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[ CAS No. 109384-19-2 ] {[proInfo.proName]}

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Chemical Structure| 109384-19-2
Chemical Structure| 109384-19-2
Structure of 109384-19-2 * Storage: {[proInfo.prStorage]}
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Product Details of [ 109384-19-2 ]

CAS No. :109384-19-2 MDL No. :MFCD01075174
Formula : C10H19NO3 Boiling Point : -
Linear Structure Formula :- InChI Key :PWQLFIKTGRINFF-UHFFFAOYSA-N
M.W :201.26 Pubchem ID :643502
Synonyms :

Calculated chemistry of [ 109384-19-2 ]

Physicochemical Properties

Num. heavy atoms : 14
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.9
Num. rotatable bonds : 3
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 57.75
TPSA : 49.77 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.83 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.49
Log Po/w (XLOGP3) : 0.98
Log Po/w (WLOGP) : 1.0
Log Po/w (MLOGP) : 0.86
Log Po/w (SILICOS-IT) : 0.56
Consensus Log Po/w : 1.18

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.51
Solubility : 6.26 mg/ml ; 0.0311 mol/l
Class : Very soluble
Log S (Ali) : -1.61
Solubility : 4.9 mg/ml ; 0.0244 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.7
Solubility : 39.8 mg/ml ; 0.198 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.11

Safety of [ 109384-19-2 ]

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 [ 109384-19-2 ]

* 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.

  • Downstream synthetic route of [ 109384-19-2 ]

[ 109384-19-2 ] Synthesis Path-Downstream   1~80

  • 1
  • [ 143879-80-5 ]
  • [ 109384-19-2 ]
  • 4-(4-Cyano-2,3-difluoro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • 4-(6-Cyano-2,3-difluoro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • 2
  • [ 109384-19-2 ]
  • [ 321436-06-0 ]
  • [ 544694-95-3 ]
  • 3
  • [ 24424-99-5 ]
  • [ 5382-17-2 ]
  • [ 109384-19-2 ]
  • 4
  • [ 94-97-3 ]
  • [ 109384-19-2 ]
  • N-Boc-4-(5-chlorobenzotriazol-2-yl)piperidine [ No CAS ]
  • N-Boc-4-(6-chlorobenzotriazol-1-yl)piperidine [ No CAS ]
  • N-Boc-4-(5-chlorobenzotriazol-1-yl)piperidine [ No CAS ]
  • 5
  • [ 23814-12-2 ]
  • [ 109384-19-2 ]
  • 3-(1-<i>tert</i>-butoxycarbonyl-piperidin-4-yl)-3<i>H</i>-benzotriazole-5-carboxylic acid [ No CAS ]
  • 1-(1-<i>tert</i>-butoxycarbonyl-piperidin-4-yl)-1<i>H</i>-benzotriazole-5-carboxylic acid [ No CAS ]
  • 6
  • [ 452-06-2 ]
  • [ 109384-19-2 ]
  • 4-(2-amino-purin-9-yl)-piperidine-1-carboxylic acid <i>tert</i>-butyl ester [ No CAS ]
  • 7
  • [ 33216-52-3 ]
  • [ 109384-19-2 ]
  • [ 400797-99-1 ]
YieldReaction ConditionsOperation in experiment
265 mg (28%) With NaH; In N,N-dimethyl-formamide; mineral oil; A. 4-(3,5-Dichloro-pyridin-4-yloxy)-piperidine-1-carboxylic acid tert-butyl ester. To a stirred solution of 828 mg (4.12 mmol) of tert-butyl-4-hydroxy-1-piperidinecarboxylate in 10 mL of dry DMF was added 165 mg of 60% NaH in mineral oil (4.12 mmol). After stirring at room temperature for 10 min, 500 mg (2.74 mmol) of <strong>[33216-52-3]3,4,5-trichloropyridine</strong> was added. The mixture was stirred at 80 C. overnight and then partitioned between EtOAc (50 mL) and water (20 mL) and separated. The aqueous layer was further extracted with EtOAc (2*30 mL). The combined organic layers were washed with water (25 mL), brine, dried over Na2SO4, and the solvent was removed under reduced pressure. Column chromatography (silica, 60-100% CH2Cl2/hexanes) gave 265 mg (28%) of desired product. MS (electrospray): exact mass calculated for C15H20Cl2N2O3, 346.09; m/z found, 369.1 [M+Na]+. 1H NMR (CDCl3, 400 MHz): 8.45 (s, 2H), 4.66 (m, 1H), 3.90-3.80 (br m, 2H), 3.26 (m, 2H), 1.96-1.83 (br m, 4H),1.47 (s, 9H).
  • 8
  • [ 40594-98-7 ]
  • [ 109384-19-2 ]
  • [ 922516-57-2 ]
YieldReaction ConditionsOperation in experiment
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃; EXAMPLE 32 Preparation of N-methyl-2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]-2H-1,2,3-triazole-4-carboxamide(Compound 232) Step A: Preparation of 1,1-dimethylethyl 4-[4-(ethoxycarbonyl)-2H-1,2,3-triazol-2-yl]-1-piperidinecarboxylate. To a solution of t-butyl 4-hydroxypiperidine-1-carboxylate (0.43 g, 3.3 mmol) and triphenylphosphine (1.05 g, 4.0 mmol) in tetrahydrofuran (15 mL) at 0 0C was added dropwise diethyl azodicarboxylate (0.63 mL, 4.0 mmol). After 5 minutes <strong>[40594-98-7]ethyl 1H-1,2,3-triazole-4-carboxylate</strong> (0.43 g, 3.0 mmol, prepared according to D. R. Buckle, C. J. M. Rockell, J. Chem Soc, Perkin Transaction 1 1982, 2, 627-630.) was added in tetrahydrofuran (5 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was purified by medium pressure liquid chromatography (MPLC) using 15 to 40 percent ethyl acetate in hexanes as eluant to afford 0.42 g of the title compound as an oil. 1H NMR (CDCl3) delta 1.41 (t, 3H), 1.47 (s, 9H), 2.13 (m, 4H), 2.97 (m, 2H), 4.19 (m, 2H), 4.42 (q, 2H), 4.69 (m, IH), 8.04 (s, IH).Additionally eluting before the title compound was isolated 0.35 g of 1,1-dimethylethyl 4-[5-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl]-1-piperidinecarboxylate. 1H NMR (CDCl3) delta 1.41 (t, 3Eta), 1.48 (s, 9H), 2.09 (m, 2H), 2.29 (m, 2H), 2.94 (m, 2H), 4.30 (m, 2H), 4.39 (q, 2H), 5.27 (m, IH), 8.13 (s, IH).
  • 9
  • [ 109384-19-2 ]
  • [ 214360-76-6 ]
  • 4-[3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenoxy]piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
79% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 36h; The first step of Scheme 20: To a solution of 4-<strong>[214360-76-6]3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol</strong> (441 mg, 2.0 mmol), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (603.8 mg, 3.0 mmol) and triphenylphosphine (788 mg, 3.0 mmol) in THF (5 mL) was added DIAD (0.59 mL, 3.0 mmol) dropwise at 0 C. The resulting solution was stirred at room temperature for 36 h. The solvent was removed and the crude product was purified on the CombiFlash column eluting with hexanes/EtOAc to give the desired compound, 4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (635 mg, 79%) as a colorless crystalline solid. 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 1.33 (m, 12H) 1.48 (m, 9H) 1.75 (m, 2H) 1.89 (m, 2H) 3.37 (m, 2H) 3.67 (m, 2H) 4.53 (m, 1H) 7.01 (m, 1H) 7.29 (m, 1H) 7.34 (d, J=2.78 Hz, 1H) 7.40 (m, 1H).
  • 10
  • [ 81382-45-8 ]
  • [ 109384-19-2 ]
  • 4-(piperidin-4-yloxy)-1H-indazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
32% To a solution of <strong>[81382-45-8]1H-indazol-4-ol</strong> (200 mg, 1.49 mmol) in tetrahydrofuran (10 ml) were added tert-butyl 4-hydroxypiperidine-1-carboxylate (300 mg, 1.49 mmol), triphenylphosphine (430 mg, 1.64 mmol) and a 40%-dibenzyl azodicarboxylate-dichloromethane solution (0.855 ml, 1.79 mmol) at 0C. After 1 hour, the mixture thus obtained was warmed up to room temperature. After stirring overnight, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform (30 ml) and washed with a 1M-aqueous sodium hydroxide solution (20 ml). Extraction with chloroform (30 ml) was carried out again and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate). The mixture thus obtained was dissolved in methanol (2 ml) and 4N-hydrochloric acid-dioxane (2 ml) was added thereto at room temperature. After 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in methanol (5 ml) and the pH was adjusted to 10 by dropwise addition of a 2M aqueous sodium hydroxide solution. The resulting mixed solution was concentrated under reduced pressure, dried and then purified by a silica gel column chromatography (eluent: chloroform/methanol = 10/1 ? chloroform/methanol/(1%-NH3 aq) = 10/1) to obtain 4-(piperidin-4-yloxy)-1H-indazole (103 mg, 32%). Melting point: 162-165C
  • 11
  • [ 81945-73-5 ]
  • [ 109384-19-2 ]
  • 4-(pyrazol-1-yloxy)piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
A solution of ferf-butyl 4-hydroxypiperidine-1-carboxylate (6.04 g, 30 mmol), <strong>[81945-73-5]1-<strong>[81945-73-5]hydroxypyrazole</strong></strong> (2.52 g, 30 mmol) and tributylphosphine (9.74 mL, 39 mmol) intetrahydrofuran (100 mL) was stirred under nitrogen at 0 C. A solution of 1,1'-(azodicarbonyl)dipiperidine (9.84 g, 39 mmol) in tetrahydrofuran (100 mL) was added and themixture was stirred at room temperature for 16 hours, filtered and evaporated to dryness.The residue was triturated with dichloromethane (100 mL), filtered and evaporated todryness yielding a crude yellow oil (18.5 g) containing 4-(pyrazol-1-yloxy)-piperidine-1-carboxylic acid ferf-butyl ester, which was used without further purification in the followingstep.1H NMR (400MHz, CDCI3): £1.46 (s, 9H), 1.87 (m, 2H), 3.16 (m, 2H), 3.36 (m, 2H), 3.84 (m,2H), 4.61 (m, 1H), 6.18 (t, 1H), 7.27 (dd, 1H), 7.31 (dd, 1H); HPLC-MS (Method A): m/z =168 (M-Boc+H)+; Rt = 3.60 min.
  • 12
  • [ 848438-50-6 ]
  • [ 109384-19-2 ]
  • [ 848438-51-7 ]
YieldReaction ConditionsOperation in experiment
96% With di-isopropyl azodicarboxylate; triphenylphosphine; In dichloromethane; for 20.0h; 4-Chloroquinazolin-6-ol (250 mg) in DCM (10 ml) was treated with triphenylphosphine (540 mg), 1-TERT-BUTOXYCARBONYL-4-HYDROXYPIPERIDINE (414 mg) and DIAD (420 mg) and stirred under nitrogen for 20 hours. The solution was purified by chromatography using ethyl acetate-isohexane as eluant to give tert-butyl 4- [ (4- chloroquinazolin-6-yl) oxy] PIPERIDINE-1-CARBOXYLATE (96%) as a white solid; Mass spectrum MH+ 364.
