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Chemical Structure| 452-73-3 Chemical Structure| 452-73-3

Structure of 452-73-3

Chemical Structure| 452-73-3

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Product Details of [ 452-73-3 ]

CAS No. :452-73-3
Formula : C7H6ClF
M.W : 144.57
SMILES Code : CC1=CC=C(F)C=C1Cl
MDL No. :MFCD00000572
InChI Key :CSARJIQZOSVYHA-UHFFFAOYSA-N
Pubchem ID :96747

Safety of [ 452-73-3 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H225-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338
Class:3
UN#:1993
Packing Group:

Computational Chemistry of [ 452-73-3 ] Show Less

Physicochemical Properties

Num. heavy atoms 9
Num. arom. heavy atoms 6
Fraction Csp3 0.14
Num. rotatable bonds 0
Num. H-bond acceptors 1.0
Num. H-bond donors 0.0
Molar Refractivity 36.38
TPSA ?

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

0.0 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.19
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

3.71
Log Po/w (WLOGP)?

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

3.21
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.

3.64
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

3.37
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.22

Water Solubility

Log S (ESOL):?

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

-3.57
Solubility 0.0392 mg/ml ; 0.000271 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.

-3.4
Solubility 0.0574 mg/ml ; 0.000397 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

-3.66
Solubility 0.0319 mg/ml ; 0.000221 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

Low
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

Yes
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.

-4.55 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

2.0
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<2.0
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)

1.32

Application In Synthesis of [ 452-73-3 ]

* 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 [ 452-73-3 ]

