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CAS No. : | 52763-21-0 | MDL No. : | MFCD00012792 |
Formula : | C15H20ClNO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | UQOMEAWPKSISII-UHFFFAOYSA-N |
M.W : | 297.78 | Pubchem ID : | 2723880 |
Synonyms : |
|
Num. heavy atoms : | 20 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.47 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 81.9 |
TPSA : | 46.61 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.01 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 2.96 |
Log Po/w (WLOGP) : | -1.78 |
Log Po/w (MLOGP) : | 1.69 |
Log Po/w (SILICOS-IT) : | 2.41 |
Consensus Log Po/w : | 1.06 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.44 |
Solubility : | 0.107 mg/ml ; 0.000361 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.6 |
Solubility : | 0.0745 mg/ml ; 0.00025 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.67 |
Solubility : | 0.0638 mg/ml ; 0.000214 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.38 |
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: |
* 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 |
---|---|---|
100% | With palladium 10% on activated carbon; hydrogen; sodium carbonate In ethanol at 50℃; for 48 h; Autoclave | 1-tert-butyl 4-ethyl3-oxopiperidine-1,4-dicarboxylate (74) A mixture of ethyl 1-benzyl-3-oxo-4-piperidinecarboxylate hydrochloride (10.0 g,33.58 mmol), Pd/C (10percent wt., 1.0 g), Boc20 (14.64g, 67.16 mmol), Na2C03 (3.56 g,33.58 mmol) and EtOH (100 ml)was loaded into a Parr autoclave. Hydrogen was10 introduced (38 bar), and the mixturewas stirred at 50 oc for 48 h. Afterthe autoclave was cooled to 25 oc the hydrogen pressurewas released, the catalyst was removed by filtration, and the mixture was concentrated under reduced pressureto give a yellow oil. Purification by column chromatography (hexane: EtOAc 2:1) gave the title compound(9.10 g, 100percent) as a clear oil.15Rf = 0.70 (hexane:EtOAc 2:1); 1H NMR (CDCI3,400 MHz) o 12.10 (s, 1H, enolform -OH),4.25 (q, J= 7.1 Hz, 2H), 4.04 (s, 2H), 3.50 (t, J= 5.8 Hz, 2H), 2.33 (t, J= 5.8 Hz, 2H),1.48 (s, 9H), 1.32 (t, J = 7.1 Hz, 3H); HRMS (CI) calc. for C13H21NOs (M+NH4)+ 289.1763, found: 289.1759. |
94% | With triethylamine In diethyl ether; ethanol | EXAMPLE 33A 1-tert-butyl 4-ethyl 3-oxo-1,4-piperidinedicarboxylate Ethyl 1-benzyl-3-oxopiperidine-4-carboxylate hydrochloride (24.16 g, 81.1 mmol) in ethanol (250 mL) was treated with triethyl amine (11.3 mL, 81.1 mmol), di-tert-butyl dicarbonate (18.6 g, 85.3 mmol) and 10percent Pd/C (0.13 g). After stirring under H2 (1 atm) at 50° C. for 1 hour, the mixture was allowed to cool to ambient temperature and filtered through diatomaceous earth with an ethanol (2*20 mL) rinse. The filtrate was concentrated under reduced pressure. The residue was treated with diethyl ether (200 mL) and refiltered with a diethyl ether rinse (2*30 mL). The filtrate was concentrated under reduced pressure to provide the title compound as a yellow oil (20.6 g, 94percent yield). 1H NMR (CD3OD, 300 MHz) δ 1.32 (t, J=6.9 Hz, 3H), 1.48 (s, 9H), 2.32-2.26 (m, 3H), 3.5 (t, J=5.7 Hz, 1H), 4.0 (br s, 1H), 4.24 (q, J=6.9 Hz, 2H); MS (DCI/NH3) m/z 272 (M+H)+, 289 (M+NH4)+. |
88% | Stage #1: With hydrogen In ethanol at 20℃; for 15 h; Stage #2: With triethylamine In ethanol at 20℃; for 3 h; |
Example 1 Preparation of Compound 1benzhydryl bromide,Cs2CO3Step A - Synthesis of Intermediate Compound IBA solution of starting material IA (5.0 g, 16.8 mmol) in ethanol (50 mL) and Pd/C (0.5 g, 10percent w/w) was hydrogenated at 1 atm for 15 hours at room temperature. (BOC)2O (4.0 g, 18.3 mmol) and triethylamine (2.6 mL, 18.6 mmol) were then added to the reaction mixture. The resulting solution was allowed to stir at room temperature for about 3 hours, then filtered through celite. The filtrate was concentrated in vacuo and the resulting residue was redissolved in CH2Cl2 and washed with water. The organic phase was collected, dried over Na2SO4 and concentrated in vacuo to provide IB as brown oil (4.0 g, 88percent). |