  • 13
  • [ 392-04-1 ]
  • [ 109384-19-2 ]
  • [ 852370-09-3 ]
YieldReaction ConditionsOperation in experiment
61% With triphenylphosphine; diethylazodicarboxylate; In benzene; at 0℃; for 1h; A mixture of <strong>[392-04-1]methyl 4-fluoro-2-hydroxybenzoate</strong> (5.1 g, 30 mmol), triphenylphosphine (9.5 g, 36 mmol),1-tert- butoxycarbonyl-4-hydroxypiperidine (6 g, 30 mmol), and benzene (10 mL) was heated until all solids dissolved. The solution was cooled to0 C, then sonicated while adding <Desc/Clms Page number 41>diethyl azodicarboxylate (6.3 g, 36 mmol) dropwise. After the addition was complete, the reaction mixture was sonicated for an additional 60 min, diluted withCH2Cl2 (25 mL), and purified by flash chromatography, eluting with 10% EtOAc in hexanes to yield the title compound (6.45 g, 61%) as a white solid. 1NMR IS-MS, m/e 354(mol) Analysisfor ClgH24FNO5 :Calcd :C, 61. 18 ; H, 6.85 ; N, 3.98 ;Found: C, 60.98 ;H, 6.86 ; N, 4.04.
  • 14
  • [ 10320-42-0 ]
  • [ 109384-19-2 ]
  • [ 862313-62-0 ]
YieldReaction ConditionsOperation in experiment
54% With cesium fluoride; In N,N-dimethyl-formamide; at 20℃; for 24h; Cesium fluoride (17.8 g, 117.5 mmol) was added to a solution of 2-chloro-5-nitro- pyrimidine (12.5 g, 78.3 mmol) and tert-butyl 4-hydroxypiperidine-l-carboxylate (15.8 g, 78.3 mmol) in DMF (375 mL). The resulting mixture was stirred for 24 h at room temperature. The insoluble solids were removed by filtration were filtred through a short pad of diatomaceous earth and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc (200 mL) and washed successively with water (150 mL) and brine (50 mL). The organic layer was dried over MgS04, filtered and concentrated to dryness. Purification by flash chromatography over silica gel (gradient of EtOAc in heptane from 0 to 35percent) gave the pure compound 9a as a white solid (13.9 g, 54percent). MR (300 MHz, Chloroform-i ) delta 1.47 (s, 9H), 1.76 - 1.92 (m, 2H), 1.98 - 2.13 (m, 2H), 3.21 - 3.44 (m, 2H), 3.63 - 4.00 (m, 2H), 5.26 - 5.50 (m, 1H), 9.29 (s, 2H). MS m/z 269 (M+H-tBu)+.
38% With cesium fluoride; In DMF (N,N-dimethyl-formamide); at 20℃; for 12h; Example 226 3-{(2-[(1-cyclobutylpiperidin-4-yl)oxy]-pyrimidin-5-yl}-2-methyl-5-(trifluoromethyl)-4(3H)-quinazolinone (1) Manufacture of t-butyl-4-[(5-nitroglycerine-pyrimidin-2-yl)oxy]piperidine-1-carboxylate 2-chloro-5-nitroglycerine-pyrimidine (80 mg, 0.5 mmol), t-butyl-4-hydroxypiperidine-1-carboxylate (100 mg, 0.5 mmol) and cesium fluoride (114 mg, 0.75 mmol) were mixed in dimethylformamide, and stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure, the product was purified by silica gel column chromatography (hexane/ethyl acetate=10/0-3/7), and the target compound (61 mg, 38%) was thus obtained as a light yellow solid.
30% With cesium fluoride; In N,N-dimethyl-formamide; at 20℃; for 24h; Cesium fluoride (5.71 g, 37.6 mmol) was added to a solution of 2-Chloro-5-nitro- pyrimidine (4.0 g, 25.0 mmol) and 4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester (5.0 g, 25.0 mmol) in DMF (120 mL). The resulting mixture was stirred for 24 h at roomtemperature. The insolubles were collected by filtration through a short pad of diatomaceous earth. The filtrate was concentrated under reduced pressure. The residue was taken in EA (40 mL) and washed successively with water (40 mL) and brine (20 mL). The organic layer was dried over MgSO4, filtered, and concentrated to dryness. Chromatography over silica gel (gradient of EA in heptane from 0 to 35%) gave the pure product as a white solid (2.43 g, 30%). ?H NMR (300 IVIFIz, Chloroform-cl) 1.47 (s, 9H),1.76- 1.92 (m, 2H), 1.98-2.13 (m, 2H), 3.21 -3.44 (m, 2H), 3.63 -4.00 (m, 2H), 5.26-5.50 (m, 1H), 9.29 (s, 2H). MS m/z 269 C,4H20N405 (M+H-tBu).
  • 15
  • [ 40107-07-1 ]
  • [ 109384-19-2 ]
  • [ 879324-69-3 ]
YieldReaction ConditionsOperation in experiment
77% With 1-tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-2Lambda5,4Lambda5-catenadi(phosphazene); In acetonitrile; at 100℃; for 0.5h;Microwave; The mixture of <strong>[40107-07-1]4-chloro-6-iodo-quinoline</strong> (217.5 mg, 1 mmol, prepared by similar procedure to example 1e), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (150 mg, 0.75 mmol), and 1-tert-butyl-2,2,4,4-pentakis(dimethylamino)-2lambda5, 4lambda5-catenadi(phosphazene) in tetrahdyrofuran (2M, 0.75 ml, 1.5 mmol) in acetonitrile (3.5 ml) was stirred at 100° C. for 30 min in microwave instrument (Personal Chemistry). After cooling the reaction, the solvent was evaporated, followed by addition of water, some of sodium carbonate saturated solution. The resulting solution was extracted with dimethylene chloride three times. The combined organic layer was dried over the brain, sodium sulfate, then evaporated to give a reddish gel. Flash chromatography (Merck silica gel 60, 230-400 mesh, 0percent-3percent methanol in dichloromethane for 30 min) afforded 4-(6-iodo-quinolin-4-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (262.5 mg, 77percent) as A light yellow solid. LC-MS m/e 455 (MH+).
  • 16
  • [ 24424-99-5 ]
  • [ 5382-17-2 ]
  • [ 144-55-8 ]
  • [ 109384-19-2 ]
YieldReaction ConditionsOperation in experiment
100% In 1,4-dioxane; (a) 1-(Tert-Butoxycarbonyl)-4-hydroxypiperidine <strong>[5382-17-2]4-Hydroxypiperidine hydrochloride</strong> (3 g) was dissolved in dioxane (30 ml), added with di-tert-butyl dicarbonate (5.2 g) and stirred at room temperature for 10 minutes. The reaction mixture was added with 8percent aqueous sodium hydrogencarbonate (60 ml) and further stirred for 3.5 hours. Dioxane was evaporated under reduced pressure, and the aqueous layer was extracted with ethyl acetate (60 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified to obtain 4.81 g of the title compound. Yield: 100percent. 1H-NMR (CDCl3) delta (ppm); 1.46 (11H, m), 1.86 (2H, m), 3.04 (2H, m), 3.85 (3H, m)
100% In 1,4-dioxane; (a) 1-(tert-Butoxycarbonyl)-4-hydroxypiperidine <strong>[5382-17-2]4-Hydroxypiperidine hydrochloride</strong> (3 g) was dissolved in dioxane (30 ml), added with di-tert-butyl dicarbonate (5.2 g) and stirred at room temperature for 10 minutes. The reaction mixture was added with 8percent aqueous sodium hydrogencarbonate (60 ml) and further stirred for 3.5 hours. Dioxane was evaporated under reduced pressure, and the aqueous layer was extracted with ethyl acetate (60 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain 4.81 g of the title compound. Yield: 100percent. 1H-NMR (CDCl3); delta (ppm) 1.46 (11H, m), 1.86 (2H, m), 3.04 (2H, m), 3.85 (3H, m)
  • 17
  • [ 10465-78-8 ]
  • [ 123-08-0 ]
  • [ 109384-19-2 ]
  • [ 207798-38-7 ]
YieldReaction ConditionsOperation in experiment
With triphenylphosphine; In tetrahydrofuran; ethyl acetate; Step 3 Synthesis of 4-(1-t-butoxycarbonyl-4-piperidyloxy)benzaldehyde: 770 mg (3.83 mmol) of 1-t-butoxycarbonyl-4-hydroxypiperidine and 467 mg (3.83 mmol) of 4-hydroxybenzaldehyde were dissolved in 20 ml of THF. 1.2 g (4.6 mmol) of triphenylphosphine and 790 mg (4.6 mmol) of N,N,N',N'-tetramethylazodicarboxyamide were added to the obtained solution, and they were stirred overnight. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound. Yield: 240 mg (0.79 mmol) (21%) H-NMR (CDCl3) delta 1.47 (9H, t), 1.70-2.03 (4H, m), 3.31-3.42 (2H, m), 3.62-3.71 (2H, m), 4.58-4.63 (1H, m), 6.99 (2H, d), 7.83 (2H, d), 9.88 (1H, s)
  • 18
  • [ 658-07-1 ]
  • [ 141-78-6 ]
  • [ 109384-19-2 ]
  • [ 1972-28-7 ]
  • [ 337520-54-4 ]
YieldReaction ConditionsOperation in experiment
76% With triphenylphosphine; In hexane; dichloromethane; Reference Example 104 4-(1-t-Butoxycarbonylpiperidin-4-yloxy)-3,5-difluoronitrobenzene To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (1.73 g), <strong>[658-07-1]2,6-difluoro-4-nitrophenol</strong> (1.37 g) and triphenylphosphine (2.67 g) in dichloromethane (30 ml) was added dropwise diethyl azodicarboxylate (1.57 ml) in an ice bath and the mixture was stirred at room temperature for 9 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=6/1 as an eluant to give the desired compound (2.13 g, yield 76%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) delta ppm: 1.47 (9H, s), 1.77-1.85 (2H, m), 1.89-1.96 (2H, m), 3.35 (2H, m), 3.72 (2H, m), 4.62 (1H, m), 7.87 (2H, m).
