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Chemical Structure| 446-30-0 Chemical Structure| 446-30-0

Structure of 4-Chloro-2-fluorobenzoic acid
CAS No.: 446-30-0

Chemical Structure| 446-30-0

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Product Details of [ 446-30-0 ]

CAS No. :446-30-0
Formula : C7H4ClFO2
M.W : 174.56
SMILES Code : O=C(O)C1=CC=C(Cl)C=C1F
MDL No. :MFCD00042468
InChI Key :ZLPXBWMVZANJJQ-UHFFFAOYSA-N
Pubchem ID :99152

Safety of [ 446-30-0 ]

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

Computational Chemistry of [ 446-30-0 ] 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.

1.35
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

2.6
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

2.29

Water Solubility

Log S (ESOL):?

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

-2.9
Solubility 0.221 mg/ml ; 0.00127 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.

-3.03
Solubility 0.162 mg/ml ; 0.000928 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.

-5.52 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)

1.33

Application In Synthesis of [ 446-30-0 ]

* 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 [ 446-30-0 ]

[ 446-30-0 ] Synthesis Path-Downstream   1~2

  • 1
  • [ 446-30-0 ]
  • [ 56456-49-6 ]
YieldReaction ConditionsOperation in experiment
224 mg With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 16h; To a solution of 4-chloro-2-fluorobenzoic acid (300mg) in THF (15m1) was added at 0CLiAIH4 (130mg). The suspension was stirred at 0C for 16h. The reaction mixture wasdiluted with EA and aq. solution of potassium sodium tartrate and stirred for lh at rt. The layers were separated and the org. phase was further washed with water. The combined org. layers were dried over MgSO4, filtrated off and evaporated in vacuo. The crude was purified by CC (Buechi Sepacore, 5g cartridge, solvent A: DCM, solvent B: 3N ammonia in MeOH, gradient in %B: 0 to 5, flow rate: 6.0 mI/mm) to afford 224mg of colourless oil. LCMS: (A) tR = 0.68 mm; [M+H]: not visible.
224 mg With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 16h;Inert atmosphere; To a solution of 4-chloro-2-fluorobenzoic acid (300 mg) in THF (15 ml_) was added at 0C UAIH4 (130 mg). The suspension was stirred at 0C for 16h. The reaction mixture was diluted with EA and aq. solution of potassium sodium tartrat and stirred for 1 h at rt. The layers were separated and the org. phase was further washed with water. The combined org. layers were dried over MgS04, filtrated off and evaporated in vacuo. The crude was purified by CC (Buchi Sepacore, 5g cartridge, solvent A: DCM, solvent B: 3N ammonia in MeOH, gradient in %B: 0 to 5, flow rate: 6.0 imL/min) to afford 224 mg of colourless oil. LC-MS (A) tR = 0.68 min; [M+H]+: not visible.
224 mg With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 16h; To a solution of 4-chloro-2-fluorobenzoic acid (300mg) in THF (15ml) was added at 0C UAIH4 (130mg). The suspension was stirred at 0C for 16h. The reaction mixture was diluted with EA and aq. solution of potassium sodium tartrat and stirred for 1 h at rt. The layers were separated and the org. phase was further washed with water. The combined org. layers were dried over MgS04, filtrated off and evaporated in vacuo. The crude was purified by CC (Buchi Sepacore, 5g cartridge, solvent A: DCM, solvent B: 3N ammonia in MeOH, gradient in %B: 0 to 5, flow rate: 6.0 ml/min) to afford 224mg of colourless oil. LC-MS (A) tR = 0.68min; [M+H]+: not visible.
  • 2
  • [ 175711-83-8 ]
  • [ 446-30-0 ]
YieldReaction ConditionsOperation in experiment
77% With copper (II) nitrate tetrahydrate; oxygen; In acetonitrile; at 180℃; under 18751.9 Torr; for 1.5h;Green chemistry; <strong>[175711-83-8]2-fluoro-4-chloroacetophenone</strong> 25g (144.9mmol, 1.0eq), Cu(NO3)2·4H2O 7.0g (29.0mmol, 0.2eq), acetonitrile 250mL (10V),The temperature of the outer bath of the reaction coil was raised to 180 C, and the coil pressure was adjusted to 2.5 MPa with oxygen to start the charging. The residence time of the system was 1.5 h and the oxygen was 3 to 5 eq.The system was directly pumped into 375 mL of purified water, and the pH of the system was adjusted to 12-14 with NaOH solids.The aqueous phase was extracted twice with 125 mL MTBE, and the aqueous phase was adjusted to pH 1 with concentrated HCl.A large amount of solid was precipitated, and 19.3 g of the target product was obtained by filtration, yield 77%.
 

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