[ CAS No. 6296-99-7 ] {[proInfo.proName]}

Name: 6296-99-7|Diethyl 2-(aminomethylene)malonate|97%
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SKU: A171102
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2D 3D

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Quality Control of [ 6296-99-7 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 6296-99-7 ]

SDS Specification

Alternatived Products of [ 6296-99-7 ]

Product Details of [ 6296-99-7 ]

CAS No. :	6296-99-7	MDL No. :	MFCD01075695
Formula :	C₈H₁₃NO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WDTWMEZMHUEZKH-UHFFFAOYSA-N
M.W :	187.19	Pubchem ID :	226751
Synonyms :

Calculated chemistry of [ 6296-99-7 ]

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 :	78.62 Å²

Pharmacokinetics

GI absorption :	High
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) :	-6.72 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.92
Log Po/w (XLOGP3) :	1.02
Log Po/w (WLOGP) :	-0.04
Log Po/w (MLOGP) :	0.01
Log Po/w (SILICOS-IT) :	0.08
Consensus Log Po/w :	0.6

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.25
Solubility :	10.6 mg/ml ; 0.0566 mol/l
Class :	Very soluble
Log S (Ali) :	-2.26
Solubility :	1.03 mg/ml ; 0.00549 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-0.57
Solubility :	49.8 mg/ml ; 0.266 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	4.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.2

Safety of [ 6296-99-7 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

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.

Upstream synthesis route of [ 6296-99-7 ]
Downstream synthetic route of [ 6296-99-7 ]

[ 6296-99-7 ] Synthesis Path-Upstream 1~11

1
[ 6296-99-7 ]
[ 7251-53-8 ]

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

2
[ 87-13-8 ]
[ 6296-99-7 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 13, p. 3441 - 3444
[2] Journal of the American Chemical Society, 1961, vol. 83, p. 4225 - 4228
[3] Gazzetta Chimica Italiana, 1974, vol. 104, p. 715 - 729
[4] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1981, p. 561 - 570
[5] Australian Journal of Chemistry, 1992, vol. 45, # 10, p. 1571 - 1576
[6] Patent: WO2009/21957, 2009, A2, . Location in patent: Page/Page column 19
[7] Journal of Agricultural and Food Chemistry, 2007, vol. 55, # 3, p. 608 - 613
[8] Patent: US6333336, 2001, B1,

3
[ 28783-55-3 ]
[ 6296-99-7 ]

Reference： [1] Australian Journal of Chemistry, 1992, vol. 45, # 10, p. 1571 - 1576

4
[ 131776-39-1 ]
[ 6296-99-7 ]

Reference： [1] Patent: EP376870, 1990, A1,

5
[ 17758-33-7 ]
[ 105-53-3 ]
[ 6296-99-7 ]

Reference： [1] Synlett, 2004, # 4, p. 703 - 707

6
[ 54535-14-7 ]
[ 6296-99-7 ]

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

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

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

8
[ 76369-62-5 ]
[ 87-13-8 ]
[ 6296-99-7 ]

Reference： [1] Australian Journal of Chemistry, 2004, vol. 57, # 7, p. 685 - 688

9
[ 105-53-3 ]
[ 6296-99-7 ]

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

10
[ 1117-96-0 ]
[ 54535-09-0 ]
[ 6296-99-7 ]

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

11
[ 87-13-8 ]
[ 6296-99-7 ]

Reference： [1] Justus Liebigs Annalen der Chemie, 1897, vol. 297, p. 77

[ 6296-99-7 ] Synthesis Path-Downstream 1~88

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

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

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

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

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

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

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

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

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

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

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

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

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

Reference： [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).

Reference： [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
[ 6296-99-7 ]
[ 108-94-1 ]
[ 58780-88-4 ]

Yield	Reaction Conditions	Operation in experiment
	With toluene-4-sulfonic acid; In toluene; at 127℃; for 48.0h;	To a solution of cyclohexanone (4.6 ml, 44.3 mmol) in toluene (170 ml) is added 2- aminomethylene-malonic acid diethyl ester (8.3 g, 44.3 mmol) and p-toluenesulfonic acid (305 mg, 1.77 mmol). The reaction mixture is heated to 127°C for 48h in a Dean-Stark trap to remove water. The crude mixture is concentrated in vacuo and purified by MPLC (500 g silica gel, eluent cyclohexane:EtOAc 80:20 to 70:30) to give 2-(cyclohex-1 - enylaminomethylene)-malonic acid diethyl ester.

Reference： [1]Journal of Heterocyclic Chemistry,1975,vol. 12,p. 1245 - 1254
[2]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3441 - 3444
[3]Patent: WO2009/21957,2009,A2 .Location in patent: Page/Page column 19
[4]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2538 - 2541

10
[ 6296-99-7 ]
[ 141-97-9 ]
[ 58780-91-9 ]

Reference： [1]Journal of Heterocyclic Chemistry,1975,vol. 12,p. 1245 - 1254

11
[ 6296-99-7 ]
[ 583-60-8 ]
[ 58780-96-4 ]

Reference： [1]Journal of Heterocyclic Chemistry,1975,vol. 12,p. 1245 - 1254

12
[ 6296-99-7 ]
[ 120-92-3 ]
[ 58780-87-3 ]

Reference： [1]Journal of Heterocyclic Chemistry,1975,vol. 12,p. 1245 - 1254
[2]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3441 - 3444
[3]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2538 - 2541

13
[ 6296-99-7 ]
[ 120-92-3 ]
[ 58780-95-3 ]

Reference： [1]Journal of Heterocyclic Chemistry,1975,vol. 12,p. 1245 - 1254

14
[ 6296-99-7 ]
[ 123-54-6 ]
[ 58780-90-8 ]