  • 19
  • [ 110-87-2 ]
  • [ 24057-28-1 ]
  • [ 109384-19-2 ]
  • [ 152491-44-6 ]
YieldReaction ConditionsOperation in experiment
In dichloromethane; water; d N-BOC-4-[(tetrahydropyran-2-yl)oxy]piperidine With stirring, 8.16 ml (0.09 mol) of 3,4-dihydro-2H-pyran and 1.5 g (0.006 mol) of pyridinium-(toluene-4-sulfonate) are added to a solution of 12.08 g (0.06 mol) of N-BOC-4-hydroxypiperidine (cf. EP 0 278 621) in 300 ml of methylene chloride. The reaction mixture is stirred for 2.5 hours at room temperature, then washed with 2*50 ml of brine:water (1:1) mixture, dried over sodium sulfate and concentrated under vacuum, giving the title compound in the form of a colourless oil; Rf =0.58 (silica gel/ethyl acetate:hexane (2:1), which gradually solidifies in crystalline form at 0 C.
  • 20
  • [ 24424-99-5 ]
  • [ 40064-34-4 ]
  • [ 109384-19-2 ]
YieldReaction ConditionsOperation in experiment
With sodium borohydrid; N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide; ethanol; water; REFERENCE EXAMPLE 18 N-tert-Butoxycarbonyl-4-hydroxypiperidine 7.14 g of 4-piperidone.monohydrate.hydrochloride was dissolved in 50 ml of dimethylformamide and 10 ml of water, and to the solution were added 25 ml of diisopropylethylamine and 9.5 g of di-tert-butyl dicarbonate at a room temperature with stirring, and the reaction mixture was stirred for 4 hours. After adding water and saturating with sodium chloride, the reaction mixture was extracted twice with 300 ml of chloroform. The extract was dried over magnesium sulfate and evaporated under a reduced pressure to obtain 9.6 g of residue, which was then dissolved in 100 ml of ethanol. To the solution was added 1.83 g of sodium borohydride with stirring under ice cooling, and the mixture was stirred for 90 minutes under the same condition, and then for 30 minutes at a room temperature. After adding saturated sodium chloride aqueous solution, the reaction mixture was alkalized with sodium bicarbonate and extracted twice with 600 ml of chloroform. The extract was dried over magnesium sulfate and evaporated under a reduced pressure, and resulting residue was subjected to a silica gel column and eluted with hexane/ethyl acetate (2:1), to obtain 8.03 g of the title compound in a colorless amorphous form. 1 H-NMR (CDCl3, delta ppm): 1.35-1.6 (2H, m), 1.45 (9H, s), 1.75-1.95 (2H, m), 3.03 (2H, ddd, J=13.13, 10.28, 4.00 Hz), 3.75-3.95 (3H, m).
  • 21
  • [ 7651-82-3 ]
  • [ 109384-19-2 ]
  • [ 918490-55-8 ]
YieldReaction ConditionsOperation in experiment
With polystyrene-bound triphenylphosphine; triethylamine; In dichloromethane; at 20℃;Product distribution / selectivity; AAV1 :To 500 mg (1.5 mmol) of triphenylphosphine (bound to polystyrene, 3mmol/g) and 10 ml of dichloromethane 0.195 mL (1.2 mmol) of diethylazodicarboxylate (or alternatively diisopropylazodicarboxylate) were added. The reaction mixture was allowed to shake for 10 min. and then 0.14 mL of triethylamine, 145 mg of <strong>[7651-82-3]6-hydroxyisoquinoline</strong> (7) (or an equivalent amount of a different suitable isoquinol) (reagent 1) and 1 mmol of the desired, boc-protected aminoalcohol (reagent 2) was added. The reaction was shaken at room temperature until no further conversion could be observed by LCMS. For workup, the solution was filtered, the residue was washed with dichloromethane and EPO <DP n="90"/>the organic layer was washed twice with 1 N sodium hydroxide, twice with water and once with brine, dried over magnesium sulfate and evaporated. The crude product was purified by preparative HPLC to yield the boc protected coupled product.
  • 22
  • [ 1075-11-2 ]
  • [ 109384-19-2 ]
  • [ 918490-55-8 ]
YieldReaction ConditionsOperation in experiment
With sodium hydride; In ISOPROPYLAMIDE; at 80℃; for 2h;Product distribution / selectivity; 4-(lsoquinolin-6-yloxy)-pipehdine-1 -carbocyclic acid-tert-butylester (154) EPO <DP n="103"/>7.49 g of 4-Hydroxy-piperidine-i-carboyclic acid-tert-butylester are dissolved in 20 mL of dry dimethyl acetamide. 1.49 g of sodium hydride (60%) are added. Then a solution of 3.65 g 6-Fluoroisoquinoline (23) is added dropwise. The solution is heated at 80 0C for 2 hours, then the solvent is removed and the residue is taken up in dichloromethane. The organic layer is extracted twice with water and then with brine, dried over magnesium sulfate and evaporated to dryness. The crude product is purified by silica gel chromatography to yield 6.22g of 4-(lsoquinolin-6-yloxy)-piperidine-1- carbocyclic acid-tert-butylester. R1 = 1.32 min (Method No.1). Detected mass: 329.1 (M+H+).
With sodium hydride; In ISOPROPYLAMIDE; at 80℃; for 2h; 7.49 g of 4-hydroxy-piperidine-1-carboxylic acid-tert-butylester were dissolved in 20 ml_ of dry dimethyl acetamide. 1.49 g of sodium hydride (60%) were added. Then a solution of 3.65 g of <strong>[1075-11-2]6-fluoroisoquinoline</strong> (3) in dimethyl acetamide was added dropwise. The solution was heated at 80 0C for 2 hours, then the solvent was removed and the residue was taken up in dichloromethane. The organic layer was extracted twice with water and then with brine, dried over magnesium sulfate and evaporated to dryness. The crude product was purified by silica gel chromatography to yield 6.22 g of 4-(isoquinolin-6-yloxy)-piperidine-1-carboxylic acid-tert-butylester (7). Rt = 1.32 min (Method B). Detected mass: 329.1 (M+H+).
  • 23
  • [ 5470-65-5 ]
  • [ 109384-19-2 ]
  • [ 929281-95-8 ]
YieldReaction ConditionsOperation in experiment
75% With di-isopropyl azodicarboxylate; triphenylphosphine; In diethyl ether; at 25℃; for 18h; <strong>[5470-65-5]3-Bromo-4-nitrophenol</strong> (11.6 g, 53.2 mmol), 1,1-dimethylethyl 4-hydroxy-1- piperidinecarboxylate (10.7 g, 53.2 mmol) and triphenylphosphine (24 g, 91 mmol) were combined in diethyl ether (400 ml_) at room temperature. Diisopropyl azodicarboxylate (17.2 ml_, 87.8 mmol) was added over 10 min. The solution was stirred at 25 °C for 18 h. The reaction mixture was extracted with 1 N sodium hydroxide (2 x 50 ml_), and brine (100 mL). The organic fractions were combined, dried over magnesium sulfate, filtered, and concentrated onto silica gel. Purification by column chromatography (0 to 40percent ethyl acetate:hexanes) provided 16.0 g (75percent) of the title compound as yellow solid. 1H NMR (300 MHz, DMSO-dfe): delta 8.04 (d, 1 H, J= 9.2 Hz), 7.48 (d, 1 H, J= 2.6 Hz), 7.18 (dd, 1 H1 J= 2.6, 9.2 Hz), 4.79 (m, 1 H)1 3.6 (m, 2H), 3.15 (m, 2H)1 1.89 (m, 2H)1 1.52 (s, 2H), 1.38 (s, 9H).
  • 24
  • [ 28489-45-4 ]
  • [ 109384-19-2 ]
  • [ 936368-79-5 ]
YieldReaction ConditionsOperation in experiment
80% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 22℃; Add diisopropyl azodicarboxylate (3.0 mL, 15.5 mmol) dropwise to a cold mixture of 6-methyl-5- nitro-pyridin-2-ol (1.54 g, 10.0 mmol), 4-hydroxy-piperidine-l-carboxylic acid tert-butyl ester (2.05 g, 10.0 mmol), and triphenylphosphine (4.02 g, 15.3 mmol) in THF (25 mL) at 0 C. After addition is complete, remove cooling bath and stir the reaction mixture at 22 C overnight. Concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with hexanes and ethyl acetate to provide 4-(6-Methyl- 5-nitro-pyridin-2-yloxy)-piperidine-l-carboxylic acid tert-butyl ester as a colorless oil (2.69 g, 80% yield). MS(ES): m/z = 338.2 [M+H].
  • 25
  • [ 109384-19-2 ]
  • [ 51173-05-8 ]
  • [ 944390-86-7 ]
YieldReaction ConditionsOperation in experiment
95% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0℃; Step A: tert-Butyl 4-(5-fluoro-pyridin-2-yloxy)- 1 -piperidinecarboxylateA mixture of tert-butyl 4-hydroxy- 1 -piperidinecarboxylate (3.02 g, 15.0 mmol), 5- fluoro-2 hydroxypyridine (0.85 g, 7.50 mmol), diisopropyl-azodicarboxylate (3.03 g, 15.00 mmol), triphenylphosphine (3.90 g, 15.00 mmol) and tetrahydrofuran (100 mL) is stirred at 0 0C, allowed to come to room temperature and stirred overnight. The reaction mixture is evaporated in vacuo and purifed on silica gel using ethyl acetate/hexane as <n="86"/>the eluent. Fractions containing the product are pooled and evaporated to give the desired product (2.12 g, 95%) as a colorless solid.
93.5% With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; toluene; at 0 - 20℃; for 37.83h; <strong>[51173-05-8]5-fluoro-2-hydroxypyridine</strong> 1.844 g (16.3 mmol) with 4-hydroxy-N- Boc-piperidine 5.032 g (25 mmol) and triphenylphosphine 6.82 g in anhydrous THF (60 ml_) was stirred under Ar for 20 minutes. The mixture was cooled to 0 "C and DEAD 40% in toluene 10 ml_ (26 mmol) was added over a 20 minute period. The cooling bath temperature was gradually raised up to room temperature over 90 minutes and the reaction was then continued at room temperature for 36 hours. The reaction was quenched with 50% H2O2 (0.5 mL), a few spoons of silica were added to the mixture and stirred for 10 minutes. The resulting slurry was filtered through a pad of silica (2x2 in) and <n="44"/>the silica was washed with EtOAc (400 ml_). The combined filtrates were evaporated and the residue was dried under high vacuum. The residue was diluted with toluene (20 ml_) and cyclohexane (20 mL) was added. The mixture was allowed to crystallize for 1 hour, the precipitate was removed by filtration and the filtrates were evaporated. The material was applied onto a column of silica (80 g) in hexanes and eluted with a gradient of EtOAc in hexanes, 0 to 20% EtOAc. The purified intermediate was dried under high vacuum. Y = 4.526 g (93.5%) of the Boc-protected intermediate as a white crystalline solid.
  • 26
  • [ 22245-83-6 ]
  • [ 109384-19-2 ]
  • [ 442199-31-7 ]
  • [ 442198-38-1 ]
YieldReaction ConditionsOperation in experiment
Preparation 39 Tert-Butyl 4-[3-(trifluoromethyl)-2-pyridyl]oxy)-1-piperidinecarboxylate The title compound was obtained from tert-butyl 4-hydroxy-1-piperidinecarboxylate and 3-(trifluoromethyl)-2-hydroxypyridine in the same manner as in Preparation 13. 1H-NMR (300 MHz, CDCl3) delta 8.33-8.24(m, 1H), 7.90-7.81(m, 1H), 6.99-6.90(m, 1H), 5.48-5.33(m, 1H), 3.63-3.44(m, 4H), 1.99-1.77(m, 4H), 1.47(s, 9H).