83% | With hydrogen; sodium hydrogencarbonate In ethanol; water at 20℃; for 48 h; | Preparation 46; 1 -ferf-Butyl-4-ethyl-3-oxopiperidine-1 ,4-dicarboxylate; To a solution of ethyl-i-benzyl-S-oxopiperidine^-carboxylate hydrochloride (51.3 g, 170 mmol) in ethanol (200 mL) and water (200 mL) was added di-fe/f-butyl dicarbonate (40.8 g, 187 mmol), sodium hydrogen carbonate (14.3 g, 170 mmol), palladium on carbon (18.1 g, 17.0 mmol) and the reaction mixture was hydrogenated at room temperature at 10 Bar for 48 h. The mixture was filtered through Arbocel.(R). and the filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, the aqueous phase was extracted with ethyl acetate and the combined organic solution was evaporated to give the title compound as a brown oil (44.1 g, 83percent). 1H NMR (300 MHz, CDCI3) δ 12.03 (s, 1 H), 4.22 (q, 2H), 4.05 (s, br, 2H), 3.49-3.50 (m, 2H), 2.35-2.36 (m, 2H), 1.46 (s, 9H), 1.30 (t, 3H); LC-MS (ESf): 270 [M-H]. |
72% | With hydrogen; triethylamine In ethanol for 10 h; | F. 3-Oxo-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (34a2) To ethyl-N-benzyl-3-oxo-4-piperidinecarboxylate hydrochloride (25 g, 95.7 mmol) in EtOH was added di-t-butyl-dicarbonate (22.7 g, 105.2 mmol), triethylamine (16 mL, 114.8 mmol) and Pd(OH)2 (1.34 g). The reaction mixture was hydrogenated under 60 psi hydrogen for 10 hours. The reaction mixture was filtered and concentrated under reduced pressure, then diluted with EtOAc and washed with water, brine and sodium sulfate to provide a yellow oil (19 g, 72percent) MS (ES-): m/z=270 (M-1) 1H NMR (400 MHz, CHLOROFORM-D) δ=1.26 (t, J=7.14 Hz, 3H) 1.41 (s, 9H) 2.23-2.32 (m, 2H) 3.06 (d, J=7.33 Hz, 2H) 3.44 (t, J=5.75 Hz, 2H) 3.98 (s, 1H) 4.19 (q, J=7.07 Hz, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With hydrogen; triethylamine In ethanol for 5 h; | Example 9: Synthesis of tert-butyl 3,7-diazabicyclo[4.2.0]octane-7-carboxylate ; The following procedures are adapted from those found in Frost et al., J. Med Chem. 49: 7843 (2006) for the synthesis of tert-butyl 3,8-diazabicyclo[4.2.0]octane-8-carboxylate. While the procedures support the synthesis of the single enantiomers (by separation of one of more of the various diastereomeric intermediates via either chromatography or fractional crystallization) of tert-butyl 3,7-diazabicyclo[4.2.0]octane-7-carboxylate, the procedures reported here are for the racemate.A mixture of commercially available ethyl N-benzyl-3-oxo-4-piperidinecarboxylate hydrochloride (100 g, 0.336 mol), di-tert-butyl dicarbonate (80 g, 0.37 mol), triethylamine (43.5 g, 0.43 mol), and palladium hydroxide on carbon (60 g, 20percent in H2O) in ethanol (1.5 L) was put under 60 psi of hydrogen gas and was shaken for 5 h. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to provide 1 -tert-butyl 3- ethyl 4-oxopiperidine-1, 3-dicarboxylate (85 g, 93percent yield), which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With sodium methylate In methanol at 25℃; for 20 h; Inert atmosphere | To a solution of sodium methoxide (25 wt-percent in methanol) (67.6 mL, 296 mmol) and methanol (70 mL) at 25 °C was added formamidine acetate (11.00 g, 106 mmol) and then ethyl N-benzyl-3-oxo-4-piperidine carboxylate hydrochloride (25.16 g, 84 mmol). The resulting mixture was stirred at 25 °C for 20 h. The mixture was cooled to 0 °C. Water (90mL) was added, followed by the dropwise addition of acetic acid (6.05 mL, 106 mmol), and the reaction mixture was stirred at 25 °C for another 3 h. The mixture was reduced in volume under vacuum until most of the methanol had been removed. The suspension was filtered. The solids were washed with water and thendried under vacuum to afford 7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (16.10 g, 79 percent) as an off-white solid; LC/MS:m/z 242.06 (M + H)+, 0.598 min (method 12). 1H-NMR (500 MHz, CDCl3) δ12.61 (br s, 1 H), 7.99 (s, 1 H), 7.38-7.26 (m, 5 H),3.73 (m, 2 H), 3.50 (m, 2 H), 2.74 (m, 2 H), 2.66 (m, 2 H). |
