.13 |
Solubility : | 0.152 mg/ml ; 0.00074 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.64 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With oxalyl dichloride; dimethyl sulfoxide; triethylamine; In dichloromethane; at -70 - 20℃; | A round bottom flask was charged with oxalyl chloride (16.2 g, 0.12 mol), dichloromethane (150 mL) and anhydrous dimethyl sulfoxide (20 mL). Stir the reaction mixture mass in a cryo bath at -70 C for 15 min. The resulting mixture is charged dropwise with N-benzyl piperidine alcohol 3 (20 g, 0.097 mol), along with triethylamine (24.6 g, 0.24 mol) and continued stirring for the next 15 min. After that, the mass is allowed to attain room temperature overnight, then diluted with dichloromethane (100 mL) and quenched with cold water. The organic layer was washed subsequently with 5 % HCl solution, brine solution, 5 % sodium bicarbonate solution and dried over sodium sulfate. Toluene was removed in vacuo to afford N-benzyl piperidine-4-carboxaldehyde (4, 19.2 g, 96 %). |
85% | To a stirred solution of N-Benzyl 4-hydroxy methyl piperidine (lOOgms, 0.4878 mol) in toluene (2 L) at -10C to -15C, dimethyl sulfide (30gms, 0.4828 mol) and triethyl amine (62gms, 0.6127mol) were added in single lot under argon and stirred for 15-30 min. N-Chlorosuccinamide (180 g, 1.3480mol) was added lot wise for lhr to the flask, at a rate so as to maintain the internal temperature at - 10C to -15C. Completion of reaction was monitored by Gas Chromatography (GC) or Thin layer chromatography (TLC). After completion of reaction slowly add dilute Sodium hydroxide (NaOH) solution (40gms in 1200ml of water) was added slowly at temprature less than -5C. After the addition the mixture was warmed to 20C stirred for lhr at 20C. The aqueous and organic layers were separated. Collected organic layer was extracted with sodium bisulphite solution (140gms in 1100ml of water). The product layer was washed with dicholoromethane (200 mL). Sodium carbonate solution (25% in water) was added to product aqueous layer to adjust pH to 9.5 to 9.8. The product was extracted with dichloromethane and concentrated to give crude product which on high vacuum at 0.1 mm gave N-Benzyl 4-formylpiperidine residue as a color less oil (84 g, 85% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; for 1h; | To a THF solution (2 ml) of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (40 mg, 0.11 mmol), prepared as described in Example 1, (1-benzyl-4-piperidyl)methanol (27 mg 0.13 mmol), and triphenylphospine (86 mg, 0.32 mmol) was added diethyl azodicarboxylate (0.15 ml, 0.38 mmol). After 1 hour, the reaction mixture was concentrated. The crude material was purified by preparative HPLC to give the title compound, 2-((1-benzylpiperidin-4-yl)methyl)-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (6.1 mg, 10percent) as a yellow solid. MS M+H=544; 1HNMR (CDCl3) delta 8.19 (1H), 7.42 (2H), 7.32-7.20 (9H), 7.11(2H), 4.19 (1H), 4.02(2H), 3.66 (2H), 2.63 (2H), 2.12 (2H), 1.91(4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; | a 1-Benzyl-1-azonia-bicyclo[2,2,1]heptane methanesulfonate Methanesulfonyl chloride (0.22 mL, 2.85 mmole) in dichloromethane (2 mL) was added dropwise to a ice-cooled solution of N-benzyl-4-hydroxymethyl-piperidine (531 mg, 2.59 mmol) and N,N-diisopropylethylamine (0.66 mL, 3.88 mmol) in dichloromethane (3 mL). The mixture was stirred for 5 min, diluted with tert-butyl methyl ether, washed with water and brine. The solvents were removed to give the sub-title compound. 