  • 27
  • [ 33252-63-0 ]
  • [ 109384-19-2 ]
  • [ 194668-47-8 ]
  • [ 442198-38-1 ]
YieldReaction ConditionsOperation in experiment
Preparation 16 Tert-Butyl 4-[5-(trifluoromethyl)-2-pyridyl]oxy}-1-piperidinecarboxylate The title compound was obtained from tert-butyl 4-hydroxy-1-piperidinecarboxylate and <strong>[33252-63-0]5-trifluoromethyl-2-hydroxypyridine</strong> in the same manner as in Preparation 13. 1H-NMR (300 MHz, CDCl3) delta 8.40(br s, 1H), 7.76(dd, J=2,8 Hz, 1H), 6.69(d, J=8 Hz, 1H), 5.33-5.23(m, 1H), 3.84-3.70(m, 2H), 3.35-3.23(m, 2H), 2.05-1.92(m, 2H), 1.80-1.66(m, 2H), 1.48(s, 9H).
  • 28
  • [ 64248-64-2 ]
  • [ 109384-19-2 ]
  • [ 1021908-40-6 ]
YieldReaction ConditionsOperation in experiment
97.2% With sodium hydride; In N,N-dimethyl-formamide; at 20 - 50℃; 26.1 4-(2-Cyano-4-fluoro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester The title compound was prepared a follows. 2-5-Difluorobenzonitrile (1.00 g, 7.2 mmol) was added at room temperature to a stirred mixture under argon of sodium hydride (55%, 207 mg, 9 mmol) in dimethylformamide (DMF) (10 ml). 4-Hydroxypiperidine-1-carboxylic acid tert-butyl ester (3.32 g, 17 mmol) was added in portions. The resulting mixture was stirred several hours at 50 C. before partitioning it between H2O and ethyl acetate (EtOAc). The organic layer was washed with sat. aq. NH4Cl sol. and brine and dried over MgSO4. Evaporation of the solvent yielded 2.24 g (97.2%, 7 mmol) of a light brown solid. MS (m/z): 321.1 (M+H+).
  • 29
  • [ 2497-18-9 ]
  • [ 109384-19-2 ]
  • (-)-4-(1-vinylbutoxy)piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • (+)-4-(1-vinylbutoxy)piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • 30
  • [ 35852-58-5 ]
  • [ 109384-19-2 ]
  • [ 647014-06-0 ]
YieldReaction ConditionsOperation in experiment
Diisopropyl azodicarboxylate (6.68 ml, [33MMOL)] was added dropwise to a solution of tert-butyl 4-hydroxypiperidine carboxylate (4.27g, 21. [2MMOL)] and triphenyl phosphine (7.78g, 29. [7MMOL)] in toluene (160 ml) at [0XB0;C] under argon. The mixture was stirred [FOR L/2 HOUR,] 2- chloro-4-trifluoromethylphenol (5. [00G,] 25. [5MMOL)] was then added dropwise and the reaction allowed to warm to RT overnight. The solvent was removed in vacuo and the residue stirred in isohexane for 1 hour. The precipitate was filtered off and the filtrate concentrated to an orange oil which was purified by flash column chromatography (10percent EtOAc in isohexane) to afford [L-FERT-BUTYL-4-(2-CHLORO-4-TRIFLUOROMETHYLPHENYLOXYMPIPERIDINE CARBOXYLATE] (4.59g, [12MMOL).] NMR: [(CDC13,] [300 MHZ)] : 7.68 (s, 1H); 7.46 (d, [1H)] ; 6.98 (d, 1H) ; 4.68 (m, 1H); 3.69-3. 44 (m, 4H); 1.79-1. 92 (m, 4H); 1.46 (s, 9H).
  • 31
  • [ 2040-90-6 ]
  • [ 109384-19-2 ]
  • [ 1058702-84-3 ]
  • 32
  • [ 40594-98-7 ]
  • [ 109384-19-2 ]
  • [ 922516-57-2 ]
  • [ 922516-58-3 ]
YieldReaction ConditionsOperation in experiment
To a solution of t-butyl 4-hydroxypiperidine-l-carboxylate (0.43 g, 3.3 mmol) and triphenylphosphine (1.05 g, 4.0 mmol) in tetrahydrofuran (15 mL) at 0 0C was added dropwise diethyl azodicarboxylate (0.63 mL, 4.0 mmol). After 5 minutes ethyl IH-1, 2,3- triazole-4-carboxylate (0.43 g, 3.0 mmol, prepared according to D. R. Buckle, C. J. M. Rockell, J. Chem Soc, Perkin Transaction 1 1982, 2, 627-630.) was added in tetrahydrofuran (5 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was purified by medium pressure liquid chromatography (MPLC) using 15 to 40 percent ethyl acetate in hexanes as eluant to afford 0.42 g of the title compound as an oil. 1H NMR (CDCl3) delta 1.41 (t, 3H), 1.47 (s, 9H), 2.13 (m, 4H), 2.97 (m, 2H), 4.19 (m, 2H), 4.42 (q, 2H), 4.69 (m, IH), 8.04 (s, IH).Additionally eluting before the title compound was isolated 0.35 g of 1,1-dimethylethyl 4-[5-(ethoxycarbonyl)-lH-l,2,3-triazol-l-yl]-l-piperidinecarboxylate. 1H NMR (CDCl3) delta 1.41 (t, 3H), 1.48 (s, 9H), 2.09 (m, 2H), 2.29 (m, 2H), 2.94 (m, 2H), 4.30 (m, 2H), 4.39 (q, 2H), 5.27 (m, IH), 8.13 (s, IH).
  • 33
  • [ 658-07-1 ]
  • [ 109384-19-2 ]
  • [ 337520-54-4 ]
  • 34
  • [ 109384-19-2 ]
  • [ 170961-15-6 ]
  • [ 1186299-31-9 ]
YieldReaction ConditionsOperation in experiment
85% To a 0 C. solution of the commercially available tert-butyl 4-hydroxy-1-piperidine-carboxylate (1.5 g, 7.45 mmol, 1.2 eq.) in dry THF (20 mL), triphenylphosphine (2.4 g, 9.31 mmol, 1.5 eq.) was added. After complete dissolution, diethylazodicarboxylate-40% w/v in toluene- (4 mL, 9.31 mmol, 1.5 eq.) was added dropwise followed by <strong>[170961-15-6]thiazol-2-yl-carbamic acid tert-butyl ester</strong> g, 5.99 mmol, 1.0 eq.). The mixture was stirred at RT for 18 hours. The reaction was evaporated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel, eluting with cyclohexane-ethyl acetate (95:5 to 85:15) to afford 109 as a colorless gum (1.95 g, 85%)
  • 35
  • [ 103057-10-9 ]
  • [ 109384-19-2 ]
  • [ 845258-36-8 ]
YieldReaction ConditionsOperation in experiment
To a solution OF 4-HYDROXY-1-PIPERIDINECARBOXYLIC acid, 1, l-dimethylethyl ester (9. 5g, 0. 047MOL) in dry N-methylpyrrollidine (NMP) (50ml) was added sodium hydride (60% in oil) portionwise (1.88g, 0. 047mol). The mixture was allowed to stir for 30 minutes, then <strong>[103057-10-9]4-(chloromethyl)-1-(triphenylmethyl)-1H-imidazole</strong> (ref: W00244141) (16. 8g, 0. 047MOL) was added and the mixture heated to 50C for 30 min, poured into ice water and extracted with ethyl acetate. The organic extacts were washed with water and purified by flash column chromatography eluting with 1% methanolic AMMONIA/DICHLOROMETHANE to give a solid (5. 5G). 300 MHz I H NMR (CDC13) 7. 41 (1H, d), 7.32-7. 13 (15H, m), 6.81 (1H, bs), 4.49 (2H, s), 3.82-3. 77 (2H, m), 3.62-3. 54 (1 H, m), 3.05-2. 96 (2H, M), 1.85-1. 76 (2H, M), 1.57-1. 48 (2H, m), 1. 45 (9H, s)
  • 36
  • [ 26621-44-3 ]
  • [ 109384-19-2 ]
  • [ 1201935-68-3 ]
YieldReaction ConditionsOperation in experiment
17% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 25℃;Inert atmosphere; a) DIAD (5.22 rnL, 26.53 mmol) was added dropwise to a stirred solution of 3-nitro- lH-pyrazole (2 g, 17.69 mmol), tert-butyl 4-hydroxypiperidine-l-carboxylate (3.56 g, 17.69 mmol) and triphenylphosphine (5.80 mL, 26.53 mmol) in THF (30 mL) cooled to O0C under an atmosphere of nitrogen. The resulting solution was stirred at 00C for 10 minutes and then allowed to warm to room temperature and stirred overnight. The mixture was diluted with isohexane (80 mL) and EtOAc (20 mL) and stirred vigorously. The mixture was filtered and the residue washed with isohexane (20 mL). The combined filtrates were evaporated and the residue purified by chromatography on silica, eluting with a gradient of 20-100% EtOAc in isohexane. Fractions containing product were combined and evaporated to afford tert-butyl 4-(3-nitropyrazol-l-yl)piperidine-l-carboxylate (0.874 g, 17% yield); 1H NMR spectrum (300 MHz, DMSO): delta 1.42 (9H, s), 1.77 - 1.83 (2H, m), 2.04 - 2.09 (2H, m), 2.87 - 2.93 (2H, m), 4.04 - 4.09 (2H, m), 4.49 - 4.55 (IH, m), 7.07 (IH, d), 8.13 (IH, d); Mass spectrum: m/z (ESI+) (M-Phiu+H)+ = 240.98
  • 37
  • [ 10397-13-4 ]
  • [ 109384-19-2 ]
  • [ 944402-03-3 ]
YieldReaction ConditionsOperation in experiment
77% [0416] To a solution of N-Boc-4-hydroxy piperidine (2.58 g, 12.81 mmol) in tetrahydrofuran at 00C under argon, was added sodium hydride (60%, 512 mg, 12.81 mmol). After stirring for 20 minutes, a solution of 2-morpholino-4,6- dichloropyrimidine (2.0 g, 8.54 mmol) in tetrahydrofuran (20 mL) was added through a syringe. The solution was stirred for 14 hours as the ice bath warmed to room temperature. At this time, the reaction mixture was quenched with water (2 mL), and was partitioned between EtOAc (350 mL) and Na2CO3(SaI.) (75 mL). The organic layer was separated, washed with brine (50 mL), dried over Na2SO4, filtered, concentrated and the residue was purified by SiO2 chromatography (15-20% EtOAc in hexanes) to yield tert- butyl 4-(6-chloro-2-morpholinopyrimidin-4-yloxy)piperidine-l-carboxylate as a white solid (2.64 g, 77%). LCMS (m/z): 399.1 (MH+). 1H NMR (CDCl3): delta 6.00 (s, IH), 5.18 (m, IH), 3.74 (s, 8H), 3.64-3.74 (m, 2H), 3.28-3.38 (m, 2H), 1.86-1.96 (m, 2H), 1.68-1.78 (m, 2H), 1.44 (s, 9H).
