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Structure of 5470-22-4

Chemical Structure| 5470-22-4

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Product Details of [ 5470-22-4 ]

CAS No. :5470-22-4
Formula : C6H4ClNO2
M.W : 157.55
SMILES Code : O=C(O)C1=NC=CC(Cl)=C1
MDL No. :MFCD00191400
InChI Key :NNMYRMGMVLMQAY-UHFFFAOYSA-N
Pubchem ID :230890

Safety of [ 5470-22-4 ]

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

Computational Chemistry of [ 5470-22-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 10
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 1
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 36.21
TPSA ?

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

50.19 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

0.99
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

1.34
Log Po/w (WLOGP)?

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

1.43
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.

-0.51
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

1.39
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.93

Water Solubility

Log S (ESOL):?

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

-2.04
Solubility 1.44 mg/ml ; 0.00914 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.

-2.0
Solubility 1.59 mg/ml ; 0.0101 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

-2.0
Solubility 1.57 mg/ml ; 0.00998 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.

-6.31 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.

0.56

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)

1.27

Application In Synthesis of [ 5470-22-4 ]

* 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.

  • Upstream synthesis route of [ 5470-22-4 ]
  • Downstream synthetic route of [ 5470-22-4 ]

[ 5470-22-4 ] Synthesis Path-Upstream   1~2

  • 1
  • [ 5470-22-4 ]
  • [ 2767-90-0 ]
References: [1] Journal fuer Praktische Chemie (Leipzig), 1933, vol. &lt;2&gt; 138, p. 244,257.
  • 2
  • [ 5470-22-4 ]
  • [ 64-17-5 ]
  • [ 64064-56-8 ]
YieldReaction ConditionsOperation in experiment
89%
Stage #1: at 100℃; for 6 h;
Stage #2: at 20℃; for 20 h;
Step-1 : Ethyl-4-chloroypicolinate: A mixture of 4-chloropicolinic acid (20 g, 127 mmol) and thionyl chloride (200 mL) was heated to 100 °C and maintained for 6 h. The reaction was cooled to RT, and the excess of thionyl chloride was removed under vacuum. To the above obtained residue was then added ethanol (200 mL) at 0 °C drop-wise and the resulting mixture was stirred at RT for 20 h.The solvent was evaporated under vacuum and the residue was taken in ethyl acetate (1000 mL), washed with water (2x500 mL), saturated sodium bicarbonate solution (2x500 mL), brine (500 mL), dried (Na2S04) and filtered. The filtrate was evaporated to yield 21.0 g (89percent) the desired product as a semi solid. XHNMR (400 MHz, DMSO) δ 8.66 (d, = 5.0 Hz, 1Η), 8.13 (d, = 2.0Hz, 1Η), 7.49 (dd, = 5.0 &2.0HZ 1Η), 4.47 (q, = 7.0 Hz, 2Η), 1.46 (t, = 7.0 Hz, 3H); GC-MS (m/z) 185, 187 [(M)+, CI35' 37].
85%
Stage #1: at 100℃; for 6 h;
Stage #2: at 0 - 20℃; for 8 h;
Step 1:
Preparation of ethyl 4-chloropicolinate
To 4-chloropicolinic acid (1.0 g, 6.35 mmol) was added SOCl2 (10 mL) at RT.
The reaction mixture was heated at 100° C. for 6 h then concentrated to remove excess SOCl2.
To the resulting residue was added EtOH (10 mL) dropwise at 0° C. and the reaction mixture was stirred at RT for 8 h.
After completion, the reaction mixture was concentrated and diluted with EtOAc (50 mL).
The organic phase was washed with water (2*25 mL), saturated sodium bicarbonate solution (2*25 mL) and brine (25 mL).
The organic layer was dried over sodium sulfate and concentrated to afford ethyl 4-chloropicolinate (1.0 g, 85percent).
1H NMR (400 MHz, DMSO-d6) δ 8.71-8.72 (d, J=8.8 Hz, 1H), 8.09 (s, 1H), 7.84-7.85 (m, 1H), 4.34-4.39 (q, J=7.2 Hz, 2H), 1.33-1.36 (t, 3H).
83.6%
Stage #1: at 100℃; for 6 h; Inert atmosphere
Stage #2: at 20℃; for 25.5 h; Cooling with ice
Stage #3: With sodium hydrogencarbonate In water
(Reference Example A-1) Ethyl 4-chloropyridine-2-carboxylate
A mixture of 4-chloropyridine-2-carboxylic acid (39.4g) and thionyl chloride (64 ml) was heated and stirred at 100 °C under a nitrogen atmosphere for 6 hr.
The reaction mixture was allowed to cool down to room temperature.
This was concentrated under reduced pressure and distilled azeotropically with toluene.
The resultant residue was gradually added to ethanol while stirring in an ice bath.
The reaction mixture was stirred at room temperature for 25.5 hr.
The reaction mixture was concentrated under reduced pressure.
To the residue was added a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate.
The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide the titled compound as a brown oil (38.8 g, 83.6 percent).
1H-NMR Spectrum (CDCl3) δ (ppm): 1.46 (3H, t, J = 7.2 Hz), 4.50 (2H, q, J = 7.2 Hz), 7.49 (1H, dd, J = 2.0, 5.2 Hz), 8.15 (1H, d, J = 2.0 Hz), 8.67 (1H, d, J = 5.2 Hz).
55.7% for 2 h; Inert atmosphere; Reflux To a stirred solution of 4-chloropicolinic acid (15.0 g, 95.20 mmol, 1.0 equiv) in ethanol (225.0 mL, 15.0 vol. equiv) was added sulfuric acid (34.4 mL, 619 mmol, 6.5 equiv). (0376) The resulting mixture was stirred for 2 h at reflux. The completion of reaction was monitored by TLC. The solvent was removed under reduced pressure. The residue was treated with DM water (0377) (500.0 mL) and extracted with EtOAc (2 x 500 mL). The combined organic extract was washed with brine (200.0 mL), saturated solution of sodium bicarbonate (500.0 mL), dried over Na2S04 and concentrated under vacuum to afford titled compound (9.84 g, 55.7percent) as a light brown oily mass. MR (300 MHz, OMSO-d6) δ 8.70-8.69 (d, 1H), 8.08-8.07 (d, 1H), 7.83-7.81 (m, 1H), 4.39-4.31 (m, 2H), 1.35-1.29 (m, 3H). MS (ES+): 186.0 (M+l).

References: [1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 10, p. 2669 - 2672.
[2] Patent: WO2013/164769, 2013, A1, . Location in patent: Page/Page column 48.
[3] Patent: US2019/77773, 2019, A1, . Location in patent: Paragraph 1241.
[4] Patent: EP2119706, 2009, A1, . Location in patent: Page/Page column 41.
[5] Patent: WO2018/200981, 2018, A1, . Location in patent: Paragraph 0209; 0211.
 

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Technical Information

Categories

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