51814-19-8|1-Benzyl 3-ethyl 4-oxopyrrolidine-1,3-dicarboxylate| Ambeed

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Quality Control of [ 51814-19-8 ] Purity: 95% SDS Specification

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Product Details of [ 51814-19-8 ]

CAS No. :	51814-19-8
Formula :	C₁₅H₁₇NO₅
M.W :	291.30
SMILES Code :	O=C(N1CC(C(OCC)=O)C(C1)=O)OCC2=CC=CC=C2
MDL No. :	MFCD09878816
InChI Key :	FRNZCPLVDNHRIH-UHFFFAOYSA-N
Pubchem ID :	15043278

Safety of [ 51814-19-8 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 51814-19-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	21
Num. arom. heavy atoms	6
Fraction Csp3	0.4
Num. rotatable bonds	7
Num. H-bond acceptors	5.0
Num. H-bond donors	0.0
Molar Refractivity	77.72
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	72.91 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.34
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.66
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.85
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.93
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	1.63
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.48

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.44
Solubility	1.05 mg/ml ; 0.00362 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.8
Solubility	0.457 mg/ml ; 0.00157 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-3.07
Solubility	0.249 mg/ml ; 0.000853 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

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	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	Yes
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.9 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	2.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<0.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	3.06

Application In Synthesis of [ 51814-19-8 ]

* 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 [ 51814-19-8 ]

[ 51814-19-8 ] Synthesis Path-Downstream 1~35

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[ 51814-19-8 ]
[ 851912-97-5 ]

References: [1]Journal of the Chemical Society. Chemical communications,1992,p. 1767 - 1769.

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[ 51814-19-8 ]

Yield	Reaction Conditions	Operation in experiment
	With citric acid; In ethyl acetate; toluene;	REFERENCE EXAMPLE 1 1-Benzyloxycarbonyl-4-ethoxycarbonyl-3-oxopyrrolidine Ethyl acrylate (65.01 ml, 600.0 mmol) was added to a toluene (1,200 ml) solution containing N-benzyloxycarbonylglycine ethyl ester (156.3 g, 600.0 mmol) and then, under ice-cooling, sodium hydride (60% oil; 26.40 g, 660.0 mmol) was added thereto. After 10 minutes of stirring at the same temperature, the ice bath was taken off, and the mixture was stirred at room temperature for 20 minutes and then at 50 C. for 3 hours. After completion of the reaction, and under ice-cooling, the reaction solution was adjusted to about pH 3 by adding 10% citric acid aqueous solution and mixed with ethyl acetate, and the mixture was shaken and then subjected to separation of layers. The organic layer was separated and washed with saturated brine, and the water layer was further extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and then filtered, and the solvent was evaporated under a reduced pressure to obtain 196.7 g (600.0 mmol, quantitative) of the title compound. 1H-NMR (400 MHz, CDCl3) delta (ppm): 1.22-1.32 (3 H, m), 3.93-4.05 (1 H, m), 4.05-4.31 (5 H, m), 5.13-5.23 (2 H, m), 7.28-7.40 (5 H, m).

References: [1]Journal of the Chemical Society. Chemical communications,1992,p. 1767 - 1769.
[2]Patent: US6423843,2002,B1 .

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Yield	Reaction Conditions	Operation in experiment
72%		Reference Example 63 Ethyl 1-benzyloxycarbonyl-4-oxopyrrolidine-3-carboxylate To a solution of ethyl 3-[N-benzyloxycarbonyl-N-(ethoxycarbonyl methyl)amino]ethylpropionate (26.8 g, 79.5 mmol) in ethanol (200 mL), sodium ethoxide (20% solution in ethanol, 40.6 mL, 119.3 mmol) was added, and the mixture was heated under reflux for 2 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in water (100 mL). Concentrated hydrochloric acid was added to this solution in an ice bath for acidification, and the solution was extracted with chloroform (100 mL*3). The extract was washed with saturated aqueous solution of sodium chloride (100 mL), and dried with anhydrous sodium sulfate. After the filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate, 2:1) to obtain 16.7 g (72%) of the title compound as a pale brown oily product. 1H-NMR (400 MHz, CDCl3)delta ppm: 1.25-1.33 (3H, m), 3.87-4.37 (7H, m), 5.16-5.22 (2H, m), 7.23-7.41 (5H, m). MS (ESI) m/z: 314 (M+Na)+.
	With sodium ethanolate; In tetrahydrofuran; at 25 - 32℃; for 2h;	[Reference Example 3] Synthesis of 1-benzyl 3-ethyl 4-oxopyrrolidine-1,3-dicarboxylate [Show Image]; 0.35 kg of sodium ethoxide (5.15 mol) was suspended in 9.47 L of tetrahydrofuran. While this suspension was stirred, 3.16 L of a tetrahydrofuran solution containing 1. 64 kg of the crude product of ethyl 3-benzyloxycarbonyl-3-(ethoxycarbonylmethylamino)propionate (equivalent to 4.68 mol) was added dropwise at an internal temperature of 25 to 32C. The mixture was then stirred at an internal temperature of 25 to 32C for 2 hours. While the reaction mixture was stirred, 5.15 L of 1 mol/L hydrochloric acid (pH 4.78) was added at an internal temperature of 27 to 28C and the mixture was stirred for 10 minutes (pH changed from 4.78 to 4.76). Subsequently, tetrahydrofuran (approx. 12 L) was evaporated under reduced pressure. To the resulting residue, 7.89 L of ethyl acetate was added and the mixture was stirred for 5 minutes. The reaction mixture was then allowed to stand and the organic layer (top layer) was collected. To this layer, 3.95 L of water was added and the mixture was stirred for 5 minutes. The mixture was allowed to stand again and the organic layer (top layer) was collected. To this layer, 3.95 L of 28% brine was added and the mixture was stirred for 5 minutes. The mixture was allowed to stand again and the organic layer (top layer) was collected. To this layer, 0.39 kg of anhydrous sodium sulfate was added and the mixture was stirred for 1 hour. The resulting solid was separated by filtration and washed with 1.58 L of ethyl acetate. The filtrate and the wash were combined and concentrated under reduced pressure. This product was then dried under reduced pressure at an external temperature of 40C for 30 minutes. The resulting pale brown oil (1.52 kg) was dissolved in 9.47 L of diisopropyl ether and the solution was stirred at an internal temperature of 25C. Once the formation of crystals was observed (internal temperature of 25C), the solution was further stirred for 15 minutes at an internal temperature of 25 to 28C. Subsequently, the solution was cooled in an ice bath under stirring and was kept stirred for 30 minutes at an internal temperature of 10C or below. The crystals were then collected by filtration at an internal temperature of 7 C and washed with a chilled, 4: mixtures of diisopropyl ether/hexane (3.95 L, internal temperature of 3C). The washed crystals were drained for 15 minutes and air-dried overnight. Subsequently, the product was dried under reduced pressure at 40C for 9 hours. This gave 1.03 kg of the title compound as a faintly yellowish white powder (75% yield in the two steps). Melting Point: 56.6-59.7C EI-MS : m/z 91 (base peak), 291 (M)+
	With sodium methylate; In toluene; at -5 - 25℃;	5 ~ 10 780ml toluene was added to 3000ml reaction flask, was added 36.2g sodium methoxide,After stirring for 5 minutes, the temperature was lowered to -5 to 0 C, a solution of 480 ml of a toluene solution of the compound represented by the formula 4-1 was added dropwise,After the dropwise temperature was raised to 20-25 C and stirred for 2-3 hours, TLC (thin layer chromatography) showed that the reaction was completed and added,Add water 400ml, concentrated hydrochloric acid was added dropwise at 20 ~ 25 , adjusted pH3-4, stirred for 30 minutes, the pH was measured in the 3-4;The organic layer was separated, concentrated under reduced pressure at 60-65 C, concentrated and dried, then added with anhydrous ethanol l60-65 C with toluene,With two, each 120ml, evaporated to give after the oil that compound of Formula 3, the reaction is as follows