  • 38
  • [ 109384-19-2 ]
  • [ 1029413-55-5 ]
YieldReaction ConditionsOperation in experiment
Example 82A tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate The title compound was prepared as described in Example 41A substituting tert-butyl 4-hydroxypiperidine-1-carboxylate for 1-methylpiperidin-4-ol.
  • 39
  • [ 109384-19-2 ]
  • [ 71902-33-5 ]
  • [ 1189551-57-2 ]
YieldReaction ConditionsOperation in experiment
99% With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 17h; t-Butyl 4-hydroxypiperidine-1-carboxylate (1.04 g, 5.00 mmol) was added to a N,N-dimethylformamide suspension (5.0 ml) of 60percent sodium hydride (229 mg, 6.00 mmol), at 0°C, and stirring was carried out at room temperature for 30 minutes. Further, at 0°C, <strong>[71902-33-5]3,5-difluoropyridine</strong> (645 mg, 5.50 mmol) was added, and stirring was carried out for 16.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed sequentially with water and saline, and then dried over anhydrous sodium sulfate. The organic layer was concentrated and the resulting residue was purified by silica gel column chromatography to afford t-butyl 4-[(5-fluoropyridin-3-yl)oxy]piperidine-1-carboxylate (1.48 g, yield 99percent) as a colorless oil. 1H-NMR (CDCl3, 400 MHz) delta: 8.16-8.11 (2H, m), 6.96 (1H, dt, J=10.2, 2.3 Hz), 4.52-4.47 (1H, m), 3.73-3.67 (2H, m), 3.39-3.33 (2H, m), 1.99-1.73 (4H, m), 1.47 (9H, s). MS (ESI, m/z): 297 (M+H)+.
  • 40
  • [ 855400-66-7 ]
  • [ 109384-19-2 ]
  • [ 1266114-18-4 ]
YieldReaction ConditionsOperation in experiment
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; STEP B: tert-Butyl 4-(3-bromo-5-methoxyphenoxy)piperidine-1-carboxylate 3-Bromo-5-methoxyphenol (0.18 g, 0.89 mmol) and triphenylphosphine (0.284, 1.07 mmol) were taken into THF (5 mL) and the resulting mixture cooled to 0 C. 4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.18 g, 0.89 mmol), and DIAD (0.207 mL, 1.07 mmol) were taken up into THF (5 mL) and added slowly to the mixture, which was then stirred at room temperature over night. The resulting mixture was taken into EtOAc and washed with saturated NaHCO3 and brine. The solvent was dried over sodium sulfate and removed in vacuo. The resulting residue was purified on normal phase chromatography (EtOAc/heptane) to yield tert-butyl 4-(3-bromo-5-methoxyphenoxy)piperidine-1-carboxylate. MH+386.2, 388.2
  • 41
  • [ 109384-19-2 ]
  • [ 582313-57-3 ]
  • [ 1236284-39-1 ]
YieldReaction ConditionsOperation in experiment
59% With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; toluene; at 20℃; for 1h;Inert atmosphere; To a solution of the compound (1.20 g) obtained in the above (1) in tetrahydrofuran (215 mL) were added 1-tert-butoxycarbonyl-4-hydroxypiperidine (3.52 g), triphenylphosphine (7.33 g) and a solution of diethyl azodicarboxylate in toluene (12.7 mL), and the mixture was stirred under nitrogen atmosphere at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel (solvent; hexane/ethyl acetate = 80/20 to 60/40) to give the titled compound (1.47 g) as a powder (yield: 59percent). MS(APCI)m/z; 355/357[M+H]+.
  • 42
  • [ 216766-12-0 ]
  • [ 109384-19-2 ]
  • [ 1353754-93-4 ]
  • 43
  • [ 31169-27-4 ]
  • [ 109384-19-2 ]
  • [ 1384951-80-7 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 12h;Sealed reactor; Example 50: tert-butyl 4-(7-(4-methanesulfonyl-phenyl)thieno[3,2- d]pyrimidin-4-yloxy)piperidine-l-carboxylateStep 50-1 tert-butyl 4-(7-bromothieno[3,2-d1pyrimidin-4-yloxy)piperidine-l- carboxylateTo <strong>[31169-27-4]7-bromo-4-chlorothieno[3,2-d]pyrimidine</strong> obtained in Step 1-3) of Preparation Example 1, t-butyl 4-hydroxypiperidine-l -carboxylate, K2C03 and N,N- dimethylformamide were added, and stirred at 100°C for 12 hours in a hermetically sealed reactor. The reaction mixture was cooled to room temperature, extracted with ethyl acetate and distilled water, and the organic layer thus obtained was washed with water and a saline solution. Subsequently, the washed organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound. 1H NMR (300 MHz, DMSO-</6): delta 8.41(s, 1H), 7.88(s, 1H), 5.54(m, 1H), 3.56(m, 2H), 3.40(m, 2H), 1.96(m, 2H), 1.77(m, 2H), 1.41(s, 9H).
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 12h; To <strong>[31169-27-4]7-bromo-4-chlorothieno[3,2-d]pyrimidine</strong> obtained in Step 1-3) of Preparation Example 1, t-butyl 4-hydroxypiperidine-1-carboxylate, K2CO3 and N,N-dimethylformamide were added, and stirred at 100° C. for 12 hours in a hermetically sealed reactor. The reaction mixture was cooled to room temperature, extracted with ethyl acetate and distilled water, and the organic layer thus obtained was washed with water and a saline solution. Subsequently, the washed organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound. [0437] 1H NMR (300 MHz, DMSO-d6): delta 8.41 (s, 1H), 7.88 (s, 1H), 5.54 (m, 1H), 3.56 (m, 2H), 3.40 (m, 2H), 1.96 (m, 2H), 1.77 (m, 2H), 1.41 (s, 9H).
  • 44
  • [ 213265-83-9 ]
  • [ 109384-19-2 ]
  • [ 1403829-84-4 ]
YieldReaction ConditionsOperation in experiment
98% With potassium tert-butylate; In tetrahydrofuran; at -78℃; Step A: Preparation of tert-Butyl 4-(6-Chloro-5-fluoropyrimidin-4- yloxy)piperidine- 1 -carb oxylate.To a solution of <strong>[213265-83-9]4,6-dichloro-5-fluoropyrimidine</strong> (1.00 g, 5.99 mmol) and tert-butyl 4- hydroxypiperidine-1 -carboxylate (1.205 g, 5.99 mmol) in THF (10 mL) at -78 C was added 1 M potassium teri-butoxide solution in THF (5.99 mL, 5.99 mmol) dropwise. The mixture became thick and additional THF (10 mL) was slowly added. After stirring for 15 min, the mixture was diluted with water and extracted with EtOAc. The organic layer was concentrated under reduced pressure and purified by silica gel flash column chromatography to give the title compound as a colorless oil, which solidified slowly (1.9561 g, 98%). Exact mass calculated for Ci4H19ClFN303: 331.1, found: LCMS m/z = 332.4 [M+H]+; lU NMR (400 MHz, CDC13) delta ppm 1.45 (s, 9H), 1.75-1.85 (m, 2H), 1.98-2.04 (m, 2H), 3.28-3.36 (m, 2H), 3.75-3.81 (m, 2H), 5.30- 5.39 (m, 1H), 8.31 (s, 1H).
98% With potassium tert-butylate; In tetrahydrofuran; at -78℃; for 0.25h; Example 1.1: Preparation of 4-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yloxy)-5-fluoro-6-(2- methyl-6-(methylsulfonyl)pyridin-3-yloxy)pyrimidine (Compound 1).Step A: Preparation of tert-Butyl 4-(6-Chloro-5-fluoropyrimidin-4- yloxy)piperidine-l-carboxylate.To a solution of <strong>[213265-83-9]4,6-dichloro-5-fluoropyrimidine</strong> (1.00 g, 5.99 mmol) and teri-butyl 4- hydroxypiperidine-1 -carboxylate (1.205 g, 5.99 mmol) in THF (10 mL) at -78 C was added 1 M potassium teri-butoxide solution in THF (5.99 mL, 5.99 mmol) dropwise. The mixture became thick and additional THF (10 mL) was slowly added. After stirring for 15 min, the mixture was diluted with water and extracted with EtOAc. The organic layer was concentrated under reduced pressure and purified by silica gel flash column chromatography to give the title compound as a colorless oil that slowly became a white solid (1.9561 g, 98%). Exact mass calculated for ^Eta19alphaRhoNu303: 331.1, found: LCMS m/z = 332.4 [M+H]+; lU NMR (400 MHz, CDC13) delta ppm 1.45 (s, 9H), 1.75-1.85 (m, 2H), 1.98-2.04 (m, 2H), 3.28-3.36 (m, 2H), 3.75-3.81 (m, 2H), 5.30-5.39 (m, 1H), 8.31 (s, 1H).
98% With potassium tert-butylate; In tetrahydrofuran; at -78℃; for 0.25h; To a solution of <strong>[213265-83-9]4,6-dichloro-5-fluoropyrimidine</strong> (1.00 g, 5.99 mnmol) and tert-butyl 4- hydroxypiperidine-i-earboxylate (1,205 g, 5.99 mmol) in ?THF (10 mL) at -78 CC was added 1 M potassium tert-butoxide solution in ?[HF (5.99 mL, 5.99 mmol) dropwise. The mixture became thick and thus more THF (10 mL) was slowly added. After stirring for 15 mm, themixture was quenched with water and extracted with EtOAc. The organic layer was concentrated under reduced pressure and purified by Biotage column chromatography to afford the title compound (1.9561 g, 5.90 mmoi, 98%) as a colorless oil that slowly became a white solid. Exact mass calculated for C,4H,9CIFN,03: 331.1, found: LCMS ink = 332.4[M+H]t ?H NMR (400 MHz, CDCi3) 3 ppm 1.45 (s, 9H), 1,75-1.85 (m, 2H), 1.98-2.04 (m, 2H), 3.28-3.36 (m, 2H), 3.75-3.81 (m, 2H), 5.30-5.39 (m, 1H), 8.31 (s, iH).
