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Structure of 13452-14-7

Chemical Structure| 13452-14-7

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Product Details of [ 13452-14-7 ]

CAS No. :13452-14-7
Formula : C9H7NO3
M.W : 177.16
SMILES Code : CC1=NC2=C(O1)C=C(C=C2)C(=O)O
MDL No. :MFCD07787266
InChI Key :GFYDDTFAVDJJAI-UHFFFAOYSA-N
Pubchem ID :18475689

Safety of [ 13452-14-7 ]

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

Computational Chemistry of [ 13452-14-7 ] Show Less

Physicochemical Properties

Num. heavy atoms 13
Num. arom. heavy atoms 9
Fraction Csp3 0.11
Num. rotatable bonds 1
Num. H-bond acceptors 4.0
Num. H-bond donors 1.0
Molar Refractivity 45.93
TPSA ?

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

63.33 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.59
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

1.69
Log Po/w (WLOGP)?

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

1.83
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.

0.9
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

1.69
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.54

Water Solubility

Log S (ESOL):?

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

-2.45
Solubility 0.629 mg/ml ; 0.00355 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.

-2.63
Solubility 0.411 mg/ml ; 0.00232 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

-2.67
Solubility 0.376 mg/ml ; 0.00212 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.

-6.18 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)

2.17

Application In Synthesis of [ 13452-14-7 ]

* 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 [ 13452-14-7 ]
  • Downstream synthetic route of [ 13452-14-7 ]

[ 13452-14-7 ] Synthesis Path-Upstream   1~6

  • 1
  • [ 136663-23-5 ]
  • [ 13452-14-7 ]
YieldReaction ConditionsOperation in experiment
97%
Stage #1: With sodium hydroxide In ethanol; water at 20℃; for 2 h;
Stage #2: With hydrogenchloride In ethanol; water
Preparation Example K-2.
2-Methyl-benzoxazole-6-carboxylic acid
To a solution of 2-methyl-benzoxazole-6-carboxylic acid methyl ester (301 mg, 1.57mmol) in ethanol (10mL) was added an aqueous solution of 2N sodium hydroxide (10mL), and the mixture was stirred for 2 hours at room temperature. 2N Hydrochloric acid was added to the reaction mixture to adjust the pH to 4, and the solution was extracted with ethyl acetate.
The organic layer was washed with brine, dried over anhydrous sodium sulfate, then, evaporated in vacuo, and the title compound (270mg, 1.52mmol, 97percent) was obtained.
This was used in the next reaction without purification.
1H-NMR Spectrum (DMSO-d6) δ (ppm): 2.64 (3H, s), 7.73 (1H, d, J=8.0Hz), 7.93(1 H, dd, J=1.2, 8.0Hz), 8.15 (1 H, d, J= 1.2Hz).
97%
Stage #1: at 20℃; for 2 h;
Stage #2: With hydrogenchloride In water
To a solution of 2-methyl-benzoxazole-6-carboxylic acid methyl ester (301 mg, 1.57mmol) in ethanol (10mL) was added an aqueous solution of 2N sodium hydroxide (10mL), and the mixture was stirred for 2 hours at room temperature. 2N Hydrochloric acid was added to the reaction mixture to adjust the pH to 4, and the solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, then, evaporated in vacuo, and the title compound (270mg, 1.52mmol, 97percent) was obtained. This was used in the next reaction without purification. 1H-NMR Spectrum (DMSO-d6) δ(ppm) : 2.64 (3H, s), 7.73 (1 H, d, J=8.0Hz), 7.93(1 H, dd, J=1.2, 8.0Hz), 8.15 (1 H, d, J= 1.2Hz).
90% With lithium hydroxide monohydrate; water In tetrahydrofuran for 2 h; To methyl 2-methyl-1,3-benzoxazole-6-carboxylate (8) (12.2 g, 0.064 mol) in THF (300 mL)/H2O (100 mL) was added lithium hydroxide monohydrate (5.4 g, 0.128 mol), and the mixture was vigorously stirred. After 2 h the THF was removed under vacuum. The remaining aqueous phase was acidified with HOAc and exhaustively extracted with CH2Cl2. The pooled organic extract was dried (Na2SO4) and concentrated to give a beige solid (10.2 g, 90percent yield): mp 245–246 °C (lit.40 245–246 °C); TLC (SiO2, ethyl acetate/methanol (90:10), UV) single spot Rf 0.38. 1H NMR (300 MHz, DMSO); δ 2.66 (s, 3H, NCH3), 7.75 (d, J = 8.3 Hz, 1H, H-5), 7.96 (dd, J = 8.3, 1.4 Hz, 1H, H-4), 8.16 (d, J = 0.7 Hz, 1H, H-7), 13.12 (bs, 1H, OH).
65%
Stage #1: With lithium hydroxide monohydrate; water In tetrahydrofuran; methanol at 25℃; for 2 h;
Stage #2: With hydrogenchloride In tetrahydrofuran; methanol
To a solution of methyl 2-methylbenzo[d]oxazole-6-carboxylate (2.0 g, 10 mmol) in tetrahydrofuran/methanol/water (1: 1 : 1, 15 mL) was added lithium hydroxide hydrate (0.88 g, 21 mmol). The resulting mixture was stirred at 25 °C for 2 hours. On completion, the mixture was acidified with hydrochloric acid, resulting in formation of a solid. The solid was collected by filtration, washed with water and dried in vacuo to give compound B-130 (1.2 g, 65percent yield) as a white solid.

