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Chemical Structure| 220000-87-3 Chemical Structure| 220000-87-3

Structure of 4-Chloro-N-methylpicolinamide
CAS No.: 220000-87-3

Chemical Structure| 220000-87-3

4-Chloro-N-methylpicolinamide

CAS No.: 220000-87-3

4.5 *For Research Use Only !

Cat. No.: A198094 Purity: 97%

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Product Details of [ 220000-87-3 ]

CAS No. :220000-87-3
Formula : C7H7ClN2O
M.W : 170.60
SMILES Code : ClC1=CC=NC(=C1)C(=O)NC
MDL No. :MFCD02185921
InChI Key :BGVBBMZMEKXUTR-UHFFFAOYSA-N
Pubchem ID :1476814

Safety of [ 220000-87-3 ]

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

Computational Chemistry of [ 220000-87-3 ] Show Less

Physicochemical Properties

Num. heavy atoms 11
Num. arom. heavy atoms 6
Fraction Csp3 0.14
Num. rotatable bonds 2
Num. H-bond acceptors 2.0
Num. H-bond donors 1.0
Molar Refractivity 42.24
TPSA ?

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

41.99 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.82
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

1.09
Log Po/w (WLOGP)?

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

1.09
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.

0.52
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

1.51
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.21

Water Solubility

Log S (ESOL):?

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

-1.86
Solubility 2.38 mg/ml ; 0.0139 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.

-1.56
Solubility 4.65 mg/ml ; 0.0273 mol/l
Class?

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

Very 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

-3.02
Solubility 0.162 mg/ml ; 0.000948 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.

-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

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)

1.39

Application In Synthesis of [ 220000-87-3 ]

* 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 [ 220000-87-3 ]