  • 45
  • [ 109384-19-2 ]
  • [ 147754-12-9 ]
  • [ 1164178-34-0 ]
YieldReaction ConditionsOperation in experiment
92% a) 1.35 g 4-Fluoro-2-methyl-benzonitrile, dissolved in DMF, was added to 2.11 g 4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester and 0.6 g sodium hydride in 30 mL DMF. The mixture was stirred at room temperature (rt) until the reaction was complete. The reaction was quenched with water. The aqueous layer was extracted with ethylacetate (AcOEt) or methyl tert. butyl ether (MTB ether). The combined organic layers were washed with brine, dried and concentrated to to give 2.6 g (yield 81percent) 4-(4-Cyano-3-methyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. Mass: (C18H24N2O3): calcd. 316, found 261 [M+H-t(C4H9)]+
92% 1 ) 4-(4-Cvano-3-methvi-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester b) 22.6 g Potassium tert. butoxide, 33.2 g 4-Hydroxy-piperidine-1-carboxylic acid tert- butyl ester and 300 mL MTB ether were stirred for 1h at reflux. A solution of 20.3 g 4- Fluoro-2-methyl-benzonitrile, dissolved in 250 mL MTB ether was added within 20 min to the suspension and heating to reflux was continued for 7 h. The reaction was quenched with water. The organic layer was separated and washed with water and concentrated to give 54.8 g (yield 92percent) of 4-(4-Cyano-3-methyl-phenoxy)-piperidine-1- carboxylic acid tert-butyl ester. H NMR (500 MHz, d6-DMSO) delta 1.40 (s, 9H), 1.47-1.55 (m, 2H), 1.88-1 .95 (m, 2H), 2.43 (s, 3H), 3.13-3.22 (m, 2H), 3.63-3.70 (m, 2H), 4.66- 4.73 (m, 1 H), 6.96 (dd, J = 8.6, 2.4 Hz, 1 H), 7.07 (d, J = 2.3 Hz, 1 H), 7.67 (d, J = 8.7 Hz, 1 H).
  • 46
  • [ 109384-19-2 ]
  • [ 147754-12-9 ]
  • [ 1417697-15-4 ]
  • 47
  • [ 50-65-7 ]
  • [ 109384-19-2 ]
  • [ 1420290-93-2 ]
YieldReaction ConditionsOperation in experiment
58% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 4h; [00134] To a solution of niclosamide (200 mg, 0.6 mmol) and PPh3 (288 mg,1.1 mmol) in THF (10 mL) was added tert-butyl4-hydroxypiperidine-1-carboxylate (222 mg,1.1 mmol) and DIAD (222 mg, 1.1 mmol). The reaction mixture was stirred at r.t. for 4 h, andthen it was partitioned between EtOAc (50 mL) and H20 (20 mL ). The organic layer waswashed with brine (10 mL), dried with anhydrous Na2S04, and concentrated to give the crudeproduct. This residue was purified with silica gel column (hexane/EtOAc = 3/1) to affordHJC-1-16 (180 mg, 58%) as a white solid. 1H NMR (600 MHz, CDCh) o 10.17 (s, 1H), 8.85(d, 1H, J= 9.6 Hz), 8.32 (s, 1H), 8.20 (d, 1H, J= 6.0 Hz), 8.17 (s, 1H), 7.46 (d, 1H, J= 8.4Hz), 7.03 (d, 1H, J = 6.0 Hz), 4.61-4.63 (m, 1H), 3.99-3.41 (m, 2H), 2.98-3.02 (m, 2H), 210-2.12 (m, 2H), 1.81-1.83 (m, 2H), 1.45 (s, 9H)
  • 49
  • [ 89583-07-3 ]
  • [ 109384-19-2 ]
  • [ 1174044-47-3 ]
YieldReaction ConditionsOperation in experiment
28.8% To a suspension of sodium hydride (1.9 g, 79.49 mmol, 4.0 eq, 60% dispersion in mineral oil) in THF (20 ml) tert-butyl 4-hydroxypiperidine-1-carboxylate (5.0 g, 19.87 mmol, l .Oeq) in THF (20 mL) was added at 0C. The reaction mixture was stirred at 0C for 30 minutes., <strong>[89583-07-3]4-(2-bromoethyl)morpholine</strong> (step 1) (4.6 g, 23.84 mmol, 1.2eq) in THF (40 ml) was added and the reaction was allowed to reach to room temperature and heated to reflux for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was quenched with saturated NH4Cl solution (20 ml) and extracted with EtOAc (2x50 ml). The combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by silicagel column chromatography by using methanol: dichloromethane as an eluent to obtain the desired product (1.8 g, 28.8% yield) as a yellow liquid. 1H NMR (300 MHz, CDCl3): delta ppm 3.81-3.68 (m, 6H), 3.63-3.56 (m, 2H), 3.48-3.4 (m, 1H), 3.11-3.03 (m, 2H), 2.59 (t, J = 6.0 Hz, 2H), 2.53-2.49 (m, 4H), 1.88-1.79 (m, 2H), 1.58-1.42 (m, 2H), 1.43 (s, 9H); ES Mass: [M+H]+ 315.12.
  • 50
  • [ 52427-05-1 ]
  • [ 109384-19-2 ]
  • C16H21BrN2O5 [ No CAS ]
  • 51
  • [ 2075-46-9 ]
  • [ 109384-19-2 ]
  • [ 1029413-55-5 ]
  • 52
  • [ 109384-19-2 ]
  • [ 269409-70-3 ]
  • [ 889865-34-3 ]
YieldReaction ConditionsOperation in experiment
69% With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; toluene; at 0 - 20℃; for 20h;Inert atmosphere; Enzymatic reaction; Triphenylphosphine (9.53 g, 36.4 mmol), and DEAD (40% w/w DEAD in toluene, 16.1 mL, 40.9 mmol) in THF (80 mL) was cooled at 0 C and stirred under nitrogen atmosphere. A mixture of 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenol (5.0 g, 22.7 mmol) and 4-hy droxypiperi dine- 1-carboxy lie acid tert-butyl ester (5.72 g, 28.4 mmol) in THF (10 mL) was added dropwise to the reaction. The cooling bath was removed and furthered stirred at rt for 20 h. The reaction was evaporated under vacuum, stirred with ether, and the white solid filtered off. The filtrate was evaporated under vacuum and purified by ISCO silica gel chromatography ( 0-20% EtOAc / hexanes) to obtain 4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- phenoxy]-piperidine-l-carboxylic acid tert-butyl ester (6.3 g, 69%). LCMS m/z = 404 (M + 1).
38% With triphenylphosphine; 1,1'-azodicarbonyl-dipiperidine; In tetrahydrofuran; at 0 - 20℃; In a 1 00 ni L round-bottomed flask, tri phenyl hosph i n e (1.25 g, 4.77 mmol, Eq: 1.05), ivY-butyl 4-hydro.xypiperidine- 1 -carboxylate (915 mg, 4.54 mmol, Eq: 1 .00 ) and 4-( 4.4,5, 5.-tetramethyl- l ,3,2-dioxaborolan-2-yl)phenol (1 g. 4.54 mmol. Eq : 1 .00 ) were combined with THF (25.0 ml ) to give a colorless suspension. Cooled the reaction to 0C, 1 . 1 '-(azodicarbonyl )dipipcridine ( 1 .2 g, 4.77 mmol, Eq: 1.05 ) in THF (5 m l .) was added. The reaction mixture was slowly raised to room temperature and stirred overnight, concentrate the solution. The compound was purified by column chromatography (Hexanes/EtOAc = 70/30) to give 0.7 g (38%) oil. M Hi 403.9
3 g In a 500 ml round bottom flask, a mixture of fe/f-butyl 4-hydroxypiperidine-1 -carboxylate (5 g, 24.88 mmol) (CAS 109384-19-2), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (CAS 269409-70-3) (6 g, 27.36 mmol) and PPh3 (9.78 g, 37.31 mmol) in dry THF (200 ml) was stirred at 0 C for 5 min. Then, DIAD (10 g, 49.75 mmol) was added dropwise at 0 C and stirred for 3 h. The RM was then concentrated. Purification of the residue by flash chromatography on silica gel eluting with 20% EtOAc in petroleum ether afforded 3 g of the title compound as a white solid. LC-MS (method J): Rt = 1 .73 min, [M+NH4]+ = 404.
  • 53
  • [ 109384-19-2 ]
  • [ 1048970-17-7 ]
  • 54
  • [ 109384-19-2 ]
  • [ 5382-17-2 ]
YieldReaction ConditionsOperation in experiment
99% With hydrogenchloride; In 1,4-dioxane; at 20℃; for 2.0h; A mixture of tert-butyl 4-hydroxypiperidine- 1 -carboxylate (5 g, 24.84 mmol, 1.00 equiv) and HC1 (saturated solution in 30 mL of 1 ,4-dioxane) was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum to afford the title compound (3.4 g, 99percent) as an off- white solid.
90% With hydrogenchloride; In diethyl ether; at 20℃; for 2.0h; A solution of N-Boc-4-hydroxypiperidine (600 mg, 3.0 mmol) in HCl/Et20 (2.0 M, 10 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue obtained washed with Et20 and dried to give the title product (370 mg, 90percent) as white solid which was used without purification.
7.0 g With hydrogenchloride; In ethyl acetate; at 20℃; To a solution of ieri-butyl 4-hydroxypiperidine-1-carboxylate (10.9 g, 49.7 mmol, 1 .0 eq) in EtOAc (40 mL) was added a saturated solution of HCI in EtOAc (10 mL), and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated to give the title compound (7.0 g) as a white solid
  • 55
  • [ 348-62-9 ]
  • [ 109384-19-2 ]
  • tert-butyl 4-(4-chloro-2-fluorophenoxy)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; toluene; at 0 - 65℃; for 15h; j0150j To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (250 mg, 1.242 mmol) in THF (4.14 mL) was added <strong>[348-62-9]4-chloro-2-fluorophenol</strong> (0.15 mL, 1.366 mmol) and triphenylphosphine (391 mg, 1.49 1 mmol). The mixture was cooled to 0 C and DEAD (0.81 mL, 2.050 mmol) (40% wt in toluene) was added dropwise. The mixture was heated at 65 oC for 15 h. The material was concentrated and purified via flash column chromatography (0- 100% EtOAc in hexanes) to afford tert-butyl 4-(4-chloro-2-fluorophenoxy)piperidine- 1- carboxylate (270 mg, 65%). ESI-MS mlz [M+H]+ 330.1.