1H NMR (400 MHz, CDCl3): delta7.63 (2H, m); 7.41 (3H, m); 5.03 (2H, s); 3.88 (2H, m); 3.65 (2H, s); 3.40 (2H, m); 2.88 (1H, m); 2.83 (3H, s); 2.27 (2H, m); 1.73 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; lithium aluminium tetrahydride; In tetrahydrofuran; ethanol; ethyl acetate; | EXAMPLE 18A STR36 Intermediate: 1-Benzyl-4-oxiranylpiperidine A slurry of 4-piperidinyl ethyl ester (6.36 mol), K2 CO3 (10.98 mol) and benzyl chloride (7.63 mol) in ethanol (5 L) was stirred at room temperature under nitrogen for forty-eight hours. The pale yellow slurry was filtered through celite. The filtrate was concentrated to an orange oil which was stirred with EtOAc (3 L) and H2 O (1.5 L) for five minutes. The organic layer was isolated, washed with H2 O (2*500 mL) and brine (1*500 ml) dried (MgSO4) and filtered. The filtrate was concentrated to give ethyl N-benzyl isonipecotate as an orange oil. LAH (1M solution in THF, 4.37 mol) was diluted with THF (4 L), the solution was chilled to 0° C. via IPA/dry-ice bath, under nitrogen. A solution of ethyl N-benzyl isonipecotate (2.95 mol) in THF (4 L) was added over two hours. The cold bath was removed and the solution was stirred for three hours before heating at reflux for eighteen hours. The heating mantle was removed and the solution was stirred at room temperature for eighteen hours before being quenched at 0° C. by the dropwise addition of: EtOAc (110 mL), H2 O (164 mL), 10percent aqueous sodium hydroxide (246 mL) and H2 O (410 mL). The slurry was stirred at room temperature for eighteen hours and filtered which provided N-Benzyl-4-hydroxymethylpiperidine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | a) Indole-3-carboxylic acid was converted to its acid chloride and then reacted with <strong>[67686-01-5]1-benzyl-4-piperidinemethanol</strong> (D7) using the method given in Example 1a. The resulting orange oil was chromatographed on silica gel eluding with chloroform/ethanol (9:1) to afford (1-benzyl-4-piperidyl)methyl indole-3-carboxylate as a yellow oil (88percent) 1 H NMR (CDCl3); delta: 9.24(s,1H), 8.12-8.20(m,1H), 7.81(d,1H), 7.20-7.45(m,8H), 4.20(d,2H), 3.53(s,2H), 2.90-3.04(m,2H), 1.73-2.10(m,5H), 1.36-1.58(m,2H). | |
88% | a) Indole-3-carboxylic acid was converted to its acid chloride and then reacted with <strong>[67686-01-5]1-benzyl-4-piperidinemethanol</strong> (D7) using the method given in Example 1a. The resulting orange oil was chromatographed on silica gel eluding with chloroform/ethanol (9:1) to afford (1-benzyl-4-piperidyl)methyl indole-3-carboxylate as a yellow oil (88percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; | EXAMPLE 21 (E)-1-Benzyl-4-[(3-phenyl-2-propeneyloxy)methyl]piperidine hydrochloride Sodium hydride (0.80 g, 20 mmol, 60percent oil disp.) and <strong>[67686-01-5]1-benzyl-4-hydroxymethyl-piperidine</strong> (4.1 g, 20 mmol) were stirred at room temperature in dry tetrahydrofuran (40 mL) under a nitrogen atmosphere. After H2 gas evolution had ceased (ca. 2 hours), cinnamyl chloride (2.8 mL, 20 mmol) was added. After 42 hours, the mixture was heated to reflux for 26.5 hours, then cooled. The reaction was quenched with water (40 mL), then extracted with ethyl acetate (200 mL). The organic phase was extracted with H2 O (40 mL), brine (40 mL), dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluding with ethyl acetate, concentrated, and distilled (bp 188°-190° C. at 0.6 Torr) to yield a pale yellow oil (2.72 g, 42percent). HRMS: Calculated for C22 H27 NO: 321.2093; found: 321.2094. To a solution of the free base (2.56 g, 8.0 mmol) in dry diethyl ether was added dropwise 1.0 M HCl in diethyl ether (8.8 mL, 8.8 mmol). A precipitate quickly formed, which was collected by filtration, rinsed with diethyl ether, and dried under high vacuum to yield the hydrochloride salt (2.5 g, 88percent) which melted at 162°-164° C. Analysis: Calculated for C22 H27 NO.HCl: C,73.83; H,7.89; N,3.91; found: C,73.35; H,7.91; N,4.00. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With triphenylphosphine; In ethyl acetate; benzene; | EXAMPLE 68 1-Benzyl-4-(4'-Fluorophenoxymethyl)piperidine A mixture of 4 fluorophenol (6.01 g, 54 mmol), triphenylphosphine (6.87 g, 64 mmol), and <strong>[67686-01-5]1-benzyl-4-hydroxymethylpiperidine</strong> (11.0 g, 54 mmol) in benzene (300 mL) was stirred at 10°-15° C. Diethyl azodicarboxylate (11.2 g, 10.1 mL, 64 mmol) was added dropwise. The reaction mixture was heated to reflux temperature and stirred for 24 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate; the organic solution was washed with water three times, a 2N sodium hydroxide solution three times, dried over magnesium sulfate and filtered. Solvent was removed in vacuo to give crude product. Column chromatography (ethyl acetate:hexanes::1:1) gave, after removal of solvent, a pale yellow oil (3.88 g, 24percent yield): 7.40-7.25 (m, 5H), 7.0-6.7 (m, 4H), 3.75 (d, 2H, J=4), 3.50 (s, 2H), 2.9 (br d, 2H, J=4), 2.1-1.25 (m, 7H); IR (neat): 3084(m), 3062(m), 2921(s), 2802(s), 2758(s), 1601(m), 1505(s), 1467(s), 1454(s), 1394(s); HR-MS: Calcd. for C19 H22 FNO: 299.1684; Found: 299.1685. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In toluene; | b) 0.248 g (0.00121 mol) of <strong>[67686-01-5]1-benzyl-4-hydroxymethyl-piperidine</strong> was dissolved in 5 ml of toluene and treated with 0.2 ml (0.00145 mol) of triethylamine and 0.155 ml (0.00133 mol) of benzoyl chloride. The mixture was boiled at reflux for 18 hrs., the solvent was distilled off and the residue was taken up in ether. The organic phase was washed with water and saturated sodium chloride solution and dried over magnesium sulfate. It was concentrated and the residue was chromato-graphed on silica gel with ethyl acetate/hexane (1:1) as the eluent. 0.2 g (53percent) of 1-benzylpiperidin-4-ylmethyl benzoate was obtained as a yellow oil. MS: me/e (percent basic peak)=309 (C20 H23 NO2+, 18), 308 (17), 232 (14), 204 (41), 159 (18.6), 105 (25.5), 91 (100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; triphenylphosphine; In water; ethyl acetate; toluene; | a) 0.3 g (0.00146 mol) <strong>[67686-01-5]1-benzyl-4-hydroxymethyl-piperidine</strong>, 0.137 g (0.00146 mol) of phenol and 0.45 g (0.0017 mol) of triphenylphosphine were dissolved in 10 ml of toluene, cooled to 10° and treated slowly with 0.264 ml (0.0017 mol) of diethyl azodicarboxylate. The mixture was stirred at 90° for 25 hrs. The solvent was removed, the residue was taken up in ethyl acetate, washed three times with 40 ml of water each time and three times with 40 ml of 2N aqueous NaOH each time and the organic phase was dried over magnesium sulfate. The solvent was removed. The residue was chromatographed on silica gel with ethyl acetate/hexane (1:2) as the eluent. 0.17 g (41.4percent) 1-benzyl-4-phenoxymethylpiperidine was obtained as white crystals; m.p. 56°-57°. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dimethyl sulfoxide; triethylamine; In dichloromethane; | Method B A solution of oxalyl chloride (3 g, 2.06 mL, 23.6 mmol) in dichloromethane (100 mL) was cooled to -78° C. with stirring under a nitrogen atmosphere. A solution of dimethyl sulfoxide (3.7 g, 3.36 mL, 47.3 mmol) in dichloromethane (100 mL) was added dropwise. The reaction mixture was stirred for 15 minutes. A solution of <strong>[67686-01-5]1-benzyl-4-hydroxymethylpiperidine</strong> (3.6 g, 17.6 mmol) in dichloromethane (100 mL) was added dropwise; then the reaction mixture was stirred at -65° to -60° C. for 15 minutes. The reaction mixture was cooled to -78° C. and triethylamine (6.83 g, 9.41 mL, 67.5 mmol) was added in one portion. The reaction mixture was warmed to ambient temperature over 6h, then it was poured onto water, mixed and extracted three times with ether. The combined organic layers were dried over magnesium sulfate and filtered. Solvent was removed in vacuo. Column chromatography (ethyl acetate) gave the product, a clear pale yellow liquid (2.64 g), which was identical in all respects to the product obtained in Part B; Method A. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4-(1-benzylpiperid-4-ylmethoxy)acetoacetate Treatment of ethyl 4-chloroacetoacetate with 1-benzylpiperidine-4-methanol according to the method of Example 22(i) gave the title compound as an oil which was used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; lithium aluminium tetrahydride; potassium carbonate; In tetrahydrofuran; ethanol; water; ethyl acetate; | EXAMPLE 18A Intermediate: 1-Benzyl-4-oxiranylpiperidine A slurry of 4-piperidinyl ethyl ester (6.36 mol), K2CO3 (10.98 mol) and benzyl chloride (7.63 mol) in ethanol (5 L) was stirred at room temperature under nitrogen for forty-eight hours. The pale yellow slurry was filtered through celite. The filtrate was concentrated to an orange oil which was stirred with EtOAc (3 L) and H2O (1.5L) for five minutes. The organic layer was isolated, washed with H2O (2x500 mL) and brine (1x500 ml) dried (MgSO4) and filtered. The filtrate was concentrated to give ethyl N-benzyl isonipecotate as an orange oil. LAH (1M solution in THF, 4.37 mol) was diluted with THF (4 L), the solution was chilled to 0° C via IPA/dry-ice bath, under nitrogen. A solution of ethyl N-benzyl isonipecotate (2.95 mol) in THF (4L) was added over two hours. The cold bath was removed and the solution was stirred for three hours before heating at reflux for eighteen hours. The heating mantle was removed and the solution was stirred at room temperature for eighteen hours before being quenched at 0° C by the dropwise addition of: EtOAc (110 mL), H2O (164 mL), 10percent aqueous sodium hydroxide(246 mL) and H2O (410 mL). The slurry was stirred at room temperature for eighteen hours and filtered which provided N-Benzyl-4-hydroxymethylpiperidine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N-methyl-acetamide; water; | EXAMPLE 10 1-phenyl-2-[[1-(phenylmethyl)piperidin-4-yl]methoxy]-4,5,6,7-tetrahydro-1H-benzimidazole fumarate 0.031 g (1.33 mmol) of sodium hydride at 60percent and 0.25 g of <strong>[67686-01-5]1-benzyl-4-piperidinemethanol</strong> are gradually heated to 70° C. in 0.5 ml of dimethylformamide until the evolution of hydrogen ceases. The mixture is cooled to 0° C. and 0.23 g (1 mmol) of 2-chloro-1-phenyl-4,5,6,7-tetrahydro-1H-benzimidazole dissolved in 0.5 ml of dimethylformamide is added. The mixture is heated at 100° C. for 10 hours, water is added and the compound is extracted with methylene chloride. After concentration, it is purified on silica gel with a 97:3:0.3 CH2Cl2/CH3OH/NH4OH mixture. 0.15 g of a thick oil is recovered which is salified in the fumarate form in alcohol. Yield=19.6percent (m.p.=102° C.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20 - 60℃; for 12h; | Example 35 (1-Benzylpiperidin-4-yl)methanol 40 (Scheme 12) To a stirred solution of 4-(hydroxymethyl)piperidine 38 (0.01 mol) and DIEA (0.02 mol) in anhydrous acetonitrile (20 ml) was added a solution of benzylbromide 39 (0.012 mol) in anhydrous acetonitrile (5 ml) at room temperature. The resulting mixture was heated at 55-60° C. for 12 hours. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated on rotavapor and the residue was diluted with ethyl acetate (50 ml). The resulting ethyl acetate solution was washed with water, dried over anhydrous sodium sulfate (Na2SO4) and evaporated the solvent. The residue was purified by silica gel column chromatography using a gradient of 0 to 100percent ethyl acetate and hexane to get the title piperidine 40 in 98percent yield (2.00 g) yield. 1H NMR (400 MHz, CDCl3): delta 1.26-1.33 (2H, m); 1.43-1.52 (1H, m); 1.70 (2H, broad d); 1.96 (2H, broad t); 2.90 (2H, broad d); 3.48 (2H, s); 3.49 (2H, s); 7.30 (5H, m). MS (ESI): m/z=206.20 (M+H+). |