[ 452-73-3 ] Synthesis Path-Downstream   1~1

  • 1
  • [ 452-73-3 ]
  • [ 112108-73-3 ]
YieldReaction ConditionsOperation in experiment
81% With sulfuric acid; potassium nitrate; at -5 - 20℃;Product distribution / selectivity; b) Synthesis of the aromatic nitro compounds;: 55 g (380 mmol) 2-chloro-4-fluoro toluene are dissolved in 500 ml cone. sulfuric acid and cooled to-5 to 0 C in an ice bath. To this solution, 50.6 g (500 mmol) KNO3 is added in portions within 1 h. The reaction mixture is allowed to warmed up to room temperature overnight and then poured onto ice. After customary workup, 60 g (81 %) 27 (Rt. = 2.73 min (method C) ) is obtained as a yellow oil which crystallises in the refrigerator.
81% With sulfuric acid; potassium nitrate; at -5 - 20℃; 55 g (380 mmol) 2-Chloro-4-fluoro toluene are dissolved in 500 ml concentrated sulfuric acid and cooled to-5-0 C in an ice bath. To this solution, 50.6 g (500 mmol) potassium nitrate are added in several portions within 1 h. The reaction mixture is warmed up to room temperature overnight and then poured onto ice. The yellow suspension is extracted 3x with 11 tert. - Butyl-methylether each time and the combined organic phases are washed neutral with NaHCO3-solution. The organic phase is stirred with Na2SO4 and 10 g charcoal, filtered and the filtrate is evaporated to dryness. Yield : 60 g (81 %) 6, yellow oil, which crystallises in the refrigerator
81% With sulfuric acid; potassium nitrate; at -5 - 20℃; 55 g (380 mmol) 2-Chloro-4-fluoro toluene in 500 ml conc. Sulfuric acid are cooled to-5-0 C gekuehlt and treated within one hour with 50.6 g (500 mmol) potassium nitrate in several portions. The reaction mixture is allowed to warm up to room temperature overnight and then poured onto ice. The yellow suspension is extracted 3x with 11 tert.-Butyl-methylether and the combined organic phases are washed neutral using NaHCO3-solution. The organic phase is stirred with Na2SO4 and 10 g charcoal, filtered and and the filtrate is evaporated. Yield : 60 g (81 %) 25, yellow oil, crystallises in the refrigerator 0.55 g (2.81 mmol) 25 in DMF are treated with 0.59 g (3.38 mmol) N-Boc-N- methylaminoethanol and 2.11 g (6.47 mmol) cesium carbonate and stirred overnight at 50 C. the reaction mixture is filtered and the filtrate is evaporated. The residue is taken up in ethylacetate, washed with water, dried using Na2SO4, filtered and evaporated. Yield : 0.94 g (97 %), brown oil The thus obtained nitro compound is hydrogenated in THF at room temperature using H2 and Raney-Ni. The catalyst is removed by filtration and the filtrate is evaporated to dryness. Yield : 0.83 g (96 %) 26, brown oil
51.2% With sulfuric acid; potassium nitrate; at 0 - 20℃; for 22.0h; 2-Chloro-4-fluoro-1-methylbenzene (5.000 g, 34.585 mmol) and Potassium nitrate (4.371 g, 43.232 mmol) was added to a mixture of sulfuric acid (12.536 mL, 235.180 mmol) at 0 & The mixture was slowly added so that the internal temperature did not exceed 10 C, slowly raised to room temperature, and stirred for 22 hours.The reaction mixture was cooled in an ice bath and poured into 50 ml of water. After completion of the reaction, the mixture was extracted three times with 50 ml of ethyl acetate.The combined organic layers were washed with a saturated aqueous sodium chloride solution, and water was removed with anhydrous magnesium sulfate, followed by filtration and concentration under reduced pressure.The concentrate was purified by column chromatography (SiO2, 80 g cartridge; ethyl acetate / hexane = 0% to 5%) and concentrated to give 1-chloro-5-fluoro-2-methyl- , 51.2%) as a pale yellow liquid.
2.085 g (80%) With KNO3; In conc. H2 SO4; 2-Chloro-4-fluoro-5-nitrotoluene. To a stirred solution of 2-chloro-4-fluorotoluene (2.000 g, 1.383 mmol, Aldrich, used as received) in conc. H2 SO4 (15.0 mL) at 0 C., KNO3 (1.400 g, 1.385 mmol) was added in one lot. The resulting pale yellow solution was allowed to warm to 28 C. and stirred overnight at 28 C. It was then poured into ice (100 g) and extracted with ethyl acetate (2*100 mL). Ethyl acetate was dried over anhydrous Na2 SO4, removed under vacuum, and the resulting oil was dried further under vacuum to afford 2.085 g (80%) of title compound as an oil, which was used as such for the next reaction; 1 H NMR (CDCl3): delta2.422 (s, 3H), 7.325 (d, 1H, J1 =10.2 Hz), 7.973 (d, 1H, J1 =5.2 Hz).
With sulfuric acid; potassium nitrate; In 1,2-dichloro-ethane; Step A Synthesis of 2-chloro-4-fluoro-5-nitrotoluene Concentrated sulfuric acid (250 ml) was added to a stirred solution of 2-chloro-4-fluorotoluene (50.0 g, 0.346 mole) in ethylene dichloride (250 ml) at 0 C. Potassium nitrate (35.0 g, 0.346 mole) was then added slowly, maintaining the temperature below 10 C. The reaction was monitored by gas chromatography. Upon the disappearance of 2-chloro-4-fluorotoluene, the reaction mixture was poured into ice and extracted with methylene chloride. The dried organic layer was concentrated under reduced pressure to yield 60.0 g of 2-chloro-4-fluoro-5-nitrotoluene. This reaction was repeated several times.
