Structure of 5166-67-6
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CAS No. : | 5166-67-6 |
Formula : | C9H17NO2 |
M.W : | 171.24 |
SMILES Code : | O=C(C1CN(C)CCC1)OCC |
MDL No. : | MFCD00006496 |
InChI Key : | VFJJNMLPRDRTCO-UHFFFAOYSA-N |
Pubchem ID : | 97981 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H227-H315-H319-H335 |
Precautionary Statements: | P210-P261-P264-P271-P280-P302+P352-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P370+P378-P403+P233-P403+P235-P405-P501 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.89 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 51.36 |
TPSA ? Topological Polar Surface Area: Calculated from |
29.54 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.55 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.98 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.51 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.0 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.12 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.23 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.32 |
Solubility | 8.18 mg/ml ; 0.0477 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.19 |
Solubility | 11.1 mg/ml ; 0.0648 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.24 |
Solubility | 9.92 mg/ml ; 0.0579 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.65 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.2 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | The starting material was prepared as follows: (R)-Ethyl nipecotate (5.7 g 365 mmol), (prepared by resolution of ethyl nipecotate by treatment with L(+)-tartaric acid as described in J. Org. Chem. 1991, (56), 1168), was dissolved in 38.5% aqueous formaldehyde solution (45 ml) and formic acid (90 ml) and the mixture heated at reflux for 18 hours. The mixture was allowed to cool and added dropwise to cooled saturated aqueous sodium hydrogen carbonate solution. The mixture was adjusted to pH12 by addition of sodium hydroxide and the mixture was extracted with methylene chloride. The organic extract was washed with brine, dried (MgSO4) and the solvent removed by evaporation to give (R)-ethyl 1-methylpiperidine-3-carboxylate (4.51 g, 73%) as a colourless oil. MS-ESI: 172 [MH]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Preparation 12 Ethyl 1-methylpiperidine-3-carboxylate 3 g of ethyl piperidine-3-carboxylate, 4 ml of aqueous formaldehyde, 300 mg of 10% Pd/C and 4 ml of glacial acetic acid are placed under an atmosphere of hydrogen (1 atm.) at 20 C. for 17 hours. After filtering off the catalyst over Celite and washing with 50 ml of ethanol, the solution is evaporated under reduced pressure and yields an oily residue. The residue is diluted with a mixture of toluene/water (1/1) and the pH is adjusted to 9 by adding 20% K2CO3. After separation of the two phases, the aqueous phase is extracted twice with toluene. The organic phases are washed with water, dried over Na2SO4 and yield a lightly coloured oil. Distillation under reduced pressure yields 2.4 g of the expected product. Boiling point: 105-110 C. (P=20 mmHg) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With LiAlH4; In tetrahydrofuran; water; | EXAMPLE 9 Reduction of Ethyl 1-methylnipecotate To a cooled solution of filtered or unfiltered LiAlH4 (2 mole) under argon was added <strong>[5166-67-6]ethyl 1-methylnipecotate</strong> (1 mole) in THF. After addition was complete, reaction was heated to 40 to 50 C. for 2 hr and then stirred overnight at room temperature. The reaction was quenched by adding H2O, and aqueous NaOH using cooling as required. The solution was then filtered and solids were washed with fresh THF. Yields were determined by GC analysis of crude filtered reaction solutions using nonane as an internal standard. Essentially no difference in yields was observed with filtered or unfiltered LiAlH4 solutions. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sodium hydroxide; In tetrahydrofuran; water; | A solution of (R)-<strong>[5166-67-6]ethyl 1-methylpiperidine-3-carboxylate</strong> (5.69 g, 33 mmol) in ether (20 ml) was added dropwise to a stirred solution of lithium aluminum hydride (36.6 ml of a 1M solution in THF, 36.6 mmol) in ether (85 ml) cooled to maintain a reaction temperature of 20 C. The mixture was stirred for 1.5 hours at ambient temperature and then water (1.4 ml), 15% aqueous sodium hydroxide solution (1.4 ml) and then water (4.3 ml) were added. The insolubles were removed by filtration and the volatiles removed from the filtrate by evaporation to give (R)-(1-methylpiperidin-3-yl)methanol (4.02 g, 94%) as a colourless oil. 1H NMR Spectrum: (DMSOd6) 1.06(q, 1H); 1.51-1.94(m, 5H); 2.04(s, 3H); 2.34(br s. 1H); 2.62(m, 1H); 2.78(d, 1H); 3.49(m, 1H); 3.59(m. 1H); MS-ESI: 130 [MH]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12.1 g (74.4%) | With sodium hydroxide; lithium hexamethyldisilazane; In tetrahydrofuran; ethyl acetate; | Ethyl 1-methyl-3-(2'-fluorobenzyl-nipecotate To a solution of <strong>[5166-67-6]ethyl 1-methylnipecotate</strong> (10.0 g, 58.4 mmol) in dry tetrahydrofuran (350 ml) was added at -78 C. lithium bis(trimethylsilyl)amide (80.0 ml, 80.0 mmol) as a 1.0M solution in tetrahydrofuran and the resulting solution was allowed to stir at -78 C. for 3 hours. To this was added 2-fluorobenzylchloride (7.0 ml, 8.5 g, 59 mmol) and the resulting solution was allowed to warm to room temperature over 5 hours. Thin-layer chromatography showed reaction was not complete. More 2-fluorobenzylchloride (20 ml, 2.4 g, 17 mmol) was added to the reaction mixture and the resulting solution was allowed to stir overnight, ca. 18 hours. The tetrahydrofuran was removed by evaporation in vacuo and the orange residue was dissolved in ethyl acetate. The organic solution was extracted with 0.5N HCl (4*100 ml) and the aqueous acid extracts were combined and made basic with 10N NaOH. The aqueous was then extracted with ethyl acetate (5*100 ml) and the combined extracts were dried over MgSO4 and concentrated to yield 12.1 g (74.4%) of ethyl 1-methyl-3-(2'-fluoro)-benzyl-nipecotate as an orange oil. 1 H-NMR (CDCl3) delta: 7.22-7.15 (m, 1H), 7.10-6.95 (m, 3H), 4.14-4.05 (m, 2H), 3.01 (bd, 1H, J=10.3 Hz), 2.87 (s, 2H), 2.58 (bd, 1H, J=10.3 Hz), 2.24 (s, 3H), 2.04-1.95 (m, 3H), 1.69-1.60 (m, 2H), 1.30-1.22 (m, 1H), 1.16 (t, 3H, J=7.1 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetone; at 20℃; | N-Methyl-ethyl nipecotate (85):Ethyl nipecotate (5.0 g, 0.032 mol) was dissolved in acetone (50 niL). Methyl iodide (3 mL, 0.048 mol) was added dropwise over 1 hour and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated to remove acetone and partitioned between saturated sodium bicarbonate (50 mL) and ethyl acetate (1 x 5OmL). The aqueous layer was extracted with an additional 2 x 50 mL ethyl acetate. The combined organics were washed with 2 x 50 mL water, 1 x 50 mL saturated sodium chloride, and dried over Na2SO4. The dried organics were evaporated to 1.43 g of oil. The material was used without further purification. MS (ESI) m/z 172 [M+H]+. | |
Example 19: Synthesis of 3-Methyl-5-(l-methylpiperidin-3-yl)-l,2,4-oxadiazole; [00322] N-Methyl-ethyl nipecotate (4c):Ethyl nipecotate (5.0 g, 0.032 mol) was dissolved in acetone (50 mL). Methyl iodide (3 mL, 0.048 mol) was added dropwise over 1 hour and the mixture was stirred at roomtemperature for 1 hour. The mixture was concentrated to remove acetone and partitioned between saturated sodium bicarbonate (50 mL) and ethyl acetate (1 x 50mL). The aqueous layer was extracted with an additional 2 x 50 mL ethyl acetate. The combined organics were washed with 2 x 50 mL water, 1 x 50 mL saturated sodium chloride, and dried over a2S04. The dried organics were evaporated to an oil to obtain 1.43 g. The material was used without further purification. MS (ESI) m/z 172 [M+H]+. | ||
In acetone; at 20℃; for 2h; | Ethyl nipecoiate (5.0 g, 0.032 mol) was dissolved in acetone (50 mL). Methyl iodide (3 rnL, 0.048 mol) was added dropwise over 1 hour and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated to remove acetone and partitioned between saturated sodium bicarbonate (50 mL) and ethyl acetate (I x SOmL). The aqueous layer was extracted with an additional 2 * 50 mL ethyl acetate. The combined organics were washed with 2 x 50 mL water, 1 chi SO mL saturated sodium chloride,were evaporated to an oil to obtain 1.43 g. The material was used without further purification. MS (ESi) m/z 172 [M+H]-h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium methylate; In tetrahydrofuran; for 2h;Reflux; | 3-Methyl-5-(l-methylpiperidin-3-yl)-l,2,4-oxadiazole (86):N-methyl-ethyl nipecotate (85) (0.7 g, 0.0041 mol) and acetamide oxime (0.75g, 0.0102 mol) were dissolved in 30 mL tetrahydrofuran. Sodium methoxide (1.Ig9 0.0205 mol) was added and the mixture was heated at reflux for 2 hours. The mixture was concentrated to remove THF and partitioned between water (25 mL) and dichloromethane (1 x 25 mL). The aqueous layer was extracted with an additional 2 x 25 mL dichloromethane. The combined organics were washed with 1 x 50 mL saturated sodium chloride, and dried over Na2SO4. The dried organics were evaporated to an oil. The residue was chromatographed with 5 g silica gel, 5% methanol/ethyl acetate, to obtain 0.51 g of the free base. Hydrochloric acid in ethanol (2.5 M) (1.6 mL, 0.011 mol) was added and the mixture was concentrated to dryness. Crystallization from ethanol/MTBE afforded 436 mg of 86 as white solid. MS (ESI) m/z 182 [M+H]+. 1H NMR (DMSO-d6) delta 1.59-1.66 (m, 1 H), 1.88-1.98 (s, 2 H), 2.17-2.20 (d, IH), 2.34 (s, 3 H), 2.77 (s, 3 H), 2.92-2.95 (m, 1 H), 3.18-3.21 (m, 1 H), 3.37-3.47, (d, IH), 3.60- 3.78, (m, 2H). | |
