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Chemical Structure| 133831-28-4 Chemical Structure| 133831-28-4

Structure of 133831-28-4

Chemical Structure| 133831-28-4

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Product Details of [ 133831-28-4 ]

CAS No. :133831-28-4
Formula : C11H9NO3
M.W : 203.19
SMILES Code : O=C(C1=CC2=C(C=C1)C(C=O)=CN2)OC
MDL No. :MFCD00216479
InChI Key :KRDRROJESQUFMJ-UHFFFAOYSA-N
Pubchem ID :735867

Safety of [ 133831-28-4 ]

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

Computational Chemistry of [ 133831-28-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 15
Num. arom. heavy atoms 9
Fraction Csp3 0.09
Num. rotatable bonds 3
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 54.97
TPSA ?

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

59.16 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.48
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

1.36
Log Po/w (WLOGP)?

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

1.77
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.

0.74
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

2.52
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.57

Water Solubility

Log S (ESOL):?

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

-2.2
Solubility 1.27 mg/ml ; 0.00627 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.

-2.2
Solubility 1.27 mg/ml ; 0.00624 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

-3.31
Solubility 0.0986 mg/ml ; 0.000485 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.

-6.57 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.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

1.0 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)

1.48

Application In Synthesis of [ 133831-28-4 ]

* 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 [ 133831-28-4 ]

[ 133831-28-4 ] Synthesis Path-Downstream   1~2

  • 1
  • [ 50820-65-0 ]
  • [ 33513-42-7 ]
  • [ 133831-28-4 ]
YieldReaction ConditionsOperation in experiment
86% To DMF (20.9 g, 285.4 mmol, 22.0 mL, 1.0 eq) in a three-necked flask equipped with a stirrer, a thermometer at 0 C, was slowly added dropwise POCl3 (43.8 g, 285.4 mmol, 26.5 mL, 1.0 eq). After the addition, the mixture was stirred for 1 h at 0 C. Then methyl 1H-indole-6- carboxylate (50.0 g, 285.4 mmol, 1.0 eq) in DMF (600 mL) was added to the reaction mixture dropwise at 0 C. The mixture was allowed to warm to room temperature and stirred for 3 h with solid precipitating out. Then H2O (200 mL) was added to the mixture and the solution was basified with NaOH to pH=8~9. The basified solution was stirred at 100 C for additional 2 h. Water (2 L) was added to the mixture, and the resulting suspension was stirred for 0.5 h, and filtered. The filter cake was washed with H2O (200 mL) and dried under reduced pressure to give methyl 03-1-1 (50.0 g, 86%).1H NMR (DMSO, 400 MHz): δ 12.43 (br. s., 1H), 10.05-9.92 (m, 1H), 8.56-8.43 (m, 1H), 8.23-8.09 (m, 2H), 7.87-7.79 (m, 1H), 3.97-3.77 (m, 3H).
52% With trichlorophosphate; at 20℃;Cooling with ice; Methyl 1H-indole-6-carboxylate (65 mg, 0.37 mmol) was dissolved in 10 mL of N,N-dimethylformamide under stirring, and phosphorus oxychloride (86 mg, 0.56 mmol) was added under ice bath, and the addition was completed, naturally warmed to room temperature and reacted overnight. TLC detected all the disappearance of the raw materials, quenched by adding 5 mL of water under ice bath, extracted with ethyl acetate (20 mL*3), The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (PE:EA=3:1) to obtain 39 mg of pale yellow solid, yield: 52%.
27% With trichlorophosphate; at 0 - 20℃; for 0.5h; To a stirred solution of compound 26 (2.5 g, 14.28 mmol) in DMF (30 mL) at 0 C, POd3 (5.47 g, 35.7 mmol) was added and stirred at RT for 30 mm. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with ice cold water (100 mL); the obtained solid was filtered and dried in vacuo. The crude compound waspurified by silica gel column chromatography using 10% EtOAc/hexane to afford compound 27 (0.78 g, 27%) as an off-white solid. TLC: 30% EtOAc/Hexane (Rf: 0.4); ‘H NMR (400 MHz, DMSO-d6): ö 12.42 (s, 1H), 9.98 (s, 1H), 8.50 (s, 1H), 8.21 - 8.04 (m, 2H), 7.84 (d, J= 8.4 Hz, 1H), 3.88 (s, 3H), LCMS Observed (m/z): 203.95 (M+1).
7% With trichlorophosphate; at 0 - 20℃; for 2h;Inert atmosphere; General procedure: To a solution of 1a (5.00 g,28.57 mmol) in dry DMF (20 ml) was added POCl3 (3.62 ml, 38.86 mol) at 0 C under N2 and then stirred at room temperature for 2 h. The reaction was quenched with H2O (60 ml) at 0 C and adjusted the pH to 7-8 with 2 M NaOH. The resulting solution was heated to 70 C and stirred for 30 min. After cooling to room temperature, the precipitate was filtered and washed with MeOH to give 2a as a light pink solid (5.22 g, 90%),
With trichlorophosphate; at 0 - 80℃; for 17h; POCb (5.25 g, 34.25 mmol, 3.18 mL, 1.5 eq) was added to DMF (15 mL) dropwise and stirred at 0 C for 1 h. Then a solution of methyl l//-indole-6-carboxylate (4 g, 22.83 mmol, 1 eq) in DMF (25 mL) was added to the mixture. The mixture was stirred at 80 C for 16 h. The reaction mixture was quenched by addition 0 (100 mL) at 0 C and stirred for 30 min at 25 C. The reaction mixture was filtered and the filter cake was concentrated to yield a residue which was added MeOH (35 mL) and stirred at 25 C for 1 h. The slurry was filtered and the filter cake was washed with MeOH (20 mL x 2). The filter cake was concerned to yield methyl 3-formyl-lH-indole-6-carboxylate (3.15 g, 13.95 mmol, 61.1% yield, 90.0% purity) as a light yellow solid. NMR (500 MHz, DMSO-rfd) d ppm 12.44 (s, 1H), 10.10-9.85 (m, 1H), 8.50 (s, 1H), 8.23-8.07 (m, 2H), 7.94-7.68 (m, 1H), 3.90-3.84 (m, 3H).

  • 2
  • [ 50820-65-0 ]
  • [ 100-97-0 ]
  • [ 133831-28-4 ]
YieldReaction ConditionsOperation in experiment
77% With water; iodine; In N,N-dimethyl-formamide; at 150℃; under 5171.62 Torr; for 0.133333h;Flow reactor; General procedure: The continuous flow reactor system consisted of the dual pump (KP-22-13, SS), PTFE tubing (length: 16 m, ID: 1 mm), T-junction (1.25 mm thru-hole), back pressure regulator (40, 75, 100, 250 psi), oil bath and hot plate. In this experiment, we used BOLA PTFE tubing to experiment at high temperature. In order to react stably at the temperature above the boiling point of water, looked for the maximum temperature conditions according to the pressure of the back pressure regulator in which the bubble does not occur. The reaction started in the concentration of indole (1.0 mmol), HMTA (2.0 mmol) and I 2 (1.0 mmol) in solvent (10 mL). Since this reaction proceeds in a single phase of liquid, the reaction time was set by the inner volume of tubing and the flow rate in the continuous flow reactor. After the reaction is over, the product was quantified using 1 H NMR and the NMR yield was obtained.
 

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