  • 56
  • [ 5334-39-4 ]
  • [ 59786-31-1 ]
  • [ 109384-19-2 ]
  • methyl 3-((5-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)isonicotinate [ No CAS ]
  • methyl 3-(3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl-amino)isonicotinate [ No CAS ]
YieldReaction ConditionsOperation in experiment
To a solution of methyl 3-((l-(l-(tert-butoxycarbonyl)piperidin-4-yl) -3- methyl-lH-pyrazol-4-yl)amino)isonicotinate (1.0 g, 2.40 mmol) in DCM (10 mL) was added trifluoroacetic acid (3.07 g, 2.0 mL). The reaction mixture was stirred at 15 °C for lh. Then concentrated to give the methyl 3-(3-methyl-l-(piperidin-4- yl)-lH-pyrazol-4-yl (0729) amino)isonicotinate (1.2 g , Yield: 92percent) as 2 TFA salt which was used directly in next reaction without further purification. ESI-LCMS (m/z): 316.1 [M+1]. Same protocol used for methyl 3-((5-methyl-l-(piperidin-4-yl)- lH-pyrazol-4-yl)amino) isonicotinate
  • 57
  • [ 109384-19-2 ]
  • [ 460-00-4 ]
  • [ 889865-34-3 ]
  • 58
  • [ 109384-19-2 ]
  • [ 170961-15-6 ]
  • tert-butyl 4-(1,3-thiazol-2-yl)aminopiperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
2.2 g With diethylazodicarboxylate; In tetrahydrofuran; toluene; at 20℃; for 16h;Inert atmosphere; Cooling with ice; Under argon atmosphere, to a solution of tert-butyl N-thiazol-2-ylcarbamate (1.9 g) and tert-butyl 4-hydroxypiperidine-1-carboxylate (1.8 g) in THF (20 mL) was added diethyl azodicarboxylate (2.2 M toluene solution, 5.1 mL) under ice cooling, and the mixture was stirred at room temperature for 16 h. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography to give a solid 1 (2.2 g). To a solution of the obtained solid 1 (2.2 g) in dichloromethane (5 mL) was added TFA (5 mL), and the mixture was stirred at room temperature for 1 h 30 min. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give a solid 2 (796 mg). 6-Hydroxy-2-(pyrazolo[5,1-b][1,3]thiazol-7-yl)pyrimidine-4-carboxylic acid obtained in Reference Example 2 (100 mg) was suspended in phosphorus oxychloride (1.1 mL), diethylaniline (57 mg) was added to the suspension, and the mixture was stirred at 110 C for 2 h. The reaction solution was concentrated under reduced pressure, the concentrate was dissolved in dichloromethane (10 mL) under ice cooling, DIPEA (0.33 mL) and the solid 2 (136 mg) were added to the solution, and the mixture was stirred at room temperature for 30 min. The reaction solution was diluted with chloroform, separated by adding saturated aqueous sodium bicarbonate solution, and the aqueous layer was further extracted with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (70 mg). MS (m/z): 446, 448 [M+H]+
  • 59
  • [ 896139-85-8 ]
  • [ 109384-19-2 ]
  • Tert-butyl 4-(imidazo[1,2-a]pyridin-7-yloxy)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
48% With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; A solution of imidazo [1,2-a] pyridine-7-ol (218 mg, 1.63 mmol)N-Boc-4-hydroxypiperidine (654 mg, 3.25 mmol) and Ph3P (1.71 g, 6.52 mmol) were dissolved in THF (30 mL)Then DBAD (748 mg, 3.25 mmol) dissolved in THF (10 mL) was added dropwise to the reaction solution at 0 C,After the room temperature reaction is complete,The product was quenched by the addition of water to give the product 7 (250 mg, 48%) by vacuum spin column chromatography.
  • 60
  • [ 31181-53-0 ]
  • [ 109384-19-2 ]
  • C11H16N2O [ No CAS ]
  • 61
  • [ 109384-19-2 ]
  • [ 184416-84-0 ]
  • 2-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-3-chloroisonicotinic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (4.79 g, 23.83 mmol) in NMP(20 mL) was added NaH (60% dispersion in mineral oil, 0.95 g, 23.82 mmol) in portions at 0C After stirring for 30 minutes, <strong>[184416-84-0]2,3-<strong>[184416-84-0]dichloroisonicotinic acid</strong></strong> (0.8 g, 3.90 mmol) was addedand the reaction mixture heated at 60 00 overnight. After cooling, the mixture was poured into water and the pH adjusted to 5 by addition of a 1 M aqueous HCI solution. The aqueous phase was extracted with EtOAc and the combined organic extracts washed with water, brine, dried (Na2SO4), filtered and concentrated. The residue obtained was purified by column chromatography (MeOH/DCM = 1/10, v/v) to give the title compound (0.5 g, crude,36%). LCMS: RT2.61 mm; m/z379.1 [M+Na].
  • 62
  • [ 109384-19-2 ]
  • [ 4983-28-2 ]
  • tert-butyl 4-((2-chloropyrimidin-5-yl)oxy)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 72h;Inert atmosphere; To a solution of tert-butyl 4-hydroxypiperidine-l-carboxylate (561 mg, 2.79 mmol) in THF (5 mL) was added <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (200 mg, 1.532 mmol), triphenylphosphine (548 mg, 2.089 mmol) and DIAD (0.406 mL, 2.089 mmol) and the reaction was stirred at 20 C under an atmosphere of nitrogen for 72 h. The reaction was concentrated, and the residue subjected directly to purification by flash chromatography (60g pre-packed C-18 SNAP cartridge:35% to 90% acetonitrile (0.1% formic acid) in water (0.1% formic acid)). The desired fractions were combined and concentrated to afford the title compound (430 mg, 1.07 mmol, 77 % yield). LCMS T= 1.12 min, ES+ve 258 (M+H-tBu).
77% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 72h;Inert atmosphere; (0204) To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (561 mg, 2.8 mmol) in THF (5 mL) was added <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (200 mg, 1.53 mmol), triphenylphosphine (548 mg, 2.09 mmol) and DIAD (0.406 mL, 2.09 mmol) and the reaction mixture was stirred at 20 C. under nitrogen for 72 h. The reaction mixture was concentrated in vacuo, and the residue was subjected directly to purification by flash chromatography (60 g pre-packed C-18 SNAP cartridge using a gradien elution from 35-90% acetonitrile (0.1% formic acid) in water (0.1% formic acid)). Desired fractions were combined and concentrated to afford the title compound (430 mg, 1.1 mmol, 77% yield). LCMS RT=1.12 min, ES+ve 258 (M+H-tBu).
48% With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; To a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate ( 2.5 g, 12.60 mmol) in THF (30 mL), <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (1.5 g, 11.4 mmol), TPP (7.4 g, 22.9 mmol) followed by di-tert- butyl azocarboxylate (DTAD, 5.2 g, 22.9 mmol) were added and the reaction mixture was stirred at RT overnight. Completion of the reaction was monitored by TLC. The reaction mixture was diluted with water and the aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic layer was washed with water (5 mL), brine solution (5 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 50percent EtOAc in hexane) to afford the title compound. Yield: 48percent (1.8 g, yellow solid). LCMS: (Method A) 258.2 (M-f-butyl), Rt. 4.5 min, 96.8percent (Max).
  • 63
  • [ 109384-19-2 ]
  • [ 1445-08-5 ]
  • C16H24N6O2 [ No CAS ]
  • 64
  • [ 109384-19-2 ]
  • [ 1500-85-2 ]
  • 4-(4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carbonyl)benzenesulfonylfluoride trifluoroacetate [ No CAS ]
  • 65
  • [ 109384-19-2 ]
  • [ 1500-85-2 ]
  • tert-butyl 4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate [ No CAS ]
  • 66
  • [ 109384-19-2 ]
  • [ 782501-25-1 ]
  • 67
  • [ 136888-79-4 ]
  • [ 109384-19-2 ]
  • tert-butyl 4-((5-methoxypyridin-2-yl)oxy)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Preparation of tert-butyl 4-((5-methoxypyridin-2-yl)oxy)piperidine-l- carboxylate. To a solution of tert-butyl 4-hydroxypiperidine-l-carboxylate (158 mg, 0.787 mmol) in DMF (2 mL) was added sodium hydride (60% w/w, 38 mg, 0.944 mmol). The reaction was stirred for 10 min at ambient temperature. Then <strong>[136888-79-4]2-fluoro-5-methoxypyridine</strong> (100 mg, 0.787 mmol) was added and reaction stirred overnight at 60C. The reaction was heated to 70C for an additional overnight. The reaction was cooled to ambient temperature and additional of tert-butyl 4-hydroxypiperidine-l-carboxylate (316 mg, 1.574 mmol) and sodium hydride (60% w/w, 76 mg, 1.888 mmol) was added and reaction was stirred for 60 h at 70C. The reaction was cooled to ambient temperature and diluted with DCM and washed water and brine. The combined organic extracts were dried over anhydrous Na2S04(S), filtered and concentrated in vacuo to afford the title compound (243 mg, assumed quantitative yield). MS (apci) m/z = 253.1 (M-Bu*).
  • 68
  • [ 33631-05-9 ]
  • [ 109384-19-2 ]
  • tert-butyl 4-[(2-aminopyridin-4-yl)oxy]piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
22.52% With di-isopropyl azodicarboxylate; triphenylphosphine; In dichloromethane; at 0 - 25℃; for 3h;Inert atmosphere; To a solution of compound 8.4 (500 mg, 4.54 mmol, 1 eq) in DCM (15 mL) was added compound 8.3 (913.90 mg, 4.54 mmol, 1 eq) PPh3 (1.79 g, 6.81 mmol, 1.50 eq) and DIAD (1.38 g, 6.81 mmol, 1.32 mL, 1.50 eq) in turn at 0C under N2. The resulting mixture was stirred at 25C for 3 hours. The reaction mixture was added water 20 mL, extracted with EtOAc (2OmL x 3). The combined organic layers were washed with brine (20 mL x 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate = 1:1).Compound 8.2 (300 mg, 1.02 mmol, 22.52% yield) was obtained as a white solid. ?H NIVIR(400 MHz, chloroform-d) ppm 1.47 (s, 9 H) 1.72 - 1.77 (m, 2 H) 1.88 - 1.93 (m, 2 H) 3.33 -3.37 (m, 2 H) 3.64-3.68 (m, 2 H) 4.37 (s, 2 H) 4.47-4.51 (m, 1 H) 5.98 (d, J=2.0 Hz, 1 H)6.25 (dd, J6.0 Hz, 2.0 Hz, 1 H) 7.90 (d, J 6.0 Hz, 1 H).
  • 69
  • [ 68322-84-9 ]
  • [ 109384-19-2 ]
  • t-butyl 4-(2-bromo-4-(trifluoromethyl)phenoxy)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
81% j00298J A flask was charged with t-butyl 4-hydroxypiperidine-1-carboxylate (2.0 g, 9.94 mmol, 1.00 equiv) and THF (40 mL). Then sodium hydride (60% in oil, 0.800 g, 20.0 mmol, 2.00 equiv) was added at 0 C. The resulting solution was stirred for 1 hour at room temperature and 2-bromo- 1 -fluoro-4-(trifluoromethyl)benzene (3.20 g, 13.2 mmol, 1.30 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched by water (20 mL), as described in Example 4, Step 1. The residue was chromatographed on a silica gel column to provide 3.40 g (81% yield) t-butyl 4-(2-bromo-4-(trifluoromethyl)phenoxy)piperidine- 1 -carboxylate as a white solid. LCMS (ESI, m/z): 424 [M+H].
