25063-68-7|2,2-Dimethyl-5-((pyridin-3-ylamino)methylene)-1,3-dioxane-4,6-dione| Ambeed

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Quality Control of [ 25063-68-7 ] Purity: 95% SDS Specification

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Product Details of [ 25063-68-7 ]

CAS No. :	25063-68-7
Formula :	C₁₂H₁₂N₂O₄
M.W :	248.24
SMILES Code :	O=C(C1=CNC2=CC=CN=C2)OC(C)(C)OC1=O
MDL No. :	MFCD21606919
InChI Key :	QZUHCJHZZJYTGE-UHFFFAOYSA-N
Pubchem ID :	91825792

Safety of [ 25063-68-7 ]

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

Computational Chemistry of [ 25063-68-7 ] Show Less

Physicochemical Properties

Num. heavy atoms	18
Num. arom. heavy atoms	6
Fraction Csp3	0.25
Num. rotatable bonds	2
Num. H-bond acceptors	5.0
Num. H-bond donors	1.0
Molar Refractivity	62.4
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	77.52 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.93
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	1.38
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.02
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.	0.41
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	1.41
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.23

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.36
Solubility	1.08 mg/ml ; 0.00433 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.	-2.61
Solubility	0.608 mg/ml ; 0.00245 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	-3.24
Solubility	0.142 mg/ml ; 0.000571 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.	-6.83 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.	1.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	3.0 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)	2.79

Application In Synthesis of [ 25063-68-7 ]

* 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 [ 25063-68-7 ]

[ 25063-68-7 ] Synthesis Path-Downstream 1~13

2
[ 462-08-8 ]
[ 2033-24-1 ]
[ 122-51-0 ]
[ 25063-68-7 ]

Yield	Reaction Conditions	Operation in experiment
90%		(0527) A mixture of triethyl orthoformate (1.665 mL, 10.0 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (865 mg, 6.0 mmol) was heated at 90C for 1.5 h and then cooled to 70C. 3-amino- pyridine 15 (471 mg, 5.0 mol) was slowly added over 10 min with an EtOH (20 mL) rinse while maintaining the reaction temperature between 60 and 70C. The reaction was then heated for an additional 30 min and allowed to cool to RT. The precipitate was filtered, washed with EtOH (20 mL), and dried to yield compound as a light-yellow solid (1118mg, 90%). 1H NMR (400 MHz, chloroform-i delta 1 1.25 (d, J= 14.2 Hz, 1H), 8.66 - 8.59 (m, 2H), 8.55 (dd, J= 4.8, 1.4 Hz, 1H), 7.61 (ddd, J= 8.3, 2.8, 1.4 Hz, 1H), 7.41 (dd, J = 8.3, 4.7 Hz, 1H), 1.77 (s, 6H).
72%	at 100℃; for 2h;	To a preheated (-100 00) mixture of 3-aminopyridine (0.37g, 4.0 mmol) and 2,2-dimethyl-[1 ,3}dioxane-4,6-dione (Meidrum?s acid, 0.69 g, 4.8 mmol) was added triethyl orthoformate (4.0 mL, 24.0 mmol). The solution was stirred at 100 C for 2 h. The reaction proceeded by changing color from yellow to wine red accompanying the formation of yellow precipitate. After cooling to room temperature, the excess liquid of triethyl orthoformate was removed via vacuumdistillation. The resulting solid was purified via silica gel chromatography using a gradient of 70 to 100% EtOAc in hexanes.
65%	In ethanol; at 100℃;	Meldrum?s acid (1.50 g, 10.4 mmol) was dissolved in EtOH (24 mL), and 3-aminopyridine (0.89 g, 9.5 mmol) was added to the solution followed by triethyl orthoformate (1.40 g, 9.45 mmol). The mixture was stirred with heating at 100 C until ethanol evaporated. The solid residue was dissolved in a minimal amount of hot EtOH, charcoal was added, and the suspension was heated to boiling and quickly filtered through warm Cellite. The quickly formed crystals were filtered and washed with a small amount of EtOH. The yield was 1.53 g (65%). ZS95: off-white powder, mp 135 C. IR (ATR): 3236w, 3206w, 3074w, 2993w, 2946w, 1726m, 1686s, 1619s, 1579m, 1480m, 1454w, 1413s, 1380m, 1325m, 1284m, 1262m, 1222m, 1144w, 1022w, 1000w, 936w, 847w, 822w, 803m, 778w, 726w, 704w, 654w, 604w, 507w cm-1. 1H NMR (500 MHz, CDCl3, delta): 11.26 (d, J = 13.4, H-N, exchangeable with D2O), 8.64 (d, J = 14.2, 1H), 8.63-8.61 (m, 1H), 8.56-8.54 (m, 1H), 7.66-7.62 (m, 1H), 7.43-7.39 (m, 1H), 1.77 (s, 6H). 13C NMR (125 MHz, CDCl3, delta): 165.41, 163.04, 152.74, 147.86, 140.51, 134.55, 124.68, 124.25, 105.44, 88.71, 27.06. HRMS: m/z 249.08686 corresponds to molecular formula C12H12N2O4H+ (error in ppm -0.48).

