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Chemical Structure| 29681-38-7

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Product Details of [ 29681-38-7 ]

CAS No. :29681-38-7
Formula : C8H9NO2
M.W : 151.16
SMILES Code : O=C(OC)C1=NC=C(C)C=C1
MDL No. :MFCD11040648
InChI Key :GLXLMXAFURBIEZ-UHFFFAOYSA-N
Pubchem ID :268759

Safety of [ 29681-38-7 ]

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

Computational Chemistry of [ 29681-38-7 ] Show Less

Physicochemical Properties

Num. heavy atoms 11
Num. arom. heavy atoms 6
Fraction Csp3 0.25
Num. rotatable bonds 2
Num. H-bond acceptors 3.0
Num. H-bond donors 0.0
Molar Refractivity 40.48
TPSA ?

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

39.19 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.81
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

1.85
Log Po/w (WLOGP)?

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

1.18
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.

0.66
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

1.64
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.43

Water Solubility

Log S (ESOL):?

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

-2.21
Solubility 0.923 mg/ml ; 0.0061 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.

-2.29
Solubility 0.768 mg/ml ; 0.00508 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

-2.47
Solubility 0.512 mg/ml ; 0.00339 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

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.

-5.91 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)

1.61

Application In Synthesis of [ 29681-38-7 ]

* 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.

  • Downstream synthetic route of [ 29681-38-7 ]