78.65% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60℃; | Step 1: Synthesis of 1-benzylpiperidin-4-yl)methanol To a stirred solution of (piperidin-4-yl)methanol(1 g, 8.68 mmol) in ACN (10 mL) was added DIPEA (3.02 mL, 1.36 mmol)followed by addition of benzyl bromide (1.2 mL, 17.36 mmol) and reaction heated at 60° C. for overnight. Reaction was monitored by TLC. On completion reaction mixture was concentrated under reduced pressure to give crude that was purified by combiflash chromatography, eluent 1percent CH3OH/DCM to afford (1-benzylpiperidin-4-yl)methanol (1.40 g,78.65percent) as off white solid. MS: 206.42[M++1] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.4% | Example A45; a) Preparation of intermediate 158; Reaction under N2 atmosphere. NaH (0.004488 mol) was added to DMF (12 ml), and the mixture was stirred at r.t.. A solution of l-(phenylmethyl)-4-piperidinemethanol (0.004488 mol) in DMF (4 ml) was added dropwise. The mixture was stirred for one hour. Then a solution of 5-nitro-l,3-benzodioxole (0.002992 mol) in DMF (4ml) was added dropwise to the reaction mixture and stirring was continued for one hour. A solution of 2-bromoacetic acid 1,1-dimethylethyl ester (0.004488 mol) in DMF (4ml) was added dropwise and the reaction mixture was stirred for one hour. The reaction mixture was poured out into ice water. The product was extracted with EtOAc (x2). The separated organic layer was dried, filtered and the solvent evaporated, yielding 1.78 g (96.4percent) of intermediate 158 used as such in the next step |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With 4-methyl-morpholine; In dichloromethane; for 18h; | 4-Piperidine methanol (5.49 g, 47.7 mmol) and NEt3 (6.6 mL, 47.7 mmol) were dissolved in DCM (100 mL) and treated with benzoyl chloride (5.6 mL, 48 mmol). The reaction mixture was stirred for 18 hours, then washed sequentially with 2M aq HCl solution (2.x.200 mL) and 1M aq Na2CO3 solution (100 mL), dried (MgSO4) and concentrated in vacuo to give (4-(hydroxymethyl)piperidin-1-yl)(phenyl)methanone as an orange oil which crystallised on standing. This solid was dissolved in THF (100 mL) under an argon atmosphere, cooled to 0° C. and treated with a 1M solution of LiAlH4 in THF (50 mL, 50 mmol). The reaction mixture was allowed to warm to room temperature overnight, and then quenched by sequential addition of water, 1M aq NaOH solution and more water. The reaction mixture was stirred for a further 3 hours and then filtered through celite, and the filtrate was concentrated in vacuo to a volume of ca 40 mL and dried using two 20 g Isolute HM-N cartridges, eluting with EtOAc. The eluent was concentrated to give the intermediate (1-benzylpiperidin-4-yl)methanol (8.02 g, 82percent) as a yellow oil.