References: [1]Patent: WO2019/89648,2019,A1 .Location in patent: Page/Page column 67.
[2]Journal of the American Chemical Society,2009,vol. 131,p. 763 - 777.
[3]Journal of Medicinal Chemistry,2017,vol. 60,p. 1343 - 1361.
[4]Patent: WO2017/31255,2017,A1 .Location in patent: Paragraph 0086.
[5]European Journal of Medicinal Chemistry,2019,vol. 162,p. 32 - 50.

3
[ 25063-68-7 ]
[ 53454-31-2 ]
[ 5423-54-1 ]

References: [1]Journal of the American Chemical Society,2009,vol. 131,p. 763 - 777.

4
[ 25063-68-7 ]
[ 5423-54-1 ]

Yield	Reaction Conditions	Operation in experiment
68%	In diphenylether; at 260℃; for 0.833333h;	1,5-Naphthyridin-4-ol ZS96. The solution of ZS95 (100 mg, 0.403 mmol) in diphenyl ether (3.0 mL) was refluxed for 50 min on a Bunsen burner. The mixture was then cooled to room temperature and formed precipitate was then filtered and washed with hexane. The crude product was dried, and purified by sublimation at 210 C and 20 mbar. The yield was 40 mg (68%). ZS96: white crystals, slowly sublimes at >200 C. IR (ATR): 3012m, 2925s, 2855s, 2077w, 1975w, 1623s, 1583m, 1559m, 1502s, 1461m, 1421m, 1328w, 1192w, 1137w, 1073w, 977w, 885w, 818w, 779w, 724w, 682w, 590w, 546w, 481w cm-1. 1H NMR (500 MHz, CDCl3 + d-TFA, delta): 9.15 (dd, J1 = 8.8, J2 = 1.2, 1H), 9.12-9.10 (m, 1H), 8.51 (d, J = 7.4), 8.41 (dd, J1 = 8.9, J2 = 5.4, 1H), 7.19 (d, J = 7.4, 1H). 13C NMR (125 MHz, CDCl3 + d-TFA, delta): 173.25, 147.30, 144.98, 142.03, 131.98, 131.43, 121.01, 116.06. HRMS: m/z 147.05496 corresponds to molecular formula C8H6N2OH+ (error in ppm -2.22).
	With diphenylether; at 215℃; for 4h;	(0528) Intermediate 112 (300 mg, 1.21 mmol) was added portion wise to diphenyl ether (100 ml, 630 mmol) at 215C. The solution was stirred at reflux for 4h and then cooled to room temperature. The combined precipitated solid were filtered off and washed with diethyl ether (2 x 500 ml) to give a pale brown solid. The solid was triturated in diethyl ether (2 x 500 ml), filtered off and dried under vacuum to give of intermediate 2, that was used without further purification for the next step. (78 mg, 44% yeild). 1H NMR (400 MHz, Methanol-i 4) delta 8.75 (dd, J= 4.3, 1.5 Hz, 1H), 8.15- 8.01 (m, 2H), 7.74 (dd, J= 8.6, 4.2 Hz, 1H), 6.52 (d, J= 7.4 Hz, 1H).

References: [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 1343 - 1361.
[2]European Journal of Medicinal Chemistry,2019,vol. 162,p. 32 - 50.
[3]Patent: WO2019/89648,2019,A1 .Location in patent: Page/Page column 68.

5
[ 25063-68-7 ]
[ 7689-63-6 ]

References: [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 1343 - 1361.
[2]European Journal of Medicinal Chemistry,2019,vol. 162,p. 32 - 50.
[3]Patent: WO2019/89648,2019,A1 .

6
[ 25063-68-7 ]
4-((4-methoxybenzyl)thio)-1,5-naphthyridine [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 1343 - 1361.
[2]Patent: WO2017/31255,2017,A1 .

7
[ 25063-68-7 ]
[ 79425-89-1 ]

References: [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 1343 - 1361.
[2]Patent: WO2017/31255,2017,A1 .

8
[ 25063-68-7 ]
[ 16795-72-5 ]

Yield	Reaction Conditions	Operation in experiment
75%	With dowtherm A; at 250℃; for 1h;Inert atmosphere;	To a flask containing 8a (2.6 g, 10.4 mmol) under nitrogen atmosphere was added Dowtherm A (150 mL) and placed in a pre-heated oil bath (250 C) and stirred at reflux for 1 h. During thereaction, the color of the solution changed from orange yellow to dark brown. After cooling down to room temperature, the reaction solution was filtered to isolate solid product. The solid was rinsed with diphenyl ether and acetone to give the desired product as a dark solid. Yield = 1.14 g (75%). 1H NMR (400 MHz, CD3OD + one drop TFA): 69.07 (d, J = 4.8 Hz, 1 H), 8.72 (d, J = 8.8 Hz, 1 H), 8.61 (d, J = 7.2 Hz,1 H), 8.22 (dd, J = 8.8 Hz, J = 4.8 Hz, 1 H), 7.07 (d, J = 7.2 Hz, 1 H). 130 NMR (125 MHz, CD3OD+ one drop TEA): 6172.3,147.5,145.5, 138.6, 134.8,134.4,130.1,112.2. ESI-MS (+): m/z 147.29 [M+H].

References: [1]Patent: WO2017/31255,2017,A1 .Location in patent: Paragraph 0087.

9
[ 25063-68-7 ]
[ 5423-93-8 ]