References: [1]Patent: US2006/264428,2006,A1 .Location in patent: Page/Page column 47-48.
[2]Patent: WO2006/123792,2006,A1 .Location in patent: Page/Page column 109-110.
[3]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 1273 - 1277.
[4]Patent: EP1992613,2008,A1 .Location in patent: Page/Page column 12.
[5]Archiv der Pharmazie,2008,vol. 341,p. 780 - 786.
[6]Patent: CN103922987,2016,B .Location in patent: Paragraph 0047-0049.

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[ 51814-19-8 ]
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[ 309762-63-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	With potassium carbonate; In acetone; at 45℃; for 1h;	Reference Example 64 Ethyl 1-benzyloxycarbonyl-3-methyl-4-oxopyrrolidine-3-carboxylate To a solution of <strong>[51814-19-8]ethyl 1-benzyloxycarbonyl-4-oxopyrrolidine-3-carboxylate</strong> (1.0 g, 3.4 mmol) in acetone (30 mL), potassium carbonate (0.95 g, 6.9 mmol) and methyl iodide (1 mL) were added, and the mixture was stirred at 45 C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and water (20 mL) was added to the concentrate. The mixture was extracted with ethyl acetate (20 mL*3). The extract was washed with 10% aqueous solution of sodium thiosulfate (20 mL) and saturated aqueous solution of sodium chloride (20 mL) in this order, and dried with anhydrous sodium sulfate. After the filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate, 4:1) to obtain 1.0 g (95%) of the title compound as a pale yellow oily product. 1H-NMR (400 MHz, CDCl3)delta ppm: 1.21 (3H, t, J=7.1 Hz), 1.55 (3H, s), 3.53 (1H, d, J=11.7 Hz), 3.88 (1H, d, J=19.3 Hz), 4.07-4.20 (3H, m), 4.37 (1H, d, J=12.0 Hz), 5.19 (2H, s), 7.30-7.40 (5H, m). MS (ESI) m/z: 306 (M+H)+, 328 (M+Na)+.
80.7%	With potassium carbonate; In acetone; for 3h;Reflux;	To the solution of <strong>[51814-19-8]N-benzyloxycarbonyl-4-ethoxycarbonylpyrrolidin-3-one</strong> (291 g) in acetone (1.5 l) was added potassium carbonate (200 g), followed by iodomethane (300 mL), and then the solution was refluxed for 3 hr. The reaction mixture was cooled at room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane=1:6) to obtain the desired compound (237.7 g, 80.7%). [00081] 1H-NMR(CDCl3, ppm) 1.16 (3H, t, J=7.1 Hz), 1.36 (3H, s), 3.49 (1H, d, J=12.0 Hz), 3.83 (1H, d, J=19.3 Hz), 4.00-4.17 (3H, m), 4.35 (1H, d, J=11.7 Hz), 5.16 (2H, s), 7.19-7.33 (5H, m).

References: [1]Patent: US2006/264428,2006,A1 .Location in patent: Page/Page column 48.
[2]Patent: WO2006/123792,2006,A1 .Location in patent: Page/Page column 110-111.
[3]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 1273 - 1277.
[4]Patent: US6649763,2003,B1 .Location in patent: Page/Page column 13.

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[ 309762-65-0 ]