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Chemical Structure| 57764-49-5

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Product Details of [ 57764-49-5 ]

CAS No. :57764-49-5
Formula : C10H9NO3
M.W : 191.18
SMILES Code : O1C2=C(C(=N1)C(=O)OCC)C=CC=C2
MDL No. :MFCD06659787
InChI Key :IRTACBSCHHOIPA-UHFFFAOYSA-N
Pubchem ID :14177940

Safety of [ 57764-49-5 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302
Precautionary Statements:P280-P305+P351+P338

Computational Chemistry of [ 57764-49-5 ] Show Less

Physicochemical Properties

Num. heavy atoms 14
Num. arom. heavy atoms 9
Fraction Csp3 0.2
Num. rotatable bonds 3
Num. H-bond acceptors 4.0
Num. H-bond donors 0.0
Molar Refractivity 50.1
TPSA ?

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

52.33 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.44
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

2.26
Log Po/w (WLOGP)?

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

2.0
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.

1.34
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

2.04
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.02

Water Solubility

Log S (ESOL):?

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

-2.73
Solubility 0.359 mg/ml ; 0.00188 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.

-3.0
Solubility 0.193 mg/ml ; 0.00101 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

-3.4
Solubility 0.0765 mg/ml ; 0.0004 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.

-5.86 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

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)

2.56

Application In Synthesis of [ 57764-49-5 ]

* 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 [ 57764-49-5 ]

