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Chemical Structure| 403-16-7 Chemical Structure| 403-16-7

Structure of 403-16-7

Chemical Structure| 403-16-7

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Product Details of [ 403-16-7 ]

CAS No. :403-16-7
Formula : C7H4ClFO2
M.W : 174.56
SMILES Code : O=C(O)C1=CC=C(F)C(Cl)=C1
MDL No. :MFCD00042477
InChI Key :PKTSBFXIHLYGEY-UHFFFAOYSA-N
Pubchem ID :520989

Safety of [ 403-16-7 ]

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

Computational Chemistry of [ 403-16-7 ] Show Less

Physicochemical Properties

Num. heavy atoms 11
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 38.37
TPSA ?

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

37.3 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.39
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

2.27
Log Po/w (WLOGP)?

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

2.6
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.

2.63
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

2.28
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.23

Water Solubility

Log S (ESOL):?

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

-2.69
Solubility 0.356 mg/ml ; 0.00204 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.

-2.69
Solubility 0.356 mg/ml ; 0.00204 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

-2.66
Solubility 0.379 mg/ml ; 0.00217 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.

-5.75 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)

1.36

Application In Synthesis of [ 403-16-7 ]

* 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 [ 403-16-7 ]

[ 403-16-7 ] Synthesis Path-Downstream   1~5

  • 1
  • [ 2923-66-2 ]
  • [ 403-16-7 ]
  • 2
  • [ 403-16-7 ]
  • [ 154257-76-8 ]
YieldReaction ConditionsOperation in experiment
sBuLi (97 mL, 126 mmol) was dissolved in tetrahydrofuran (THF) (200 ml.) at -78 0C and TMEDA (19.02 mL, 126 mmol) was added. 3-chloro-4-fluorobenzoic acid (10 g, 57.3 mmol, commercially available from e.g. Sigma-Aldrich, Fluorochem or Apollo) dissolved in tetrahydrofuran (THF) (50 mL) was added dropwise at -78 0C and the solution stired at this temperature for 30 minutes. Hexachloroethane (54.2 g, 229 mmol) dissolved in tetrahydrofuran (THF) (200 mL) was added dropwise and the solution stirred to room temperature over 4 hours. Water (25 mL) was added and the solution concentrated in vacuo. The residue was partitioned between diethyl ether (300 mL) and saturated sodium bicarbonate solution (50 mL) and extracted with saturated sodium bicarbonate solution (3 x 50 mL). The aqueous phase was acidified to pH1 with 5N hydrochloric acid, extracted with diethyl ether (3 x 200 mL), combined extracts dried over anhydrous magnesium sulfate and concentrated in vacuo to afford a crude solid (9.21 g). The crude solid was recrystalised from heptane/diethyl ether to afford the desired product in 4.91 g. LC/MS = 207/209/211 (M-H)-, retention time = 0.88 minutes (2 minute method). The mother liquors were concentrated in vacuo, washed with heptane and dried to afford a second batch of desired product in 2.62 g LC/MS = 207/209/211 (M-H)-, retention time = 0.88 minutes (2 minute method).
  • 3
  • [ 64-17-5 ]
  • [ 403-16-7 ]
  • [ 137521-81-4 ]
YieldReaction ConditionsOperation in experiment
96% With toluene-4-sulfonic acid; for 48.0h;Heating / reflux; To a solution of 3-chloro-4-fluoro-benzoic acid (11.75 g, 67.3 [MMOL)] in [ETOH] was added PTSA (1.2 g) and the resulting mixture was heated under reflux for 2 days. On cooling the mixture was poured into water and the aqueous phase was basified with a solution of NaOH 1 N. The product was extracted with CH2CI2 and the organic phase was dried over [NA2SO4] and concentrated under reduced pressure to give the title compound as an oil (13.08g, 96%); [APCI MS] [M/Z] 203 (MH+).
96% With toluene-4-sulfonic acid; for 48.0h;Heating / reflux; To a solution of 3-chloro-4-fluoro-benzoic acid (11.75 g, 67.3 [MMOL)] in EtOH was added PTS (1.2 g) and the resulting mixture was heated under reflux for 2 days. On cooling the mixture was poured into water. The aqueous phase was basified with a solution of [NAOH] 1 N. The product was extracted with [CH2CI2] and the organic phase was dried over [NA2SO4] and concentrated under reduced pressure to give the title compound as an oil (13.08g, 96%); [APCI MS] m/z 203 (MH+).
  • 4
  • [ 67-56-1 ]
  • [ 403-16-7 ]
  • [ 234082-35-0 ]
YieldReaction ConditionsOperation in experiment
88% With sulfuric acid;Heating / reflux; Preparative Example 29.; A round bottomed flask was charged with 3-chloro-4-fluorobenzoic acid (5.0 g, 28.6 mmol), sulfuric acid (0.84 g, 8.6 mmol), and methanol (60 mL). The solution was heated at reflux overnight. The methanol was removed in vacuo. The residue was extracted with ethyl acetate (5 x), dried over sodium sulfate, filtered and concentrated in vacuo to yield 4.73 g (88%).A round bottomed flask was charged with the ester intermediate (4.73 g, 25 mmol), potassium carbonate (3.45 g, 25 mmol), piperazine-1-carboxylic acid tert-butyl ester (5.59 g, 30 mmol) and acetonitrile (6 mL). The mixture was heated at 650C overnight and the solvent removed in vacuo. The residue was dissolved in ethyl acetate and washed with 0.5 N HCI, 0.5 N NaOH, and brine. The organics were dried over magnesium sulfate, filtered and concentrated in vacuo. There was obtained 4.79 g of intermediate 34 which was not purified further.
  • 5
  • [ 403-16-7 ]
  • [ 234082-35-0 ]
YieldReaction ConditionsOperation in experiment
69% With sulfuric acid; In methanol; for 16h;Reflux; A round bottomed flask was charged with 3-chloro-4-fluoro-benzoic acid (2.0 g, 11.4 mmol),sulfuric acid (0.33 g, 3.4 mmol), MeOH (20 mL) and refluxed for 16 h (TLC indicatedcomplete consumption of starting material). The volatiles were removed under reducedpressure; the residue was diluted with water (15 mL) and extracted with EtOAc (3 x 50 mL).The combined organic extracts were washed with brine (50 mL), dried over Na2S04 andconcentrated in vacuo to give the crude residue which was purified by columnchromatography (100-200 silica gel, 40 g, 10% EtOAc-hexane) to afford methyl3-chloro-4-fluoro-benzoate ( 1.5 g, 69%) as a light yellow oil. 1H NMR [300 MHz, CDCh]: J 8.08 (dd, J = 6.9, 2.1 Hz, 1H), 7.94-7.89 (m, 1H), 7.18 (t, J =8.7 Hz, 1H), 3.90 (s, 3H).
 

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