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Chemical Structure| 499-51-4

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Product Details of [ 499-51-4 ]

CAS No. :499-51-4
Formula : C7H5NO5
M.W : 183.12
SMILES Code : OC(=O)C1=CC(O)=CC(=N1)C(O)=O
MDL No. :MFCD00066478
Boiling Point : No data available
InChI Key :XTLJJHGQACAZMS-UHFFFAOYSA-N
Pubchem ID :8743

Safety of [ 499-51-4 ]

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

Computational Chemistry of [ 499-51-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 13
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 2
Num. H-bond acceptors 6.0
Num. H-bond donors 3.0
Molar Refractivity 40.18
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

107.72 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

-0.25
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

0.22
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

0.18
Log Po/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.

-2.01
Log Po/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

-0.33
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

-0.44

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-1.32
Solubility 8.69 mg/ml ; 0.0475 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.

-2.04
Solubility 1.66 mg/ml ; 0.00909 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

-0.2
Solubility 116.0 mg/ml ; 0.634 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.

-7.26 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.

0.56

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

0.0 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)

1.72

Application In Synthesis of [ 499-51-4 ]

* 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 [ 499-51-4 ]

[ 499-51-4 ] Synthesis Path-Downstream   1~3

  • 1
  • [ 499-51-4 ]
  • [ 64-17-5 ]
  • [ 68631-52-7 ]
YieldReaction ConditionsOperation in experiment
85% With thionyl chloride; at 0 - 20℃;Inert atmosphere; Reflux; Compound 4 was synthesized as described previously [19]. First, 12.6 mL (173 mmol) thionyl chloride was added to 50 mL of anhydrous ethanol in a round-bottom flask under argon flow cooled in an ice bath. Then, 5.03 g (27 mmol) chelidamic acid was added in small portions, and the mixture was stirred for 5 min at 0 C. The mixture was stirred for 20 h at room temperature, followed by 2 h at reflux. The solvent was removed under reduced pressure. The flask with the crude product was placed in an ice bath, and 50 mL water was added. The mixture was neutralized with 5 mL of 10% aqueous Na2CO3 and 5 mL of 50% aqueous ethanol. The precipitate was filtered and dried under reduced pressure. The product was obtained as a white solid (5.49 g (85%)). 1H NMR (400 MHz, ACN-d3) delta 7.65 (s, 2H), 4.39 (q, J = 7.1 Hz, 4H), 1.37 (t, J = 7.1 Hz, 6H).
83.92% With thionyl chloride; at 90℃; for 3h; To a solution of 4-hydroxypyridine-2,6-dicarboxylic acid (183 g, 1.0 mol) in EtOH (1500ml) was added thionyl chloride (200 ml, 2.0 mol) at room temperature and the mixture washeated at 90?C for 3 h. The mixture was cooled to room temperature, concentrated to dryness. The crude was added water 1 L and stirred at room temperature and neutralized with sodium carbonate, after filtered and washed with water (200 ml*3) to give white solid (201g, yield:83.92%). ?HNMR(CD3OD-d4) oe 7.45 (s, 1 H), 4.40 (dd, 4 H, J=7.2 Hz), 1.40 (t, 3H, J=6.8Hz).
70% With sulfuric acid; at 100℃; for 4h; The reaction was performed under air. Chelidamic acid (2 g, 9.9 mmol) was dissolved in a mixture of ethanol (75 mL) and concentrated sulfuric acid (95-97%, 1.3 mL). It was refluxed at 100 C (bath temperature) for 4 h (not more). Ethanol was rotor-evaporated. The residue was neutralized with NaHCO3 and extracted with CH2Cl2. The organic layer was washed with water and rotor-evaporated to give oil. The oil was dried under vacuum. Ether (3-5 mL) and, then, heptane (20 mL) were added to it. Brief sonication of this mixture gave a suspension of white solid product. It was filtered and washed with ice-cold heptane (10 mL). Ether induces rapid crystallization of the product, which facilitates the work-up. The product was checked by TLC and 1H NMR. If necessary, it was re-crystallized again from ether/heptane to remove the 4-ethoxy substituted by-product. White solid: 1.647 g (6.9 mmol, 70%; C11H13NO5; MW 239.22).
63% With sulfuric acid; In water; for 16h;Reflux; The compound 37 was prepared according to the procedure described in the article Chemistry-A European Journal 2008, 14, 1726. The chelidamic acid monohydrate 5 (3 g, 15 mmol) was heated at reflux in EtOH (60 ml) in the presence of 97% sulfuric acid (0.6 ml) for 16 h. The solvent was evaporated under reduced pressure, the white residue remaining was neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with DCM. The organic phase was dried with magnesium sulfate, evaporated to dryness and the diester 37 was obtained in the form of a white solid (2.27 g, 63%). Rf=0.10 (silica, CH2Cl2/MeOH 99/1); 1H NMR (CDCl3, 300 MHz) delta 7.31 (s, 2H), 4.46 (q, J=7.1 Hz, 4H), 1.42 (t, J=7.1 Hz, 6H); 13C NMR (DMSO-d6, 62.5 MHz) delta 166.0, 164.3, 149.9, 115.2, 61.4, 14.1.
56% With thionyl chloride; at 0℃;Heating / reflux; Example 35; 411 412 413Part A To chelidamic acid monohydrate 403 (12.89 g, 64.1 mmol) in ethanol (100 ml) in an ice bath was added thionyl chloride (5 ml_) slowly. The ice bath was removed and the reaction mixture was heated to reflux overnight. The ethanol was removed in vacuo and the residue was dissolved in ethyl acetate (50 ml_). The mixture was washed with saturated sodium bicarbonate until the aqueous layer was no longer acidic. The organic layer was washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated to afford a tacky white solid (11.64 g). Recrystallization of the white solid (9.25 g) from ethyl acetate/hexane/DCM afforded a crystalline white solid (7.44 g, 56%) 1H NMR (300 MHz, CDCI3) delta 7.31 (bs, 2H), 4.43 (q, 4H, J = 7.1 Hz), 1.40 (t, 6H, J = 7.1 Hz).
With toluene-4-sulfonic acid;Industry scale; Reflux; Reference Example 2-1; 4-hydroxypyridin-2.6-dicarboxylic acid diethyl esterIn ethanol (60.0 L) was dissolved 4-hydroxypyridin-2,6-carboxylic acid hydrate (3.00 kg). To the solution was added p-toluenesulfonic acid monohydrate (514 g), and the mixture was heated to reflux overnight. The reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate. Insoluble matters were filtered out, and the filtrate was concentrated under reduced pressure to give the title compound (3.48 kg) as a yellow oil. mass :240(M+ 1)+ .
With toluene-4-sulfonic acid; In water;Reflux; Reference Example 2-1 4-hydroxy-2,6-pyridinedicarboxylic acid diethyl ester In ethanol (60.0 L) was dissolved 4-hydroxy-2,6-pyridinecarboxylic acid hydrate (3.00 kg). To the solution was added p-toluenesulfonic acid monohydrate (514 g), and the mixture was heated to reflux overnight. The reaction solution was under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate. Insoluble matters were filtered out, and the filtrate was under reduced pressure to give the title compound (3.48 kg) as a yellow oil. mass: 240 (M+1)+.