79% | Stage #1: With sodium methylate In methanol at 25℃; for 20 h; Stage #2: With acetic acid In methanol; water at 0 - 25℃; |
Preparation of 1 -(4-methoxy-7-(3 -methyl- IH-1 ,2,4-triazol- 1 -yl)- 1 H-pyrrolo[2,3 - c]pyridin-3-yl)-2-(4-(pyridin-2-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)- yl)ethane-l,2-dione, compound 18; [00126] Part A: To a solution of sodium methoxide (25 wgt-percent in methanol) (67.6 mL, 296 mmol) and methanol (70 mL) at 25 0C was added formamidine acetate (11.00 g, 106 mmol) and then ethyl N-benzyl-3-oxo-4-piperidine carboxylate hydrochloride (25.16 g, 84 mmol). The resulting mixture was stirred at 25 0C for 20 h. The mixture was cooled to 0 0C. Water (90 mL) was added, followed by the dropwise addition of acetic acid (6.05 mL, 106 mmol), and the reaction mixture was stirred at 25 0C for another 3 h. The mixture was reduced in volume under vacuum until most of the methanol had been removed. The suspension was filtered. The solids were washed with water and then dried under vacuum to afford 7-benzyl-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (16.10 g, 79 percent) as an off-white solid; Mass Spec: m/e: 242.06 (M+H)+ [calc'd: 242.12]; 1H NMR (500 MHz, CDCl3) I'12.61 (br s, 1 H), 7.99 (s, 1 H), 7.38-7.26 (m, 5 H), 3.73 (m, 2 H), 3.50 (m, 2 H), 2.74 (m, 2 H), 2.66 (m, 2 H). |
70% | Stage #1: With sodium methylate In methanol at 20℃; for 20 h; Stage #2: With acetic acid In methanol; water at 0 - 20℃; for 1 h; |
To a solution of sodium methoxide (1.67 g, 30.9 mmol) in anhydrous MeOH (10 mL) at room temperature was added formamidine acetate (1.15 g, 11 mmol) in one portion as solid followed by ethyl-1-benzyl-3-oxo-4-piperidine carboxylate hydrochloride (2.63 g, 8.83 mmol) in one portion. The reaction mixture was stirred at rt for 20 h. The reaction was cooled at 0° C., and water (6 mL) was added followed by acetic acid (0.63 mL, 11 mmol) and the mixture was stirred at rt for 1 h. The mixture was concentrated under vacuum to remove the methanol and then stirred at rt overnight. The resulting solid was collected by filtration and washed with water (5 mL.x.3) and dried on filter to afford the title compound a (1.50 g, 70percent) as an orange solid. LCMS [M+H]+ 242.16. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium methylate In methanol at 25℃; for 20 h; Inert atmosphere | General procedure: To a solution of sodium methoxide (25 wt-percent in methanol) (67.6 mL, 296 mmol) and methanol (70 mL) at 25 °C was added formamidine acetate (11.00 g, 106 mmol) and then ethyl N-benzyl-3-oxo-4-piperidine carboxylate hydrochloride (25.16 g, 84 mmol). The resulting mixture was stirred at 25 °C for 20 h. The mixture was cooled to 0 °C. Water (90mL) was added, followed by the dropwise addition of acetic acid (6.05 mL, 106 mmol), and the reaction mixture was stirred at 25 °C for another 3 h. The mixture was reduced in volume under vacuum until most of the methanol had been removed. The suspension was filtered. The solids were washed with water and thendried under vacuum to afford 7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (16.10 g, 79 percent) as an off-white solid; LC/MS:m/z 242.06 (M + H)+, 0.598 min (method 12). 1H-NMR (500 MHz, CDCl3) δ12.61 (br s, 1 H), 7.99 (s, 1 H), 7.38-7.26 (m, 5 H),3.73 (m, 2 H), 3.50 (m, 2 H), 2.74 (m, 2 H), 2.66 (m, 2 H). |
