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Chemical Structure| 28281-76-7

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Product Details of [ 28281-76-7 ]

CAS No. :28281-76-7
Formula : C9H6O4
M.W : 178.14
SMILES Code : COC2=CC=C1C(OC(C1=C2)=O)=O
MDL No. :MFCD02670942
InChI Key :INEIVXABODMRMQ-UHFFFAOYSA-N
Pubchem ID :639748

Safety of [ 28281-76-7 ]

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

Computational Chemistry of [ 28281-76-7 ] Show Less

Physicochemical Properties

Num. heavy atoms 13
Num. arom. heavy atoms 6
Fraction Csp3 0.11
Num. rotatable bonds 1
Num. H-bond acceptors 4.0
Num. H-bond donors 0.0
Molar Refractivity 42.68
TPSA ?

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

52.6 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.41
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

1.57
Log Po/w (WLOGP)?

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

1.01
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.

0.98
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

1.82
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.36

Water Solubility

Log S (ESOL):?

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

-2.21
Solubility 1.1 mg/ml ; 0.00618 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.

-2.28
Solubility 0.924 mg/ml ; 0.00519 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

-2.59
Solubility 0.456 mg/ml ; 0.00256 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

Yes
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

Yes
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.

-6.27 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

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<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)

1.85

Application In Synthesis of [ 28281-76-7 ]

* 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 [ 28281-76-7 ]

