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Chemical Structure| 152305-23-2

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Product Details of [ 152305-23-2 ]

CAS No. :152305-23-2
Formula : C10H12N2O2
M.W : 192.21
SMILES Code : NC2=CC=C(C[C@H]1COC(N1)=O)C=C2
MDL No. :MFCD03411476
InChI Key :WNAVSKJKDPLWBD-VIFPVBQESA-N
Pubchem ID :7099156

Safety of [ 152305-23-2 ]

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

Computational Chemistry of [ 152305-23-2 ] Show Less

Physicochemical Properties

Num. heavy atoms 14
Num. arom. heavy atoms 6
Fraction Csp3 0.3
Num. rotatable bonds 2
Num. H-bond acceptors 2.0
Num. H-bond donors 2.0
Molar Refractivity 56.51
TPSA ?

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

64.35 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.36
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

1.06
Log Po/w (WLOGP)?

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

0.55
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.

0.84
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

1.15
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.99

Water Solubility

Log S (ESOL):?

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

-1.88
Solubility 2.51 mg/ml ; 0.013 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.

-2.0
Solubility 1.91 mg/ml ; 0.00994 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

-2.73
Solubility 0.36 mg/ml ; 0.00187 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.

-6.72 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.

1.0 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)

2.19

Application In Synthesis of [ 152305-23-2 ]

* 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 [ 152305-23-2 ]