77% | With sodium ethanolate In ethanol for 16 h; Heating / reflux | Example 51Preparation of Compounds 211, 215, 216, 225, 226 and 231Compounds 211, 215, 216, 225, 226 and 231 were prepared using the method set forth below. <n="193"/>Step A - Synthesis of7-benzyl-2-methyl-5,6, 7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-oneTo a solution of l-benzyl-3-oxo-piperidine-4-carboxylic acid ethyl ester hydrochloride (5.0 g, 16.8 mmol) in 80 mL ethanol was added acetamidine hydrochloride (2.4 g, 25.2 mmol) followed by sodium ethoxide (21percent in ethanol, 10.6 mL, 33.6 mmol). The resulting reaction was heated to reflux and allowed to stir at this temperature for 16 hours. The reaction was then cooled to room temperature, diluted with dichloromethane, and the organic phase was washed with water and brine, dried and concentrated in vacuo, the resulting residue was purified using flash column chromatography (5percent methanol in dichloromethane) to provide 7-benzyl-2- methyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one in 77percent yield. |
95% | With sodium ethanolate In ethanol; water; acetic acid | Step A: 7-Benzyl-2-methyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one A solution of sodium ethoxide in ethanol was prepared by addition of sodium metal (5.7 g, 247 mmol) to absolute ethanol (141 mL). After the sodium metal had all dissolved, ethyl 1-benzyl-3-oxo-4-piperidine carboxylate hydrochloride (21 g, 70.5 mmol) was added followed by acetamidine hydrochloride (13.3 g, 141 mmol). This mixture was stirred at reflux for 1 h, cooled to room temperature, and concentrated. The residue was dissolved in a minimum amount of water and the pH was adjusted to about 7 with glacial acetic acid. The resulting yellow precipitate was filtered, washed with water (3*), air-dried for 2 h, then vacuum-dried overnight to provide 17.1 g (95percent) of the title compound of Example 86, Step A as a yellow solid. 1H NMR (CDCl3, 250 MHz) δ7.35-7.25 (c, 5H), 3.70 (s, 2H), 3.42 (s, 2H), 2.73-2.64 (c, 2H), 64-2.60 (c, 2H), 2.41 (s, 3H); MS (APCI) 256 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium methylate In ethanol for 17 h; Heating / reflux | Commercially available ethyl 1-benzyl-3-oxo-4-piperidinecarboxylate hydrochloride (25.0 g, 84.0 mmol) was dissolved in ethanol (350 mL), and the solution was mixed with urea (25.0 g, 416 mmol) and sodium methoxide (56.7 g), followed by a reaction under reflux for seventeen hours. After checking the completion of the reaction by thin layer chromatography, the reaction mixture was cooled to yield a suspension, and the pH of the suspension was adjusted to 6.0 by the addition of diluted hydrochloric acid (4 mol/L) . The mixture was stirred at room temperature for one hour, and the precipitated crystals were collected by filtration. The crystals were reslurried with ethanol, were collected by filtration, were dried under reduced pressure and thereby yielded 7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (17.2 g, in a yield of 80percent). |
58.3% | With sodium methylate In methanol for 18 h; Reflux; Inert atmosphere | To a solution of sodium methoxide (25 wt-percent in methanol) (90 mL, 392 mmol) and MeOH(50 mL) at room temperature was added urea (7.34 mL, 163 mmol) and then ethyl N-benzyl-3-oxo-4-piperidine-carboxylatehydrochloride (9.72 g, 32.6 mmol). The resulting mixture was stirred at reflux for 18h. After cooling to room temperature the mixture, which included a heavy precipitate, was diluted with ~300 mL of water. The resulting solution was filtered to remove a small quantity of brown solid. The filtrate was adjusted to pH 6 by the dropwise addition of ~40 g of conc. hydrochloric acid. The precipitate was recovered by fitration, washed with aqueous methanol, and dried under vacuum to provide7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (4.90 g, 19.04 mmol, 58.3 percent yield) as a beige powder. LC/MS: m/z 258.11 (M + H)+, 0.572 min (method 12). |
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