Reference： [1]Journal of Heterocyclic Chemistry,1975,vol. 12,p. 1245 - 1254

15
[ 87-13-8 ]
[ 6296-99-7 ]

Yield	Reaction Conditions	Operation in experiment
96%	With ammonia; In ethanol; at 20℃; for 1.0h;	Ammonia was passed through ethanol (200 mL) for 30 minutes. Diethyl 2- (ethoxymethylene) malonate (21.6 g, 0.1 mol, 1.0 eq) was dissolved in an ammonia / ethanol solution and reacted at room temperature for 1 hour. After the reaction was detected by LC-MS and TLC, the reaction was concentrated. The crude product was purified by silica gel column chromatography (100-200 mesh silica gel, PE / EA = 5: 1) to obtain a white solid (18 g, yield: 96%)
	With ammonia; In ethanol; at 20℃; for 1.0h;	2-Ethoxymethylene-malonic acid diethyl ester (20 ml, 100 mmol) and a 10% soln. of ammonia in EtOH (37 ml, 220 mmol) are stirred at rt for 1 h. The mixture is evaporated and dried in HV to give 2-aminomethylene-malonic acid diethyl ester that is used without further purification.
	With ammonia; In ethanol;	a Diethyl aminomethylenemalonate To diethyl ethoxymethylenemalonate (50.13 g, 0.232 mmol), cooled to -20 C. under nitrogen, was added a 2.0 M solution of ammonia in ethanol (232 ml, 0.464 mmol) and the resulting solution was stirred at room temperature overnight. The solution was then evaporated in vacuo to give a quantitative yield of the title compound as a cream solid; 1H NMR (360 MHz, CDCl3) 5 1.28 (3H, t, J 7.1 Hz), 1.35 (3H, t, J 7.1 Hz), 4.19 (2H, q, J 7.1 Hz), 4.26 (2H, q, J 7.1 Hz), 5.68 (1H, br s), 8.11 (1H, dd), 8.69 (1H, br s).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3441 - 3444
[2]Patent: CN110041316,2019,A .Location in patent: Paragraph 0654; 0658-0660
[3]Journal of the American Chemical Society,1961,vol. 83,p. 4225 - 4228
[4]Gazzetta Chimica Italiana,1974,vol. 104,p. 715 - 729
[5]Journal of the Chemical Society. Perkin transactions II,1981,p. 561 - 570
[6]Australian Journal of Chemistry,1992,vol. 45,p. 1571 - 1576
[7]Patent: WO2009/21957,2009,A2 .Location in patent: Page/Page column 19
[8]Journal of Agricultural and Food Chemistry,2007,vol. 55,p. 608 - 613
[9]Patent: US6333336,2001,B1

16
[ 6296-99-7 ]
[ 502-42-1 ]
[ 58780-89-5 ]

Reference： [1]Journal of Heterocyclic Chemistry,1975,vol. 12,p. 1245 - 1254
[2]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3441 - 3444

17
[ 6296-99-7 ]
C₈H₁₁⁽²⁾H₂NO₄ [ No CAS ]

Reference： [1]Journal of the Chemical Society. Perkin transactions II,1981,p. 561 - 570

18
[ 6296-99-7 ]
[ 1188-33-6 ]
[ 114954-61-9 ]

Reference： [1]Pharmaceutical Chemistry Journal,1988,vol. 21,p. 745 - 748

19
[ 6296-99-7 ]
[ 57711-36-1 ]
[ 105079-17-2 ]

Reference： [1]Heterocycles,1990,vol. 31,p. 153 - 161

20
[ 28783-55-3 ]
[ 6296-99-7 ]

Reference： [1]Australian Journal of Chemistry,1992,vol. 45,p. 1571 - 1576

21
ammonium hydroxide [ No CAS ]
[ 87-13-8 ]
[ 6296-99-7 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1897,vol. 297,p. 77

22
[ 6296-99-7 ]
[ 5332-96-7 ]
[ 868363-14-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4998 - 5002

23
[ 6296-99-7 ]
[ 6186-22-7 ]
[ 868363-10-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4998 - 5002

24
[ 6296-99-7 ]
[ 58949-75-0 ]
[ 868363-12-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4998 - 5002

25
[ 6296-99-7 ]
[ 18617-50-0 ]

Reference： [1]Synthetic Communications,2005,vol. 35,p. 2993 - 3001

26
[ 6296-99-7 ]
[ 141-97-9 ]
[ 3424-43-9 ]

Reference： [1]Tetrahedron,2006,vol. 62,p. 6222 - 6227
[2]Synthetic Communications,2005,vol. 35,p. 2993 - 3001

27
[ 6296-99-7 ]
[ 103-79-7 ]
[ 67677-94-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4998 - 5002

28
[ 76369-62-5 ]
[ 87-13-8 ]
[ 6296-99-7 ]

Reference： [1]Australian Journal of Chemistry,2004,vol. 57,p. 685 - 688

29
[ 6296-99-7 ]
[ 244638-46-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4998 - 5002

30
[ 6296-99-7 ]
[ 244638-47-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4998 - 5002
[2]Patent: US6333336,2001,B1

31
[ 6296-99-7 ]
[ 244638-67-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4998 - 5002

32
[ 6296-99-7 ]
[ 244638-66-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4998 - 5002

33
[ 6296-99-7 ]
[ 244638-74-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4998 - 5002

34
[ 6296-99-7 ]
[ 244638-73-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4998 - 5002

35
[ 6296-99-7 ]
[ 244638-71-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4998 - 5002

36
[ 6296-99-7 ]
[ 244638-70-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4998 - 5002

37
[ 6296-99-7 ]
[ 58780-98-6 ]