With sodium methylate; In tetrahydrofuran; for 2h;Reflux; | 3-Methyl-5-(l -methylpiperidin-3-yl)-l ,2,4-oxadiazole (5c):I-N-methyl-ethyl nipecotate (4c) (0.7 g, 0.0041 mol) and acetamide oxime (0.75g, 0.0102 mol) were dissolved in 30 mL tetrahydrofuran. Sodium methoxide (l . l g, 0.0205 mol) was added and the mixture was heated at reflux for 2 hours. The mixture was concentrated to remove THF and partitioned between water (25 mL) and dichloromethane (1 x 25 mL). The aqueous layer was extracted with an additional 2 x 25 mL dichloromethane. The combined organics were washed with 1 chi 50 mL saturated sodium chloride, and dried over Na2SC>4. The dried organics were evaporated to an oil. The residue was chromatographed with 5 g silica gel, 5% methanol/ethyl acetate, to obtain 0.51 g of the free base. Hydrochloric acid in ethanol (2.5 M) (1.6 mL, 0.01 1 mol) was added and the mixture was concentrated to dryness. Crystallization from ethanol/MTBE afforded 436 mg white solid. MS (ESI) m/z 182 [M+H]+. NMR (DMSO-d6) 5 1.59- 1.66 (m, 1 H), 1.88- 1.98 (s, 2 H), 2.17-2.20 (d, 1 H), 2.34 (s, 3 H), 2.77 (s, 3 H), 2.92-2.95 (m, 1 H), 3.18-3.21 (m, 1 H), 3.37- 3.47, (d, 1H), 3.60-3.78, (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
S -N-Boe -ethyl nlpeeotate (.) (0,7 g, 0.0041 mol) and aceiamide oxirne (0.75g, 0.0102 mol) were. dissolved in 30 mL teirahydrofuran. Sodium methoxide (l.lg, 0.0205 mol) was added and. the mixture was heated at reflux for 2 hours. The mixture was concentrated to remove THF and partitioned between water (25 mL) and dichloromethane ( I x 25 mL). The aqueous layer was extracted with an additional 2 x 25 mL dichioromethane. The combined organics were washed with I< 50 mL saturated, sodium chloride, and dried over Nag&O . The dried organics were evaporated to an oil. The residue was chromatogra;phed with 5 g silica gel, 5% raethano./ethyl acetate, to obtain 0.51 g of the tree base. Hydrochloric acid in ethanol (2.5 M) (1.6 mL, 0.01 1 mol) was added and the mixture was concentrated to dryness. Crystallization fromethanol/ 'IBE fforded 436 mg white solid. MB (ESI) mlz 182 [ +B]. hi NM (DMSO-46) 5 1.59-1.66 (m, I H), 1.8.8.- 1.98 (s, 2 H), 2.17-2.20 (d, 1H), 234 (s, 3 H), 2.77 (s, 3 H), 2.92- 2.95 (m, 1 H), 3.18-3.21 (m, 1 H% 337-3.47, (d, 1H), 3.60-3.78, (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With sodium hydride; In tetrahydrofuran; mineral oil;Inert atmosphere; Schlenk technique; Molecular sieve; Reflux; | General procedure: 1-(2-Oxopyrrolidin-1-yl)acetamidoxime (2.40 equiv) was stirred in dry THF with 4A MS for 1 h, and NaH (60% inoil, 3.0 equiv) was added and stirred for 50 mins and then heated at 50 C for 30 min. A solution of an ester 5a~f (1.0 equiv) in THF was added dropwise and the reaction mixture was heated under reflux for 1.5 h. After cooling, solvent was removed from the reaction mixture and the residue was extracted with CH2Cl2. The organic extract was concentrated in vacuo, and the residue was purified by column chromatography on silica gel using chloroform/methanol (30:1~10:1) as eluent to obtain the corresponding compound 6a~f. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With platinum on carbon; hydrogen; toluene-4-sulfonic acid; at 120℃; under 30003.0 Torr; for 0.2h;Inert atmosphere; Autoclave; | General procedure: An autoclave was filled with catalyst (1 mol% based on the molar amount of amine), flushed with argon and topped up with a solution of amine (0.1 mol) and orthocarboxylic acid ester (0.11-0.3mol) in 10 ml of methanol (or ethanol) and 0.5 ml of a 0.2 M solution of anhydrous ptoluenesulphonic acid in methanol (or ethanol). The mixture was heated to 120C and hydrogen was injected to 40 bar and then the mixture was stirred at a constant pressure until hydrogen absorption could no longer be detected (0.2 - 6 h). After being filtered off from the catalyst, the filtrate was distilled. |
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