6296-99-7|Diethyl 2-(aminomethylene)malonate| Ambeed

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Quality Control of [ 6296-99-7 ] Purity: 97% SDS Specification

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Product Details of [ 6296-99-7 ]

CAS No. :	6296-99-7
Formula :	C₈H₁₃NO₄
M.W :	187.19
SMILES Code :	C(OC(C(C(OCC)=O)=CN)=O)C
MDL No. :	MFCD01075695
Boiling Point :	No data available
InChI Key :	WDTWMEZMHUEZKH-UHFFFAOYSA-N
Pubchem ID :	226751

Safety of [ 6296-99-7 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 6296-99-7 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	0
Fraction Csp3	0.5
Num. rotatable bonds	6
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	45.37
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	78.62 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.92
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	1.02
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	-0.04
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.	0.01
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	0.08
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.6

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.25
Solubility	10.6 mg/ml ; 0.0566 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.26
Solubility	1.03 mg/ml ; 0.00549 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	-0.57
Solubility	49.8 mg/ml ; 0.266 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	No
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.	-6.72 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	1.0
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	4.0 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<1.0
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)	2.2

Application In Synthesis of [ 6296-99-7 ]

* 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 [ 6296-99-7 ]

[ 6296-99-7 ] Synthesis Path-Downstream 1~35

1
[ 590-28-3 ]
[ 6296-99-7 ]
(carbamoylimino-methyl)-malonic acid diethyl ester [ No CAS ]

References: [1]Journal of the Chemical Society,1907,vol. 91,p. 1364.

2
[ 6296-99-7 ]
[ 1007476-32-5 ]
[ 19872-98-1 ]

References: [1]Chemische Berichte,1941,vol. 74,p. 1111,1114.

3
[ 6296-99-7 ]
[ 7251-53-8 ]

References: [1]Chemische Berichte,1894,vol. 27,p. 2744.

4
[ 6296-99-7 ]
formyl-malonic acid ; barium salt [ No CAS ]

References: [1]Journal of the Chemical Society,1891,vol. 59,p. 748.

5
[ 6296-99-7 ]
[ 609-08-5 ]

References: [1]Journal of the American Chemical Society,1948,vol. 70,p. 3121.

6
[ 98895-14-8 ]
[ 6296-99-7 ]

References: [1]Justus Liebigs Annalen der Chemie,1952,vol. 578,p. 48.

7
[ 6296-99-7 ]
[ 141-97-9 ]
[ 858430-60-1 ]

References: [1]Chemische Berichte,1941,vol. 74,p. 1111,1114.