[ 220000-87-3 ] Synthesis Path-Downstream   1~8

  • 1
  • [ 74537-49-8 ]
  • [ 220000-87-3 ]
  • [ 953770-85-9 ]
YieldReaction ConditionsOperation in experiment
62% With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 70℃;Heating / reflux; Step 3. Preparation of 4-(2-Methylsulfanyl-benzothiazol-6-yloxy)-pyridine-2-carboxylic acid methylamide To the solution of <strong>[74537-49-8]2-methylsulfanyl-benzothiazol-6-ol</strong> (3.76 g, 19.08 mmol, 1.0 eq) in DMF (25 mL), was added CsCO3 (15.54 g, 47.70 mmol, 2.5 eq) at room temperature. After stirring for a while, 4-chloro-pyridine-2-carboxylic acid methylamide (4.86 g, 28.62 mmol, 1.5 eq) was added to the mixture and the mixture was stirred at 70 C. under reflux condenser overnight. After cooling the reaction mixture in ice bath, water (100 mL) was added and the aqueous layer was extracted with ethyl acetate (3*150 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated in vacuo. The crude product was purified using 20 g of ISCO Silica Gel column (0%-50%-80%-100% ethyl acetate-hexane mixture over 45 min 40 mL/min run) to yield 4-(2-methylsulfanyl-benzothiazol-6-yloxy)-pyridine-2-carboxylic acid methylamide (3.88 g, 62%) as a white solid. M+H=332.1
  • 2
  • [ 220000-87-3 ]
  • [ 611226-36-9 ]
  • 3
  • [ 15777-70-5 ]
  • [ 220000-87-3 ]
  • [ 1573056-19-5 ]
YieldReaction ConditionsOperation in experiment
136 mg Example 2.2.: Synthesis of 4-{2- ethyl-4-[3-(1-methyl-2-oxo-5- trifluoromethyl-1,2-dihydro-pyridin-3-yl)-ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methyl amide 1) Synthesis of 4-(4-Cvano-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide A solution of 4-Hydroxy-3-methyl-benzonitrile (0,100 g; 0,717 mmol) in dry DMF (3 ml_) was treated with potassium-terf-butylat (0,088 g; 0,788 mmol). The reaction mixture was stirred at RT for 2 h and 4-Chloro-pyridine-2- carboxylic acid methylamide (0,130 g; 0,717 mmol) and potassium carbonat (0,020 ml; 0,358 mmol) were added. The resulting suspension was then heated to 130C for 4 days. For purification the reaction mixture was allowed to cool down to RT and it was washed with 1 N NaOH-solution (5 ml_) and water (5 ml_). The solid, that precipitated while washing, was filtrated and added into the organic layer. The aqueous phase was extracted with DCM (2 x 15 mL) and the combined organic layers were evaporated to dryness. The resulting solid was dissolved in DCM (20 mL), dried with Na2S04 and concentrated to afford the crude product. The product was purified with flash column chromatography (Combi Flash RF, Si-60, 24 g-column, gradient PE/EE 95:5 to 50:50 in 12 min then for 7 min isocratic 50:50, flow 35 ml/min, UV 254 nM) resulting in 4-(4-Cyano-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide (136,000 mg; 0,443 mmol) as yellow solid. 2) Synthesis of 4-(4-Aminomethyl-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide A solution of 4-(4-Cyano-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide (0,690 g; 0,836 mmol) in methanol (5 mL) and NH3 in methanol (20%, 5 mL) was treated with nickel sponge (0.5 g Johnson Matthey, A- 7000) and purged with H2. The reaction mixture was stirred at RT for 17.5 h with a pressure of five bar. The catalyst was filtrated off and the solvent was evaporated. The crude product was then purified by flash column chromatography (Flashmaster, UV 240 nM, 70g silica gel column, flow 20 ml/min, DCM/MeOH 9:1) yielding 4-(4-Aminomethyl-2-methyl-phenoxy)- pyridine-2-carboxylic acid methylamide (0,182 g; 0,584 mmol) as yellow resin. 3) Synthesis of 1-Methyl-3-nitro-5-trifluoromethyl-1 H-pyridin-2-one To a solution of 3-Nitro-5-(trifluoromethyl)pyridin-2-ol (60,0 g; 288,33 mmol) in DMF (500 ml) was added potassium carbonat (120,0 g; 864,99 mmol) and iodomethan (19,7 ml; 317,16 mmol). The resulting suspension was stirred for about 16 h at 80C. The reaction mixture was diluted with EtOAc and extracted 3x with water, dried over Na2SO4, filtrated and the solution evaporated to dryness. The residue was treated with THF/ petroleum ether (PE). The precipitated product was filtered off, rinsed with PE and dried in vacuo to yield a brown solid. 4) Synthesis of 3-Amino-1-methyl-5-trifluoromethyl-1H-pyridin-2-one To a solution of 1-Methyl-3-nitro-5-trifluoromethyl-1 H-pyridin-2-one (9.40 g, 42.32 mmol) in THF (100 ml) and MeOH (10 ml) was added 5% Pd/C (54% H20, 2 g). The reaction was stirred under an atmosphere of hydrogen at room temperature. After 16h additional Pd/C (4g) were added and stirring was continued under hydrogen (1 atm) for 23 hours. The solids were removed via filtration and the filtrate reduced in vacuo to yield 3-Amino-1- methyl-5-trifluoromethyl-1H-pyridin-2-one (7.9 g, 41.1 mmol). 5) Synthesis of 4-f2-Methyl-4-r3-(1-methyl-2-oxo-5-trifluoromethyl-1 ,2- dihvdro-pyridin-3-yl)-ureidomethyll-phenoxy -pyridine-2-carboxylic acid methyl amide 3-Amino-1-methyl-5-trifluoromethyl-1H-pyridin-2-one (1,64 g, 8,55 mmol) was dissolved in DCM (50 ml), 4-nitro-phenyl-chloro-formiate (1 ,90 g, 9,437 mmol) and pyridine (0,76 ml) were added. The mixture was stirred for 2 h at room temperature. Then were added 4-(4-Aminomethyl-2-methyl-phenoxy)- pyridine-2-carboxylic acid methylamide (2,32 mg, 8,55 mmol) and N-ethyl- diisopropyl-amine (2,91 ml, 17,10 mmol). The mixture was stirred for about 16 h at room temperature. To the mixture was added DCM. The organic layer was washed once with 1 N NaOH and twice with water, it was dried over Na2S04, filtrated and the solvent removed in vacuo. The residual mixture was taken up with MTBE, the resulting white precipitate was filtered off and dried in vacuo. 4-{2-Methyl-4-[3-(1-methyl-2-oxo-5-trifluoromethyl-1 ,2-dihydro-pyhdin-3-yl)- ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide was obtained as white solid (HPLC/MS: Rt=2,184 min, M+H 490.2). 1H NMR (500 MHz, DMSO-d6) ppm = 8.74 (q, J=4.6, 1H), 8.65 (s, 1 H), 8.50 (d, J=5.6, 1 H), 8.22 (d, J=2.5, 1 H), 7.96 - 7.92 (m, 1 H), 7.76 (t, J=5.9, 1 H), 7.34 - 7.31 (m, 1H), 7.29 (d, J=2.6, 1 H), 7.25 (dd, J=8.2, 2.2, 1 H), 7.15 - 7.11 (m, 1H), 7.10 (dd, J=5.6, 2.6, 1H), 4.33 (d, J=5.8, 2H), 3.57 (s, 3H), 2.79 (d, J=4.9, 3H), 2.10 (s, 3H). Method Info: HPLC/MS A: H20 + 0,05% HCOOH | B: MeCN + 0,04% HCOOH T: 30 C I Flow: 2 ml/min | Column: Chromolith RP-18e 50-4,6 mm | MS: 85- 800 amu 1% -> 00% B: 0 -> 2,8 min | 100% B: 2,8 -> 3,3 min
  • 4
  • [ 114780-06-2 ]
  • [ 123-30-8 ]
  • [ 220000-87-3 ]
  • [ 284462-37-9 ]
  • [ 284462-86-8 ]
YieldReaction ConditionsOperation in experiment
70%; 69% [0137] A solution of 4-aminophenol (256 mg, 2.35 mmol) in dry N,Ndimethylformamide (40 mL) was treated with potassium tert-butoxide (274 mg, 2.44 mmol), and the reddish-brown mixture was stirred at room temperature for 1 hour. The contents were treated with 3a and 3b (400 mg, 2.35 mmol) and potassium carbonate (974 mg, 7.05 mmol) and then heated to 80 C under argon for 4 h. The mixture was cooled to room temperature and poured into ethyl acetate (100 mL) and brine (400 mL). The combined organics were washed with brine, dried over sodium sulfate, and concentrated. The crude reaction mixture was purified by column chromatography (dichloromethane/methanol) to afford the desired 4-(4-aminophenoxy)-N- methylpyridine-2-carboxamide 4a (400 mg, 1 .65 mmol, 70%) and 4-(4- aminophenoxy)-N,N-dimethylpyridine-2-carboxamide (69%) 4b after column as a light-brown solid.
  • 6
  • [ 220000-87-3 ]
  • [ 74-88-4 ]
  • [ 114780-06-2 ]
  • 7
  • [ 399-95-1 ]
  • [ 220000-87-3 ]
  • [ 755037-03-7 ]
  • 8
  • [ 1333390-56-9 ]
  • [ 220000-87-3 ]
  • [ 755037-03-7 ]
 

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