  • 70
  • [ 109384-19-2 ]
  • [ 406913-93-7 ]
  • tert-butyl (R)-4-((1,4-dioxan-2-yl)methoxy)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
(S)-(1,4-Dioxan-2-yl)methanol (160 mg) was dissolved in dichloromethane (6 mL). The mixture was cooled to 0 C. Triethylamine (0.217 mL) was added. Methanesulfonyl chloride (0.116 mL) was added dropwise. The mixture was allowed to warm to room temperature. After two hours, saturated aqueous sodium bicarbonate (3 mL) was added. The layers were separated, and the organic layer was washed with brine (5 mL). The aqueous layers were combined and back-extracted withdichloromethane (10 mL). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum. The material was taken up in tetrahydrofuran (1 mL) and added to a solution of tert-butyl 4-hydroxypiperidine- 1 -carboxylate (300 mg) and sodium hydride (60%, 71.5 mg) that had been pre-stirred for 15 minutes in tetrahydrofuran (7 mL). The solution was stirred at room temperature overnight and quenched with a few drops of saturated aqueous ammoniumchloride. The solvent was removed under vacuum. The residue was taken up in ethyl acetate (10 mL), washed with water (2 mL), washed with brine (2 mL), dried with anhydrous sodium sulfate, filtered and concentrated. The material was used without further purification. ?H NMR (500 MHz, dimethylsulfoxide-do) 6 ppm 4.70 (d, 1H), 4.19 (q, 111), 3.814-3.74 (m, 2H), 3.68-3.59 (m, 4H), 3.52- 3.45 (m, 1H), 3.20 (s, 2H), 2.95 (m, 211), 1.71-1.65 (m, 2H), 1.28-1.20 (m, 2H), 1.40 (s, 9H), 1.41 (m,1H).
  • 71
  • [ 78539-93-2 ]
  • [ 109384-19-2 ]
  • [ 122368-54-1 ]
  • 72
  • [ 1914-65-4 ]
  • [ 109384-19-2 ]
  • C20H29NO3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
68% With 2,4,6-trimethyl-pyridine; tetrabutylammonium perchlorate; silver perchlorate; In dichloromethane; at 20℃; for 3h;Electrolysis; Molecular sieve; General procedure: With no precautions to exclude air or moisture, the ElectraSyn vial (5 ml) with a stir bar was charged with carboxylic acid (0.2 mmol, 1.0 equiv.), alcohol (0.6 mmol, 3.0 equiv.), 2,4,6-collidine (0.6 mmol, 3.0 equiv.), nBu4NPF6 (0.3 mmol, 1.5 equiv.), 3 A molecular sieves (150 mg), AgPF6 (0.3 mmol, 1.5 equiv.) and CH2Cl2 (3.0 ml). The ElectraSyn vial cap equipped with anode (graphite) and cathode (graphite) were inserted into the mixture. After pre-stirring for 15 min, the reaction mixture was electrolysed at a constant current of 10 mA for 3 h. The ElectraSyn vial cap was removed, and electrodes were rinsed with Et2O (2 ml), which was combined with the crude mixture. Then, the crude mixture was further diluted with Et2O (30 ml). The resulting mixture was washed with 2 M HCl (20 ml) and NaHCO3 (aq.) (20 ml), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by preparative thin-layer chromatography to furnish the desired product. Full experimental details and characterization of new compounds can be found in the Supplementary Information.
  • 73
  • [ 131748-14-6 ]
  • [ 109384-19-2 ]
  • C16H21F3N2O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
62% NaH (60% dispersion in mineral oil, 46 mg, .1.19 mmol) was added portionwise to a stirred solution of l-Boc-4-hydroxypiperidine (CAS: 109384-19-2; 200 mg, 0.99 mmol) in DMF (3 mL) in a sealed tube and under N2 at 0 C. The reaction mixture was stirred at 0 C for 30 min and a solution of <strong>[131748-14-6]<strong>[131748-14-6]4-chloro-2-(trifluoromethyl)pyridin</strong>e</strong> (CAS: 131748- 14-6; 271 mg, 1.49 mmol) in DMF (2 mL) was added dropwise at 0 C. The reaction mixture was stirred at 60 C for 48 h. The mixture was concentrated in vacuo. The residue was diluted with water and extracted with EtOAc. The organic layer was dried (Na2S04), filtered and the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography (silica, EtOAc in DCM, gradient from 0:100 to 50:50). The desired fractions were collected and concentrated in vacuo to afford intermediate 104 (212 mg, 62%) as colorless oil which solidified to a white solid upon standing
  • 74
  • [ 131748-14-6 ]
  • [ 109384-19-2 ]
  • C11H13F3N2O [ No CAS ]
  • 75
  • [ 1083169-00-9 ]
  • [ 109384-19-2 ]
  • C17H26N2O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
General procedure: A solution of tert- butyl 4-hydroxypiperidine-l-carboxylate (CAS: 109384- 19-2; 11.82 g, 58.72 mmol) in DMF (20 mL) was added to a stirred suspension of sodium hydride (CAS: 7646-69-7; 60% dispersion in mineral oil, 2.58 g, 64.59 mmol) in DMF (90 mL) at 0 C under N2. The mixture was stirred for 2 h and then a solution of 4-chloro-2, 6-dimethyl-pyridine (CAS: 3512-75-2; 9.15 g, 64.59 mmol) in DMF (20 mL) was added dropwise at 0 C. The mixture was allowed to warm to rt and stirred for 3 days and then at 60 C for 6 h. After cooling to rt, water was added and the mixture was extracted with EtOAc. The organic layer was separated, dried (Na2S04), filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica; EtOAc in heptane 30/70 to 100/0). The desired fractions were collected and concentrated in vacuo to yield intermediate 1 as colourless oil (2.24 g, 12%) and impure fractions, that were further purified by flash chromatography (silica; 7N solution of NTb in MeOH in DCM, 0/100 to 10/90) and then by RP HPLC (stationary phase: C18 XBridge 50 x 100 mm, 5 pm, mobile phase: gradient from 80% NH4HCO3 0.25% solution in water, 20% CH3CN to 0% NH4HCO3 0.25% solution in water, 100% CH3CN). The desired fractions were collected and evaporated in vacuo to yield additional intermediate 1 as colourless oil (3.82 g, 21%).
  • 76
  • [ 109384-19-2 ]
  • [ 25194-01-8 ]
  • tert-butyl 4-((2,6-dichloropyridin-4-yl)oxy) piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% l-Boc-4-hydroxypiperidine (CAS: 109384-19-2; 3.27 g, 15.8 mmol) was added to a stirred solution of NaH (60% dispersion in mineral oil, 661 mg, 16.5 mmol) in anhydrous THF (20 mL) at 0 C under N2 atmosphere. The mixture was warmed to room temperature and stirred for 30 min. Then, <strong>[25194-01-8]4-nitro-2,6-dichloropyridine</strong> (CAS: 25194-01- 8; 2.90 g, 15.0 mmol) was added to the mixture at 0 C and the reaction mixture was stirred at 50 C for 2 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried (MgS04), filtered and the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography (silica, heptane/EtOAc, gradient from 100:0 to 80:20). The desired fractions were collected and concentrated in vacuo to give intermediate 153 (4.2 g, 80%) as a pale yellow solid.
  • 77
  • [ 30766-12-2 ]
  • [ 109384-19-2 ]
  • C17H24N2O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
74% Triphenylphosphine (1.17 g, 4.45 mmol) was added to a stirred mixture of methyl 5- hydroxypyridine-2-carboxylate (CAS: 30766-12-2; 500 mg, 3.27 mmol) and l-Boc-4- hydroxypiperidine (CAS: 109384-19-2; 597 mg, 2.97 mmol) in anhydrous THF (30 mL) under N2 atmosphere. The reaction mixture was stirred at room temperature for 15 min, and DIAD (CAS: 2446-83-5; 0.88 mL, 4.45 mmol) was added dropwise at 0 C. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried (MgS04), filtered and the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography (silica, heptane/EtOAc, gradient from 100:0 to 30:70). The desired fractions were collected and concentrated in vacuo to afford intermediate 189 (750 mg, 74%) as a colorless oil.
  • 78
  • [ 30838-93-8 ]
  • [ 109384-19-2 ]
  • C17H26N2O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
74% A solution of l-Boc-4-hydroxypiperidine (CAS: 109384-19-2; 1.00 g, 4.97 mmol) in anhydrous DMF (4.16 mL) was added dropwise to a stirred solution of NaH (60% dispersion in mineral oil, 238 mg, 5.96 mmol) in anhydrous DMF (4.16 mL) at 0 C. The mixture was stirred at 0 C for 30 min and a solution of <strong>[30838-93-8]2-chloro-4,6-dimethylpyridine</strong> (CAS: 30838-93-8; 0.79 g, 5.47 mmol) in anhydrous DMF (4.16 mL) was added portionwise at 0 C. The reaction mixture was stirred at 60 C for 16 h and concentrated in vacuo. The residue was diluted with water and extracted with EtOAc. The organic layer was dried (Na2S04), filtered and evaporated in vacuo. The crude mixture was purified by flash column chromatography (silica, heptane/EtOAc, gradient from 100:0 to 70:30) to afford intermediate 48 (1.12 g, 74%) as a white solid.
  • 79
  • [ 95-89-6 ]
  • [ 109384-19-2 ]
  • C16H25N3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
67% With 15-crown-5; sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 80℃;Inert atmosphere; To a solution of l-Boc-4-hydroxypiperidine (CAS: 109384-19-2; 250 mg, 1.24 mmol) in anhydrous DMF (4.2 mL) under N2 atmosphere were added NaH (60% dispersion in mineral oil, 59.6 mg, 1.49 mmol) and l5-crown-5 (248 pL, 1.49 mmol). 3-Chloro-2,5- dimethylpyrazine (CAS: 95-89-6; 165 pL, 1.37 mmol) was added and the reaction mixture was stirred at 80 C. The mixture was diluted with water at 0 C and extracted with DCM. The organic layer was dried, filtered and the solvents were concentrated in vacuo. The crude mixture was purified by flash column chromatography (silica, heptane/EtOAc, gradient from 100:0 to 40:60) to afford intermediate 58 (256 mg, 67%) a colourless oil.
  • 80
  • [ 109384-19-2 ]
  • [ 209328-55-2 ]
  • [ 1189551-57-2 ]
YieldReaction ConditionsOperation in experiment
60% With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 2.0h;Inert atmosphere; Sealed tube; DBAD (CAS: 870-50-8; 1.72 g, 7.45 mmol) was added to a stirred mixture of l-Boc-4- hydroxypiperidine (CAS: 109384-19-2; 1.00 g, 4.97 mmol), <strong>[209328-55-2]5-fluoropyridin-3-ol</strong> (CAS: 209328-55-2; 618 mg, 5.47 mmol) and triphenylphosphine (1.96 g, 7.45 mmol) in THF (12.1 mL) at 0 C in a sealed tube and under N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc and washed with NaOH (5N). The organic layer was dried (Na2S04), filtered and concentrated in vacuo. The crude mixture was purified twice by flash column chromatography (silica, heptane/EtOAc, gradient from 100:0 to 70:30) to afford intermediate 74 (890 mg, 60%).
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