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[2]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 5124 - 5127.
[3]European Journal of Organic Chemistry,2016,vol. 2016,p. 122 - 131.
[4]Chemistry - A European Journal,2008,vol. 14,p. 1726 - 1739.
[5]Tetrahedron,2010,vol. 66,p. 6070 - 6077.
[6]Chemical Communications,2014,vol. 50,p. 13948 - 13951.
[7]Chemical Communications,2016,vol. 52,p. 12326 - 12329.
[8]Journal of the Chemical Society. Perkin transactions I,1996,p. 307 - 311.
[9]Inorganic Chemistry,2017,vol. 56,p. 2742 - 2749.
[10]European Journal of Inorganic Chemistry,2017,vol. 2017,p. 5310 - 5317.
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[12]Molecules,2020,vol. 25.
[13]Patent: WO2016/161960,2016,A1 .Location in patent: Paragraph 0324.
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[16]Inorganica Chimica Acta,2015,vol. 427,p. 81 - 86.
[17]Macromolecules,2012,vol. 45,p. 7179 - 7185,7.
[18]Patent: US2018/362549,2018,A1 .Location in patent: Paragraph 0088-0089; 0288.
[19]Patent: WO2008/82487,2008,A2 .Location in patent: Page/Page column 157.
[20]Annals of Nuclear Medicine,2019,vol. 33,p. 333 - 343.
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[22]Monatshefte fur Chemie,1884,vol. 5,p. 383.
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  • [ 499-51-4 ]
 

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