[ 28281-76-7 ] Synthesis Path-Downstream   1~2

  • 1
  • [ 1885-13-8 ]
  • [ 28281-76-7 ]
YieldReaction ConditionsOperation in experiment
99% With acetic anhydride; In tetrahydrofuran; for 4h;Heating / reflux; Acetic anhydride (40 ml) was added to a mixture of <strong>[1885-13-8]4-methoxyphthalic acid</strong> (30.8 g, 0.16 mol) in anhydrous tetrahydrofuran (150 ml) and the mixture was strirred and held at reflux for 4 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford 4-methoxyphthalic anhydride (27.8 g, 99%) as an off white solid. 1H NMR (DMSO-d6) 8.02 (1 H, d), 7.59 (1 H, d), 7.49 (1 H, dd), 3.97 (3H, s). MS: [M+H]+ 179.
99% With acetic anhydride; In tetrahydrofuran; for 4h;Heating / reflux; Acetic anhydride (40 ml) was added to a mixture of <strong>[1885-13-8]4-methoxyphthalic acid</strong> (30.8 g, 0.16 mol) in anhydrous tetrahydrofuran (150 ml) and the mixture was strirred and held at reflux for 4 hours. <n="227"/>Upon cooling to room temperature the solvent was removed in vacuo to afford 4-methoxyphthalic anhydride (27.8 g, 99%) as an off white solid. 1H NMR (DMSOd6) 8.02 (1 H1 d), 7.59 (1 H, d), 7.49 (1H, dd), 3.97 (3H1 s). MS: [M+H]+ 179.
99% With acetic anhydride; In tetrahydrofuran; for 4h;Heating / reflux; Acetic anhydride (40 ml) was added to a mixture of <strong>[1885-13-8]4-methoxyphthalic acid</strong> (30.8 g, 0.16 mol) in anhydrous tetrahydrofuran (150 ml) and the mixture was strirred and held at reflux for 4 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford 4-methoxyphthalic anhydride (27.8 g, 99%) as an off white solid. 1H NMR (DMSO-d6) 8.02 (1 H, d), 7.59 (1 H, d), 7.49 (1 H, dd), 3.97 (3H, s). MS: [M+H]+ 179.
99% With acetic anhydride; In tetrahydrofuran; for 4h;Heating / reflux; Acetic anhydride (40 ml) was added to a mixture of <strong>[1885-13-8]4-methoxyphthalic acid</strong> (30.8 g, 0.16 mol) in anhydrous tetrahydrofuran (150 ml) and the mixture was strirred and held at reflux for 4 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford 4-methoxyphthalic anhydride (27.8 g, 99%) as an off white solid. 1H NMR (DMSO-d6) 8.02 (1 H, d), 7.59 (1 H, d), 7.49 (1 H1 dd), 3.97 (3H, s). MS: [M+H]+ 179.
99% With acetic anhydride; In tetrahydrofuran; for 4h;Reflux; Acetic anhydride (40 ml) was added to a mixture of <strong>[1885-13-8]4-methoxyphthalic acid</strong> (30.8 g, 0.16 mol) in anhydrous tetrahydrofuran (150 ml) and the mixture was stirred and held at reflux for 4 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford 4-methoxyphthalic anhydride (27.8 g, 99%) as an off white solid. 1H NMR (DMSO-d6) 8.02 (1H, d), 7.59 (1H, d), 7.49 (1H, dd), 3.97 (3H, s). MS: [M+H]+ 179.
98% In acetic anhydride; for 18h;Reflux; Step 4: Preparation of 5-methoxyisobenzofuran-1,3-dione The compound prepared in step 3 above (0.23 g, 1.2 mmol) was dissolved in 4 ml of acetic anhydride. The prepared solution was heated under reflux for 18 hours. The temperature of the solution was cooled down to room temperature, followed by concentration by rotary evaporation. The obtained residue was purified by flash column chromatography. As a result, a target compound was obtained (0.21 g, 98%). 1H NMR (DMSO-d6, 500 MHz) delta 7.99 (d, J=8.4 Hz, 1H), 7.58 (d, J=2.3 Hz, 1H), 7.48 (dd, J=8.5, 2.3 Hz, 1H), 3.97 (s, 3H). 13C NMR (DMSO-d6, 125 MHz) delta 165.7, 163.1, 162.7, 134.0, 127.2, 122.9, 122.7, 109.3, 56.7.
78% With 1,4-diaza-bicyclo[2.2.2]octane; thionyl chloride; In dichloromethane; at 0 - 20℃; for 0.833333h; 1 ,4-Diazabicyclic[2,2,2]octane (336 mg, 3 mmol) was dissolved in anhydrous dichloromethane (3 ml_) and then stirred for five minutes while slowly adding distilled thionyl chloride (0.2 ml_, 3 mmol) at O0C. And then,<strong>[1885-13-8]4-methoxyphthalic acid</strong> (200 mg, 1 mmol) was slowly added dropwise at room temperature for 50 minutes. 10% sodium bicarbonate was added to neutralize the reaction solution and the resultant was extracted with dichloromethane.Organic layers were dried with anhydrous sodium sulfate and filtered, and the filtrate was distilled under reduced pressure, separated and then purified by a column chromatography on silica gel (hexane/ethyl acetate=3:1), to obtain139 mg of the desired compound (yield 78%).1H NMR (300 MHz, CDCI3) delta 7.92 (d, J=5.6 Hz, 1 H) 7.43 (d, J=2.9, 1 H),7.36 (dd, J=11.2, 3.0 Hz, 1 H), 3.99 (s, 1 H). 13C NMR (75 Hz, CDCI3) delta 166.17, 163.00, 162.43, 134.14, 127.28,123.22, 123.98, 108.89, 56.44.
58% With 1,4-diaza-bicyclo[2.2.2]octane; thionyl chloride; In dichloromethane; at 20℃; for 2h; To a mixture of <strong>[1885-13-8]4-methoxy-phthalic acid</strong> (1.8 g, 9.18 mmol), thionyl chloride (1.4 mL, 19.79 mmol) in CH2C12 (15 mL) is added DABCO (1.1 g, 9.81 mmol). The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with CH2C12 (100 mL), washed with H20 (75 mL x2), dried with Na2S04 and filtered. The filtrate is concentrated under reduced pressure to afford 5-methoxy-isobenzofuran-l,3- dione (950 mg, 58%).
With acetic anhydride; In tetrahydrofuran; for 4h;Reflux; The solution of <strong>[1885-13-8]4-methoxyphthalic acid</strong> (16 mmol) and Ac2O (0.4 mL) in 2 mL THF was refluxedfor 4 h. Once completed, the solvent was evaporated and the intermediate 4-methyl phthalic anhydridewas afforded. Then it was mixed with aniline (0.16 mL) in 5 mL acetic acid under reflux to afford thefinal product quantitively [27].

  • 2
  • [ 28281-76-7 ]
  • [ 22246-66-8 ]
 

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