With sulfuric acid; potassium nitrate; In 1,2-dichloro-ethane; Step A Synthesis of 2-chloro-4-fluoro-5-nitrotoluene To a mixture of 20.0 g (0.138 mole) of 2-chloro-4fluorotoluene in 50 ml of 1,2-dichloroethane which had been cooled to 0 C. was added 50 ml of concentrated sulfuric acid. While maintaining the temperature below 10 C., 14.0 g (0.138 mole) of potassium nitrate was added slowly to the mixture. After three hours the reaction mixture was poured into ice, and the resulting mixture was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was passed through a silica gel column, eluding with heptane. Appropriate fractions were combined, and the solvent was evaporated under reduced pressure, yielding 13.0 g of 2-chloro-4-fluoro-5-nitrotoluene as a yellow solid. The nmr spectrum was consistent with the proposed structure.
With sulfuric acid; potassium nitrate; at 0 - 20℃; for 1.0h; To a solution of 100 g (0.7 mol) of 2-chloro-4-fluorotoluene in 250 ml of concentrated H2SO4 is added portion-wise 85 g (0.875 mol) of KNO3 at 00C (addition of the whole amount of KNO3 is finished in about 1 hour). The reddish mixture is slowly warmed-up at room temperature overnight and quenched over crushed ice and extracted with EtOAc. The organic layers are combined, dried over MgSO4 and concentrated. The crude oil is then purified over a large silica plug (eluent: 97/3 hexanes/EtOAc) to afford 2-chloro-4-fluoro-5-nitrotoluene as a pale yellow oil that solidifies upon standing. 1H NMR (CDCl3, 400 Mz): 7.97 (d, J = 8.0 Hz, IH), 7.32 (d, J = 10.4 Hz, IH), 2.43 (s, 3H).
1.1 g With sulfuric acid; potassium nitrate; at -5 - 20℃; for 16.0h; Step 1: 1-chloro-5-fluoro-2-methyl-4-nitrobenzene 2-chloro-4-fluoro-1-methyl benzene (1.5g, 10.4mmol) and concentrated sulfuric acid (15mL) were added into a 50 mL reaction flask. The reaction mixture was cooled down to -5C?0C and then potassium nitrate (1.4g, 13.8mmol) was added in batches at this temperature. The reaction mixture was slowly increased up to room temperature and stirred for 16 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted by using ethyl acetate, and washed with saturated aqueous sodium bicarbonate and saturated brine, dried and concentrated. The crude product thus obtained was separated and purified by column chromatography (silica gel column, eluent: ethyl acetate / petroleum ether = 1:50) to obtain the title compound (yellow solid, 1.1g, 56%). (MS: [M+1] none)
With sulfuric acid; nitric acid;Cooling with ice; 135ml concentrated sulfuric acid into the reaction bottle, Stirring under ice bath cooling, 43.4 g of fuming nitric acid was added dropwise. After dripping continue to stir 30min, Form mixed acid. And 315 ml of concentrated sulfuric acid (3.5 V) and 90.0 g of 2-chloro-4-fluoro-toluene were charged in another three-necked flask. Ice salt bath cooling, The mixed acid of nitric acid and sulfuric acid is added to the sulfuric acid solution of 2-chloro-4-fluoro-toluene, Continue to react 1 ~ 2 hours. The reaction solution was slowly added to the crushed ice to stir, Ethyl acetate was extracted twice. Combined with ethyl acetate, Washed twice with water, Saturated brine once. Organic phase concentrated to dry, To give 2-chloro-4-fluoro-5-nitro-toluene as an oil.
With sulfuric acid; nitric acid;Cooling with ice; EXAMPLE 1 Preparation of 2-chloro-4-fluoro-5-nitrotoluene 135 ml of concentrated sulfuric acid was added into the reaction flask, and cooled in an ice bath under stirring, 43.4g fuming nitric acid was then added therein dropwise. After the completion of addition, the mixture was stirred continuously for 30 min to form a mixed acid. Meanwhile, 315 ml of concentrated sulfuric acid and 90.0 g of 2-chloro-4-fluorotoluene were added in another three-necked flask. The abovementioned mixed acid of nitric acid and sulfuric acid was added to the sulfuric acid solution of 2-chloro-4-fluorotoluene under cooling in an ice-salt bath, and the reaction was continued for 1 to 2 hours. The reaction solution was slowly added to the crushed ice under stirring to quench, and then extracted with ethyl acetate twice. The ethyl acetate layers was combined, and washed twice with water and once with saturated brine. The organic phase was concentrated to dryness to give oily 2-chloro-4-fluoro-5-nitrotoluene. H NMR Data 1H NMR(CDCl3, 400 MHz): delta 7.95(d, 3.8, 1H), 7.51(d, 4.2, 1H), 2.45(s, 3H).
With sulfuric acid; potassium nitrate; at 20℃; for 1.0h; Description 84. 1-Chloro-5-fluoro-2-methyl-4-nitrobenzene (D84); A solution of 2-chloro-4-fluorotoluene (4.Og) in concentrated sulfuric acid (30ml) was treated portionwise with potassium nitrate (2.8g) at <20C (internal). After 1 h more stirring with ice cooling the mixture was poured onto ice and extracted with diethyl ether. Drying and evaporation gave the title compound, 4.5g.

 

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