[ 57764-49-5 ] Synthesis Path-Upstream   1~5

  • 1
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  • [ 57764-49-5 ]
YieldReaction ConditionsOperation in experiment
96% With hydrogen; triethylamine In ethanol at 0℃; for 1 h; 10percent Palladium on carbon (1.5g) and triethylamine (7.5 g, 82.4 mmol) were added to a solution of ethyl 6-bromobenzisoxazole-3-carboxylate (20g, 0. 081mol) in ethanol (300ml) at 0 °C under an atmosphere of nitrogen. The nitrogen atmosphere was removed by evacuation and replaced with hydrogen gas, and the reaction mixture was maintained for 1 hour. The hydrogen atmosphere was removed by evacuation and replaced with nitrogen gas, and the palladium removed by filtration through Celite. The filter cake was washed with ethanol (3 x 50 mL) and the filtrates were concentrated. The residue was dissolved in dichloromethane (200 mL) and the solution was washed with water (4 x 50 mL), dried (sodium sulfate) and evaporated to provide 13.0 g of the product as a yellow solid (96percent). The ester was saponified using sodium hydroxide to provide the acid. The acid was coupled with the bicyclobase according to procedure A. Literature reference: Angell, R. M.; Baldwin, I. R.; Bamborough, P.; Deboeck, N. M.; Longstaff, T.; Swanson, S. W004010995A1 The following acid was prepared using this method: 1,2-Benzisoxazole-3-carboxylic acid.
96% With hydrogen; triethylamine In ethanol at 0℃; for 1 h; Diethyl malonate (12.6 g, 79 mmol) was added to a suspension of sodium hydride (3.16 g, 132 mmol) in dimethylsulfoxide (60 ml) over 30 min. The temperature of the reaction rose to 60 °C and the mixture clarified. 1,4-Dibromo-2-nitrobenzene (10 g, 36.0 mmol) was added and the solution was maintained for 2 h at 100 °C. The reaction mixture was allowed to cool to rt and was poured into ice (300g-400g). The precipitated solids were isolated by filtration and dried to provide 11.0 g of the product (89percent). The ester (11.0 g, 32.0 mmol) was diluted with a 2 N solution of sodium hydroxide (32 mL, 63 mmol) and the reaction mixture was maintained at room temperature for 16 h. The aqueous layer was extracted with dichloromethane (20 mL) and was acidified. The precipitated solids were isolated by filtration and dried to provide 7.00 g of the acid (89percent). Sulfuric acid (1 mL) was added to a solution of the acid (7.00 g, 27.0 mmol) in ethanol (60 ml). The reaction mixture was warmed to reflux, maintained for 2 h, and was concentrated under reduce pressure. The residue was partitioned between ethyl acetate (250 mL) and saturated sodium carbonate (50 mL) and the organic layer was washed with saturated sodium carbonate (50 mL) and brine (50 mL). The organic layer was dried (sodium sulfate) and concentrated to provide 8.00 g (98percent) of the ester as a liquid. Under N2 atmosphere, sodium ethylate was formed with sodium (33.5 g, 1.46 mol) in ethanol (1.0 L). Isoamylnitrite (225 mL) was added to a solution of the ester (420 g, 1.46 mol) in ethanol (3 L) in a 10 L three-necked round bottom flask and the mixture was warmed to 60 °C. A solution of sodium ethoxide, prepared from sodium metal (33.5 g, 1.46 mmol) in ethanol (1 L) was added dropwise and the reaction mixture was maintained for 2 h. The reaction mixture was allowed to cool to rt and was neutralized with 2 N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (4 x 2L) and the combined organic layers were washed with water (2 x 1 L) and brine (2 x 1 L) and dried (sodium sulfate). The residue was purified by chromatography (1/1 to 0/1 hexane/ethyl acetate) to provide 110 g of the product ( 28percent). 10percent Palladium on carbon (1.5g) and triethylamine (7.5 g, 82.4 mmol) were added to a solution of ethyl 6-bromobenzisoxazole-3-carboxylate (20g, 0.081mol) in ethanol (300ml) at 0 °C under an atmosphere of nitrogen. The nitrogen atmosphere was removed by evacuation and replaced with hydrogen gas, and the reaction mixture was maintained for 1 hour. The hydrogen atmosphere was removed by evacuation and replaced with nitrogen gas, and the palladium removed'by filtration through Celite. The filter cake was washed with ethanol (3 x 50 mL) and the filtrates were concentrated. The residue was- dissolved in dichloromethane (200 mL) and the solution was washed with water (4 x 50 mL), dried (sodium sulfate) and evaporated to provide 13.0 g of the product as a yellow solid (96percent). The ester was saponified using sodium hydroxide to provide the acid. The acid was coupled with 1,4-diazabicyclo[3.2.2]nonane according to procedure A.
96% With hydrogen; triethylamine In ethanol at 0℃; for 1 h; 10percent Palladium on carbon (1.5 g) and triethylamine (7.5 g, 82.4 mmol) were added to a solution of ethyl 6-bromobenzisoxazole-3-carboxylate (20 g, 0.081 mol) in ethanol (300ml) at 0° C. under an atmosphere of nitrogen. The nitrogen atmosphere was removed by evacuation and replaced with hydrogen gas, and the reaction mixture was maintained for 1 hour. The hydrogen atmosphere was removed by evacuation and replaced with nitrogen gas, and the palladium removed by filtration through Celite. The filter cake was washed with ethanol (3.x.50 mL) and the filtrates were concentrated. The residue was dissolved in dichloromethane (200 mL) and the solution was washed with water (4.x.50 mL), dried (sodium sulfate) and evaporated to provide 13.0 g of the product as a yellow solid (96percent). The ester was saponified using sodium hydroxide to provide the acid. The acid was coupled with the bicyclobase according to procedure A.
References: [1] Patent: WO2005/63767, 2005, A2, . Location in patent: Page/Page column 44-45.
[2] Patent: WO2005/111038, 2005, A2, . Location in patent: Page/Page column 66-67.
[3] Patent: US2005/250808, 2005, A1, . Location in patent: Page/Page column 40.
  • 2
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  • [ 57764-49-5 ]
YieldReaction ConditionsOperation in experiment
44% With sodium hydride In diethylene glycol dimethyl ether; mineral oil at 150℃; for 5 h; Inert atmosphere Compound 41-c (8.00 g, 33.59 mmol, 1.00 eq) was dissolved in diglyme (80.00 mL), and the above solution was added dropwise to a mixed solution of sodium hydride (2.02 g, 50.39 mmol, purity of 60percent, 1.50 eq) and diglyme (110.00 mL) with vigorously stirring under the protection of nitrogen gas. The reaction solution was slowly warmed up to 150°C, and stirred for 5 hours. After the reaction was completed, the reaction solution was added with 200 mL of water, and extracted with ethyl acetate (400 mL). The organic phase was washed with water (150 mL 3 2), dried over anhydrous sodium sulfate, filtered, concentrated, and then dissolved in heated petroleum ether. The above solution was cooled down to 0°C, the precipitated solid was filtered, and the product of compound 41-d (3.32 g, yield: 44percent) as a pale yellow solid was obtained by concentration. 1H NMR (400 MHz, DMSO-d6) δ=8.04-8.11 (m, 1H), 7.91 (d, J=8.53 Hz, 1H), 7.76 (t, J=7.78 Hz, 1H), 7.55 (t, J=7.53 Hz, 1H), 4.48 (q, J=7.36 Hz, 2H), 1.40 (t, J=7.03 Hz, 3H).
41% With sodium hydride In N,N-dimethyl-formamide at 130℃; for 8.41667 h; A solution of the nitro oxime a (5.0 g, 21.0 mmol) prepared according to the procedures described by Kemp et al. (/. Am. Chem. Soc. 1975, 97, 7305-7312) in DMF (30 mL) was added drop wise over 25 min to a vigorously stirred suspension of hexane-washed NaH (60percent in mineral oil, 840 mg, 21.0 mmol) in DMF (40 mL) under N2. The resulting dark colored solution was heated slowly to 130 0C for 8 h. It was diluted with water (200 mL), extracted with EtOAc (2 x 200 mL), washed the EtOAc with brine, dried (MgSO4), and concentrated in vacuo. The crude product was adsorbed on to Celite and purified by ISCO CombiFlash 120 g EPO <DP n="90"/>column (1-10percent ethyl acetate-hexane) to afford 1.6 g (41percent) of benzisoxazole b as an off white solid.
References: [1] Patent: EP3456711, 2019, A1, . Location in patent: Paragraph 0300; 0303.
[2] Patent: WO2006/69063, 2006, A1, . Location in patent: Page/Page column 88-89.
[3] Journal of the American Chemical Society, 1975, vol. 97, p. 7305 - 7312.
[4] Journal of Medicinal Chemistry, 1994, vol. 37, # 15, p. 2308 - 2314.
  • 3
  • [ 57764-48-4 ]
  • [ 57764-49-5 ]
References: [1] Patent: US4853027, 1989, A, .
  • 4
  • [ 3740-52-1 ]
  • [ 57764-49-5 ]
References: [1] Journal of Medicinal Chemistry, 1994, vol. 37, # 15, p. 2308 - 2314.
[2] Patent: EP3456711, 2019, A1, .
  • 5
  • [ 31912-02-4 ]
  • [ 57764-49-5 ]
References: [1] Journal of Medicinal Chemistry, 1994, vol. 37, # 15, p. 2308 - 2314.
[2] Patent: EP3456711, 2019, A1, .
 

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