8
[ 6296-99-7 ]
[ 103-71-9 ]
diethyl 2-((3-phenylureido)methylene)malonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 70℃;	Step 1: Diethyl 2-((3-phenylureido)methylene)malonate To a mixture of diethyl (aminomethylene)malonate (6.0 g, 32 mmol) and phenyl isocyanate (3.8 mL, 35 mmol) in 1,2-dichloroethane (20 mL) at rt was added N,N-diisopropylethylamine (7.2 mL, 42 mmol). The reaction mixture was then stirred at 70 C. overnight, cooled to rt, added Et2O (50 mL), and stirred for another 30 min. The resulting solid was collected by filtration, washed with ether, and dried to give the product as a white solid (4.88 g, 50%). LCMS calcd for C15H19N2O5 (M+H)+: m/z=307.1. Found: 307.2.
50%	With N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 70℃;	To a mixuture of diethyl (aminomethylene)malonate (6.0 g, 32 mmol) and phenyl isocyanate (3.8 mL, 35 mmol) in 1,2-dichloroethane (20 mL) at rt was added N,N- diisopropylethylamine (7.2 mL, 42 mmol). The reaction mixture was then stirred at 70 C overnight, cooled to rt, added Et^O (50 mL), and stirred for another 30 min. The resulting solid was collected by filtration, washed with ether, and dried to give the product as a white solid (4.88 g, 50%). LCMS calcd for C15H19N2O5 (M+H)+: m/z = 307.1. Found: 307.2.
44.5%	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 100℃; for 18.0h;	To a 40 mL vial containing diethyl 2-(aminomethylene)malonate (400 rng, 2.14 mmol), DIPEA (411 uL, 2.35 mmol) in dioxane (0.6 mL) was added isocyanatobenzene (244 uL, 2.24 mmol). The reaction was heated to 100C for 18 hours then cooled to room temperature. The precipitate that formed was collected by filtration with small dioxane and hexane rinses and dried under vacuum to give the title compound (294 mg, 44.5%) as a white solid. Ti NMR (500 MHz, DMSO-de) d 10.76 - 10.50 (m, 1H), 10.48 - 10.25 (m, 1H), 8.48 (br s, 1H), 7.59 - 7.45 (m, 2H), 7.39 - 7.25 (m, 2H), 7.16 - 7.02 (m, 1H), 4.25 (q,.7=7.0 Hz, 2H), 4.16 (q,.7=7.0 Hz, 2H), 1.31 - 1.22 (ra, 6H); LCMS (M+H) = 307; HPLC RT = 2.298 min (Column: Chromolith ODS S5 4.6 x 50 mm; Mobile Phase A: 10:90 MeOH: ater with 0.1% TFA; Mobile Phase B: 90: 10 MeOH: water with 0.1% TFA; Temperature: 40 C; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

With N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 100℃; for 6.0h;

l-Ethyl-2,4-dioxo-3-phenyl-l,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid [4-(6,7- dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. To a solution of 2- aminomethylene-malonic acid diethyl ester (0.75 g, 4.0 mmol) and phenyl isocyanate (0.57 g, 4.4 mmol) in 1 ,2-dichloroethane (20 mL) was added N,N-diisopropylethylamine (0.77 mL, 4.4 mmol) and heated at 100 C 6 h. The mixture was cooled and filtered. The solids were purified by column chromatography with 0-5% MeOH in methylene chloride. This intermediate urea was suspended in ethanol (10 mL) and 21% NaOEt in ethanol (1.29 mL, 4.0 mmol ) was added. After 18 h the solvent was removed under vacuum and the residue was slurred in ethyl acetate. The organics were washed with 1M citric acid solution, water and brine. The solvent was removed under vacuum and the residue was purified by chromatography with 0-5% MeOH in dichloromethane to give 0.50 g (40%). The ester was alkylated and hydro lyzed using methods for example 92 to give l-ethyl-2,4- dioxo-3-phenyl-l,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid. 1H NMR (DMSO) ?: 12.65 (bs, 1H), 8.82 (s, 1H), 7.54-7.43 (m, 3H), 7.32-7.29 (m, 2H), 4.02 (q, 2H, J = 7.1 Hz), 1.26 (t, 3H, J = 7.1 Hz).

References: [1]Patent: US2017/275290,2017,A1 .Location in patent: Paragraph 1003; 1004.
[2]Patent: WO2019/67594,2019,A1 .Location in patent: Page/Page column 62.
[3]Patent: WO2019/213340,2019,A1 .Location in patent: Page/Page column 83.
[4]Journal of the American Chemical Society,1934,vol. 56,p. 2754.
[5]Patent: WO2013/74633,2013,A1 .Location in patent: Page/Page column 96-97.

9
[ 1117-96-0 ]
[ 54535-09-0 ]
[ 6296-99-7 ]

References: [1]Gazzetta Chimica Italiana,1974,vol. 104,p. 715 - 729.

10
[ 947-91-1 ]
[ 6296-99-7 ]
[ 28952-52-5 ]

References: [1]Archiv der Pharmazie und Berichte der Deutschen Pharmazeutischen Gesellschaft,1970,vol. 303,p. 612 - 617.

11
[ 20082-91-1 ]
[ 6296-99-7 ]
[ 58780-94-2 ]