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Chemical Structure| 96428-50-1

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Product Details of [ 96428-50-1 ]

CAS No. :96428-50-1
Formula : C18H18N2O3
M.W : 310.35
SMILES Code : O=C(C1=C(C)N=C2C(OCC3=CC=CC=C3)=CC=CN21)OCC
MDL No. :MFCD06739215
InChI Key :RLYGWMBGMXQDQC-UHFFFAOYSA-N
Pubchem ID :44382335

Safety of [ 96428-50-1 ]

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

Computational Chemistry of [ 96428-50-1 ] Show Less

Physicochemical Properties

Num. heavy atoms 23
Num. arom. heavy atoms 15
Fraction Csp3 0.22
Num. rotatable bonds 6
Num. H-bond acceptors 4.0
Num. H-bond donors 0.0
Molar Refractivity 87.22
TPSA ?

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

52.83 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

3.33
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

4.18
Log Po/w (WLOGP)?

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

3.25
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.

2.24
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

3.14
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.23

Water Solubility

Log S (ESOL):?

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

-4.48
Solubility 0.0102 mg/ml ; 0.0000328 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-5.0
Solubility 0.00312 mg/ml ; 0.00001 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately 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

-5.6
Solubility 0.00078 mg/ml ; 0.00000251 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately 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

Yes
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

Yes
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

Yes
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.

-5.23 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

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)

2.82

Application In Synthesis of [ 96428-50-1 ]

* 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 [ 96428-50-1 ]

[ 96428-50-1 ] Synthesis Path-Upstream   1~2

  • 1
  • [ 24016-03-3 ]
  • [ 609-15-4 ]
  • [ 96428-50-1 ]
YieldReaction ConditionsOperation in experiment
54% at 100℃; for 48 h; Molecular sieve Example 1A
Ethyl 8-(benzyloxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylate
25 g (124.8 mmol) of 2-amino-3-benzyloxypyridine were dissolved in 781 ml of ethanol, 102.7 g (624.2 mmol) of ethyl 2-chloroacetoacetate and two tablespoons of 4 A molecular sieve were added, and the reaction mixture was then heated at reflux (bath temperature 100° C.) for 2 days.
The mixture was concentrated, and excess ethyl 2-chloroacetoacetate was removed on a rotary evaporator with dry ice cooling.
The residue was purified by silica gel chromatography (mobile phase cyclohexane:ethyl acetate gradient 9:1, 4:1).
This gave 20.81 g of the target compound (54percent of theory, purity 99percent).
LC-MS (Method 2): Rt=1.12 min
MS (ESpos): m/z=311 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ=1.35 (t, 3H), 2.59 (s, 3H), 4.34 (q, 2H), 5.32 (s, 2H), 7.01-7.09 (m, 2H), 7.33-7.48 (m, 3H), 7.52 (d, 2H), 8.81-8.86 (m, 1H).
54% at 100℃; for 48 h; Molecular sieve Example 29A
Ethyl 8-(benzyloxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylate
25 g of 2-amino-3-benzyloxypyridine (124.8 mmol, 1 equivalent) were dissolved in 781 ml of ethanol, and 102.7 g of ethyl 2-chloroacetoacetate (624.2 mmol, 5 equivalents) and 15 g of 4 Å molecular sieve were added.
The mixture was heated at reflux for 2 d (bath temperature 100° C.).
The mixture was then concentrated and excess ethyl 2-chloroacetoacetate was distilled off on a rotary evaporator with dry ice-cooling.
The residue was purified by silica gel chromatography (mobile phase cyclohexane:ethyl acetate 9:1, 4:1).
This gave 20.81 g of the title compound (54percent of theory).
LC-MS (Method 1): Rt=1.12 min
MS (ESpos): m/z=311 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ=1.35 (t, 3H), 2.59 (s, 3H), 4.34 (q, 2H), 5.32 (s, 2H), 7.01-7.09 (m, 2H), 7.33-7.48 (m, 3H), 7.52 (d, 2H), 8.81-8.86 (m, 1H).
54% at 100℃; for 48 h; Molecular sieve Example 23A
Ethyl 8-(benzyloxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylate
25 g (124.8 mmol) of 2-amino-3-benzyloxypyridine were dissolved in 781 ml of ethanol, 102.7 g (624.2 mmol) of ethyl 2-chloroacetoacetate and two table spoons of 4 A molecular sieve were added and the reaction mixture was then heated at reflux (bath temperature 100° C.) for 2 days.
The mixture was concentrated and excess ethyl 2-chloroacetoacetate was distilled off on a rotary evaporator using dry ice cooling.
The residue was purified by silica gel chromatography (mobile phase: cyclohexane/ethyl acetate gradient-9/1, 4/1).
This gave 20.81 g of the target compound (54percent of theory, purity 99percent).
LC-MS (Method 2): Rt=1.12 min
MS (ESpos): m/z=311 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ=1.35 (t, 3H), 2.59 (s, 3H), 4.34 (q, 2H), 5.32 (s, 2H), 7.01-7.09 (m, 2H), 7.33-7.48 (m, 3H), 7.52 (d, 2H), 8.81-8.86 (m, 1H).
54% at 100℃; for 48 h; Molecular sieve 25 g of 2-amino-3-benzyloxypyridine (124.8 mmol, 1 equivalent) were dissolved in 781 ml of ethanol, 102.7 g of ethyl 2-chloroacetoacetate (624.2 mmol, 5 equivalents) and 15 g of 4 A molecular sieve were added and the mixture was heated at reflux (bath temperature 100° C.) for 2 d. Then, the mixture was concentrated and excess ethyl 2-chloroacetoacetate was distilled off on a rotary evaporator using dry ice cooling. The residue was purified by silica gel chromatography (mobile phase cyclohexane:ethyl acetate=9:1, 4:1). This gave 20.81 g of the title compound (54percent of theory).10693] LC-MS (Method 2): R=1.12 mm10694] MS (ESpos): mlz=311 (M+H)10695] ‘H-NMR (400 MHz, DMSO-d5): ö=1.35 (t, 3H),2.59 (s, 3H), 4.34 (q, 2H), 5.32 (s, 2H), 7.01-7.09 (m, 2H),7.33-7.48 (m, 3H), 7.52 (d, 2H), 8.81-8.86 (m, 1H).

References: [1] Patent: US2014/128386, 2014, A1, . Location in patent: Paragraph 0984; 0985; 0986; 0987; 0988.
[2] Patent: US2014/128372, 2014, A1, . Location in patent: Paragraph 0489; 0490; 0491; 0492; 0493.
[3] Patent: US2017/57954, 2017, A1, . Location in patent: Paragraph 0620; 0621; 0622; 0623; 0624.
[4] Patent: US2016/347770, 2016, A1, . Location in patent: Paragraph 0691; 0692; 0693; 0694; 0695.
[5] Journal of Medicinal Chemistry, 1985, vol. 28, # 7, p. 876 - 892.
  • 2
  • [ 537-46-2 ]
  • [ 24016-03-3 ]
  • [ 609-15-4 ]
  • [ 96428-50-1 ]
References: [1] Patent: US2017/217954, 2017, A1, .
 

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