[ 29681-38-7 ] Synthesis Path-Downstream   1~3

  • 1
  • [ 186581-53-3 ]
  • [ 4434-13-3 ]
  • [ 29681-38-7 ]
  • 2
  • [ 67-56-1 ]
  • [ 4434-13-3 ]
  • [ 29681-38-7 ]
YieldReaction ConditionsOperation in experiment
59% With hydrogenchloride; In 1,4-dioxane; at 20 - 70℃; 15 ml (60 mmol) of a 4M solution of hydrogen chloride in dioxane were added dropwise to 3.00 g (21.9 mmol) of 5-methylpyridine-2-carboxylic acid in 40 ml of methanol, and the mixture was stirred at room temperature overnight. 10 ml (40 mmol) of a 4M solution of hydrogen chloride in dioxane were then added dropwise, and the mixture was initially stirred at room temperature overnight and then at 70 C. overnight. Methanol and a further 20 ml (80 mmol) of a 4M solution of hydrogen chloride in dioxane were added and the mixture was stirred at reflux overnight. The mixture was then concentrated under reduced pressure, and water and dichloromethane were added to the residue. After phase separation, the aqueous phase was washed twice with dichloromethane and the combined organic phases were washed with sodium chloride solution and then dried over sodium sulphate. After filtration, the filtrate was concentrated under reduced pressure and the residue was dried under high vacuum. This gave 2.08 g (59% of theory) of the desired product. LC-MS (Method 1A): Rt=0.55 min; MS (ESIpos): m/z=152 [M+H]+
2.08g With hydrogenchloride; In 1,4-dioxane; at 20 - 70℃;Reflux; The 15ml (60mmol) in dioxane was added dropwise a 4M solution of hydrogen chloride in 40ml of methanol 3.00g (21.9mmol) of 5-methyl-pyridine-2-carboxylic acid, and the mixture was stirred overnight at room temperature .Then added dropwise 10ml (40mmol) in dioxane solution of 4M hydrogen chloride, and the mixture was stirred first overnight at room temperature and then stirred overnight at 70 .The methanol and additional 20ml (80mmol) of 4M solution of hydrogen chloride in dioxane was added and the mixture was stirred overnight at reflux.The mixture was then concentrated under reduced pressure, and water and dichloromethane were added to the residue.After the phases were separated, the aqueous phase was washed with dichloromethane and washed twice and the combined organic phases were washed with sodium chloride solution and then dried over sodium sulfate.After filtration, the filtrate was concentrated and the residue was dried under high vacuum under reduced pressure.The thus obtained 2.08g (59%, based on the theoretical value) of the desired product.
  • 3
  • [ 29681-38-7 ]
  • [ 55876-84-1 ]
YieldReaction ConditionsOperation in experiment
66% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 5h;Reflux; A mixture of methyl 2-methylisonicotinate (leq) and a,a'-Azoisobutyronitrile (AIBN) (10%) was dissolved in carbontetrachloride (CC14). The solution was heated at 48C and N-bromosuccinimide (NBS) (1.1 eq) solution in CC14 was added drop wise and stirred for 5 hours. The reaction was cooled to room temperature and the solvent evaporated. The mixture was then extracted using dichloromethane and water followed by washing the organic layer with brine. The organic layer was dried over sodium sulfate, filtered, evaporated and the crude product was purified using SiO2 column chromatography and eluted with the solvent system EtOAc: hexanes = 2:3 to obtain pure product as white powder and the yield was 66%. 1H-NMR (400 MHz, DMSO-d6): d 8.78 (t, J= 1.48 Hz, 1H), 8.06 (d, J= 1.36 Hz, 2H), 4.82 (s, 2H), 3.89 (s, 3H). HRMS (ESI) m/z found 229.98 [M+H]+, Calculated 230.0586 [M]+.
57% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 16h; 5-(Bromomethyl)pyridine-2-carboxylate In a 500-mL round bottom flask, NBS (14.13 g, 79.38 mmol, 1.20 equiv) and AIBN (217 mg, 1.32 mmol, 0.02 equiv) were added to a solution of methyl 5-methylpyridine-2-carboxylate (10 g, 66.15 mmol, 1.00 equiv) in CCl4 (200 mL) at room temperature. The resulting solution was stirred for 16 h at 80 C. After the reaction was done, the reaction mixture was concentrated under reduced pressure. The residue was purified in a silica gel column eluting with ethyl acetate in petroleum ether (5% to 25% gradient) to afford methyl 5-(bromomethyl)pyridine-2-carboxylate (9.6 g, 57%) as yellow solid. MS: m/z=229.9 [M+H]+
50% With N-Bromosuccinimide;VAZO; In tetrachloromethane; for 18h;Heating / reflux; To a solution of 5-methylpyridirie-2-carboxylic acid methyl ester (140 mg, 0.93 mmol) in CCl4 (8 mL) was added NBS (181 mg, 1.02 mmol) and VAZO (23 mg, 0.09 mmol). The reaction was stirred at reflux for 18 h. Standard work-up and purification by flash chromatography on silica gel (10% ether in CH2Cl2) afforded 5-bromomethylpyridine-2- carboxylic acid methyl ester (107 mg, 50%).
24% With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 18h;Reflux; INTERMEDIATE 37 - PREPARATION of Methyl 5-(bromomethyl)picolinate. To a mixture of methyl 5-methylpicolinate (1.25 g; 8.27 mmol) in carbon tetrachloride (45 mL) was added N-bromosuccinimide (1.78 g, 9.92 mmol) and benzoyl peroxide (0.205 g; 0.827 mmol). The mixture was refluxed for 18 hours and the resulting suspension was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent 0 to 8% ethyl acetate in dichloromethane) to 0.450g (24%) of methyl 5- (bromomethyl)picolinate as a beige solid.ESI/APCI(+): 230 (M+H).
24% With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 18h;Reflux; To a mixture of methyl 5-methylpicolinate (1.25 g; 8.27 mmol) in carbon tetrachloride (45 mL) was added N-bromosuccinimide (1.78 g, 9.92 mmol) and benzoyl peroxide (0.205 g; 0.827 mmol). The mixture was refluxed for 18 hours and the resulting suspension was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent 0 to 8% ethyl acetate in dichloromethane) to 0.450 g (24%) of methyl 5-(bromomethyl)picolinate as a beige solid. [0623] ESI/APCI(+): 230 (M+H).
11% With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane;Reflux; Example 8. Synthesis of 1-548-101. Into a 2000-mL 4-necked round-bottom flask, was placed a solution of methyl 5-methylpicolinate (85 g, 539.68 mmol, 1.00 equiv, 96%) in CC14 (1000 mL), N-bromosuccinimide (1 10 g, 617.98 mmol, 1.10 equiv), and benzoyl peroxide (3.5 g, 14.45 mmol, 0.03 equiv). The resulting solution was heated to reflux overnight. The solids were removed by filtration. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :30-l :5). This resulted in 15 g (1 1%) of methyl 5-(bromomethyl)picolinate as a light-yellow solid.LC-MS: (ES, m/z): 232 [M+H]+

 

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Technical Information

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