References: [1] Patent: EP1782811, 2007, A1, . Location in patent: Page/Page column 60.
[2] Patent: EP1669348, 2006, A1, . Location in patent: Page/Page column 68.
[3] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 21, p. 6661 - 6664.
[4] Patent: WO2016/100184, 2016, A1, . Location in patent: Paragraph 00323-00324.
[5] Patent: US2007/160538, 2007, A1, . Location in patent: Page/Page column 19-20.
[6] Patent: EP1229027, 2002, A1, . Location in patent: Page 15.
[7] Patent: EP1229028, 2002, A1, . Location in patent: Page 15.
[8] Patent: EP1229037, 2002, A1, . Location in patent: Page 15.
[9] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 10, p. 2980 - 2985.
  • 2
  • [ 1445-45-0 ]
  • [ 2374-03-0 ]
  • [ 13452-14-7 ]
YieldReaction ConditionsOperation in experiment
100% at 100℃; for 0.0833333 h; Microwave irradiation A heterogeneous mixture of 4-amino-3-hydroxybenzoic acid (7b) (7.732 g, 0.050 mol) and 1,1,1-trimethoxyethane (16 mL) was heated to 100 °C using a microwave (55 W) and held for 5 min. The reaction was repeated two more times (7.732 g and 7.625 g), and the combined reaction mixtures were concentrated in vacuo giving the product as a tan solid in quantitative yield: mp 245–246 °C (lit.40 245–246 °C); TLC (SiO2, ethyl acetate/methanol (90:10), UV) single spot Rf 0.38; MS MH+ 178.4. 1H NMR (300 MHz, DMSO); δ 2.66 (s, 3H, NCH3), 7.75 (d, J = 8.3 Hz, 1H, H-5), 7.96 (dd, J = 8.3, 1.4 Hz, 1H, H-7), 8.16 (d, J = 0.7 Hz, 1H, H-7), 13.12 (bs, 1H, OH).
95% at 100℃; for 0.0833333 h; Microwave irradiation A solution of compound 4.1 (1.10 g) and 1,1,1-trimethoxyethane (5 mL) was heated at 100° C. for 5 minutes in a microwave. The reaction mixture was concentrated under reduced pressure to provide 1.26 g of compound 4.2 (95percent pure) as a brown powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.66 (s, 3H), 7.74 (d, J=8.4 Hz, 1H), 7.96 (dd, J=8.3, 1.4 Hz, 1H), 8.16 (d, J=1.4 Hz, 1H), 13.07 (s(br), 1H).
References: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 21, p. 6661 - 6664.
[2] Patent: US2010/305073, 2010, A1, . Location in patent: Page/Page column 20.
[3] Patent: US2003/73707, 2003, A1, .
[4] Patent: EP1229027, 2002, A1, . Location in patent: Page 18.
[5] Patent: EP1229028, 2002, A1, . Location in patent: Page 18.
[6] Patent: EP1229037, 2002, A1, . Location in patent: Page 18.
[7] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 15, p. 4998 - 5002.
[8] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 12, p. 3242 - 3253.
  • 3
  • [ 64-19-7 ]
  • [ 2374-03-0 ]
  • [ 13452-14-7 ]
YieldReaction ConditionsOperation in experiment
62% at 130℃; for 72 h; (Intermediate Example 70)
2-Methylbenzoxazole-6-carboxylic acid
4-Amino-3-hydroxybenzoic acid (4.9 g) was added to acetic acid (250 ml) and stirred for 3 days at 130°C.
The solution was concentrated under reduced pressure, and precipitates were collected by filtration.
The precipitates were dissolved in methanol and chloroform.
The solution was concentrated under reducedpressure, and precipitates were collected by filtration, washed with methanol and dried under reduced pressure to give the title compound (3.5 g, Y.: 62percent).
1H NMR; (DMSO-d6) δ (ppm): 2.6 (s, 3H), 7.7 (d, 1H), 7.9 (dd, 1H), 8.1 (d, 1H).
ESI/MS (m/z): 178 (M+H)+, 176 (M-H)-.
References: [1] Patent: EP1595866, 2005, A1, . Location in patent: Page/Page column 27.
  • 4
  • [ 63435-16-5 ]
  • [ 13452-14-7 ]
References: [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 10, p. 2980 - 2985.
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 21, p. 6661 - 6664.
  • 5
  • [ 713-52-0 ]
  • [ 13452-14-7 ]
References: [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 10, p. 2980 - 2985.
  • 6
  • [ 6427-66-3 ]
  • [ 64-19-7 ]
  • [ 13452-14-7 ]
References: [1] Journal of the Chemical Society [Section] C: Organic, 1966, p. 1980 - 1983.
 

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