[ 152305-23-2 ] Synthesis Path-Downstream   1~1

  • 1
  • [ 1116-77-4 ]
  • [ 152305-23-2 ]
  • [ 139264-17-8 ]
YieldReaction ConditionsOperation in experiment
2.4 litres of concentrated HCl are added to 7.0 litres of water in a duplicator. In such diluted HCl 1.75 kg of (<S)-4-(4-aminobenzyl)-l,3-oxazolidine-2-one of formula (I) is stirred up and the mixture is cooled down to 0C under stirring. During the cooling an aqueous solution ofNaNO2 (0.64 kg NaNO2 / 1.4 litres of water) is prepared for diazotation. At the temperature of ca. O0C a solution OfNaNO2 / H2O is slowly added to the solution of the starting substance (I) on intensive stirring and cooling. After adding of all the nitrite the mixture is further stirred at ca. O0C for ca. 30 min. Example 2 - Reduction of the diazonium saltWeighed 0.28 kg of NaOH is dissolved in 7.0 litres of water and of 2.66 kg of sodium disulphite are added under stirring. After dissolution the mixture is cooled to ca. 20C. The diazonium salt solution is slowly added to the cooled disulphite solution under intensive stirring at the temperature of 2 - 5C. The mixture is then stirred at ca. 5C for additional 30 minutes. Then, it is heated up to ca. 25C and stirred at this temperature for 45 minutes.Further it is heated under a reflux condenser to ca. 6O0C while being stirred. After heating 900 ml of concentrated HCl is added to the reaction mixture and the mixture is stirred under the reflux condenser for another 5 hours. Then the mixture is diluted with 14 litres of water. <n="7"/>Example 3 - Fischer indole reactionThe diluted reaction mixture is heated up to ca. 90C. 1.75 kg of 4,4-diethoxy-N,N- dimethylbutylamine of formula II is weighed. The weighed acetal (II) is added to the reaction mixture, which is then brought to moderate reflux (at ca. 980C) and being stirred under the reflux condenser it is left to react for about 2.5 hours. After 2.5 hours from the start of the reflux the heating of the mixture is switched off and the reaction mixture is cooled to the laboratory temperature.Example 4 - Isolation of the raw toluene solvate of ZOLMITRIPTANAt the laboratory temperature and being stirred the cooled mixture is neutralized with a ca. 20% aqueous solution of NaOH. About 4 litres of toluene is added and the mixture is stirred to make an emulsion. Then, an aqueous solution of NaOH is slowly added under stirring until pH of ca. 9.5 is achieved. After approx. 30 minutes of stirring the solid product is filtered off and washed with water. It is dried at temperatures of about 300C to the constant weight (about 10 hours).
Sodium nitrite (16 gm) in water (120 ml) was added slowly for a period of 30 minutes at 0 deg C to a solution of (S)-4-(4-Aminobenzyl)-2-oxazolidinone (40 gm), concentrated hydrochloric acid (46 ml) and water (480 ml) in round bottomed flask, cooled to 0 deg C and stirred for 1 hour. The above diazotized solution was added for a period of 30 minutes at 0 deg C to sodium sulfite (78.3 gm) in water (200 ml) in another round bottomed flask, cooled to 0 deg C, slowly allowed to room temperature, heated to 55 deg C and stirred for 15 minutes at 60 deg C. Added concentrated hydrochloric acid (80 ml) to the reaction mass, stirred for 16 hours at 60 deg C, nitrogen gas was applied and heated to 90 deg C. Water (80 ml) was added to the reaction mass for 15 minutes at 90 deg C, added 4-(dimethylamino)-butyraldehyde diethylacetal for a period of 40 minutes, heated to reflux, stirred for 3 hours at reflux, cooled to 25 - 30 deg C and the pH was adjusted to 7 by adding sodium hydroxide solution(30%, 230 ml). Extracted with ethyl acetate (7 X 200 ml), adjusted the pH of the aqueous layer to 10 by adding sodium hydroxide solution (30%, 100 ml), heated to 50 deg C and again extracted with ethyl acetate (8 X 200 ml) at 50 deg C. Both the organic layers were combined, dried with sodium sulfate, given carbon treatment and the solvent was distilled off completely under vacuum at 50 - 55 deg C, ethyl acetate (80 ml) was added to the reaction mass at 25 deg C, stirred for 1 hour and cooled to 10 deg C. Stirred for 30 minutes at 10 deg C, filtered the material and washed with chilled ethylacetate(20 ml) under nitrogen atmosphere and dried at 45 -50 deg C to yield 40 gm of (4S)-4-[[3-[2-(Dimethylamino)ethyl]~ 1 H-indol-5-yl]methyl]-2-oxazolidinone.(4S)-4-[[3-[2-(Dimethylamino)ethyl]-1H-indol-5-yl]methyl]-2-oxazolidinone (40 gm, Zolmitriptan) was dissolved in isopropanol (200 ml) at 25 deg C, heated to reflux, stirred for 40 minutes at reflux and slowly allowed to cool to 0 deg C. Stirred the reaction mass for 1 hour at 0 deg C, filtered the compound, washed with chilled isopropanol(40 ml) and dried at 40 - 45 deg C under vacuum to yield (4S)-4-[[3-[2-(Dimethylamino)ethyl]-1H-indol-5-yl]methyl]-2-oxazolidinone isopropanol solvate (32 gm, Zolmitriptan isopropanol solvate; HPLC purity. 99.32%). Zolmitriptan isopropanol solvate obtained above (32 gm) was dissolved in isopropyl acetate (2250 ml) at 25 deg C. Then the contents were heated to reflux and maintained for 30 minutes to form clear solution. The solution was cooled to 25 deg C during a period of 1 hour. The separated solid was filtered, washed with isopropyl acetate (160 ml) to obtain 32 gm of zolmitriptan isopropyl acetate solvate (HPLC purity: 99.8%).
Example - 1;The preparation of (SV4-[(3-[2-(DimethgammalaminokthyIl-lH-indol-5-gammal1methvn-2- oxazolidinone (I):Charge to the flask 300 ml of cone, hydrochloric acid, 3L of demineralised water and 250 gms of (S)-4-(4-arninobenzyl)-2-oxazolidinone. Cool the reactor contents to between 0-5 DEG C and add aqueous sodium nitrite solution (99 gms in 900ml water), maintaining the temperature below 5 DEG C. After stirring for about 30 minutes add the diazonium salt solution to a chilled aqueous solution of sodium sulphite (492 gms in 800 ml water) maintaining the temperature below 10 DEG C. After stirring for 15 minutes slowly heat the resulting mixture to about 55-60 DEG C, and then slowly add 50 ml of cone. hydrochloric acid. The solution is maintained at about 60 DEG C for about 18 hours. Dilute the reaction mixture with 5L of water and heat to about 90 DEG C. Under a nitrogen atmosphere slowly add 246 gms of 4,4-diethoxy-N, N-dimethylbutylamine and heat at reflux for about 3 hours. Cool, and adjust the mixture to about pH7 using sodium hydroxide solution. Extract with chloroform and then adjust the aqueous layer to about pHIO, again using sodium hydroxide solution. Extract the product using chloroform. Treat the combined chloroform extracts (containing the product) with decolorizing charcoal, and filter through filter aid. Distil off most of the solvent and chill the suspension to about 0 DEG C. Centrifuge the crude product, wash with chloroform and vacuum dry at 50 DEG C. (150 gms, pale yellow powder, 99.4% HPLC purity)
 

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