(1-Benzylpiperidin-4-yl)methanol was dissolved in DCM (200 mL), treated with NMM (4.5 mL) and 4-nitrophenyl chloroformate (8.09 g, 40.1 mmol) and stirred for 18 hours. The reaction mixture was then washed with 1M aq Na2CO3 solution (200 mL) and sat aq NaHCO3 solution (2.x.200 mL), dried (MgSO4) and concentrated in vacuo to give (1-benzylpiperidin-4-yl)methyl 4-nitrophenyl carbonate (11.9 g, 82percent) as a yellow solid.A portion of (1-benzylpiperidin-4-yl)methyl 4-nitrophenyl carbonate (777 mg, 2.10 mmol) was dissolved in DMF (5 mL). NEt3 (0.4 mL, 2.90 mmol), morpholine (0.30 mL, 3.41 mmol) and DMAP (10 mg) were added and the reaction mixture was stirred for 5 days before concentrating in vacuo. The residue was purified by reverse phase chromatography (gradient eluting with MeOH in water, with 1percent formic acid in each solvent, 0-100percent) followed by preparative HPLC (Phenomenex Hydro column, gradient eluting with CH3CN in water, with 0-100percent) to give a colourless gum, which was dissolved in DCM (5 mL), treated with 2M HCl in Et2O (1 mL) and concentrated in vacuo to give (1-benzylpiperidin-4-yl)methyl morpholine-4-carboxylate hydrochloride (109 mg, 15percent) as a white solid.Analytical HPLC: purity 100percent (System A, RT=4.03 min); Analytical LCMS: purity 100percent (System D, RT=4.27 min), ES+: 319 [MH]+. HRMS calcd for C18H26N2O3: 318.1943, found 318.1956. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4-Piperidine methanol (5.49 g, 47.7 mmol) and NEt3 (6.6 mL, 47.7 mmol) were dissolved in DCM (100 mL) and treated with benzoyl chloride (5.6 mL, 48 mmol). The reaction mixture was stirred for 18 hours, then washed sequentially with 2M aq HCl solution (2.x.200 mL) and 1M aq Na2CO3 solution (100 mL), dried (MgSO4) and concentrated in vacuo to give (4-(hydroxymethyl)piperidin-1-yl)(phenyl)methanone as an orange oil which crystallised on standing. This solid was dissolved in THF (100 mL) under an argon atmosphere, cooled to 0° C. and treated with a 1M solution of LiAlH4 in THF (50 mL, 50 mmol). The reaction mixture was allowed to warm to room temperature overnight, and then quenched by sequential addition of water, 1M aq NaOH solution and more water. The reaction mixture was stirred for a further 3 hours and then filtered through celite, and the filtrate was concentrated in vacuo to a volume of ca 40 mL and dried using two 20 g Isolute HM-N cartridges, eluting with EtOAc. The eluent was concentrated to give the intermediate (1-benzylpiperidin-4-yl)methanol (8.02 g, 82percent) as a yellow oil.(1-Benzylpiperidin-4-yl)methanol was dissolved in DCM (200 mL), treated with NMM (4.5 mL) and 4-nitrophenyl chloroformate (8.09 g, 40.1 mmol) and stirred for 18 hours. The reaction mixture was then washed with 1M aq Na2CO3 solution (200 mL) and sat aq NaHCO3 solution (2.x.200 mL), dried (MgSO4) and concentrated in vacuo to give (1-benzylpiperidin-4-yl)methyl 4-nitrophenyl carbonate (11.9 g, 82percent) as a yellow solid.A portion of (1-benzylpiperidin-4-yl)methyl 4-nitrophenyl carbonate (777 mg, 2.10 mmol) was dissolved in DMF (5 mL). NEt3 (0.4 mL, 2.90 mmol), morpholine (0.30 mL, 3.41 mmol) and DMAP (10 mg) were added and the reaction mixture was stirred for 5 days before concentrating in vacuo. The residue was purified by reverse phase chromatography (gradient eluting with MeOH in water, with 1percent formic acid in each solvent, 0-100percent) followed by preparative HPLC (Phenomenex Hydro column, gradient eluting with CH3CN in water, with 0-100percent) to give a colourless gum, which was dissolved in DCM (5 mL), treated with 2M HCl in Et2O (1 mL) and concentrated in vacuo to give (1-benzylpiperidin-4-yl)methyl morpholine-4-carboxylate hydrochloride (109 mg, 15percent) as a white solid.Analytical HPLC: purity 100percent (System A, RT=4.03 min); Analytical LCMS: purity 100percent (System D, RT=4.27 min), ES+: 319 [MH]+. HRMS calcd for C18H26N2O3: 318.1943, found 318.1956. |
Tags: 67686-01-5 synthesis path| 67686-01-5 SDS| 67686-01-5 COA| 67686-01-5 purity| 67686-01-5 application| 67686-01-5 NMR| 67686-01-5 COA| 67686-01-5 structure
[ N/A ]
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Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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