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Structure of 22245-83-6

Chemical Structure| 22245-83-6

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Product Details of [ 22245-83-6 ]

CAS No. :22245-83-6
Formula : C6H4F3NO
M.W : 163.10
SMILES Code : C1=CC(=C(N=C1)O)C(F)(F)F
MDL No. :MFCD00153194
InChI Key :JHDCDEHVUADNKQ-UHFFFAOYSA-N
Pubchem ID :3678411

Safety of [ 22245-83-6 ]

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

Computational Chemistry of [ 22245-83-6 ] Show Less

Physicochemical Properties

Num. heavy atoms 11
Num. arom. heavy atoms 6
Fraction Csp3 0.17
Num. rotatable bonds 1
Num. H-bond acceptors 5.0
Num. H-bond donors 1.0
Molar Refractivity 31.26
TPSA ?

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

33.12 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.06
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

1.71
Log Po/w (WLOGP)?

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

2.96
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.

1.33
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

1.89
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.79

Water Solubility

Log S (ESOL):?

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

-2.27
Solubility 0.884 mg/ml ; 0.00542 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.

-2.02
Solubility 1.55 mg/ml ; 0.00952 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

-2.33
Solubility 0.77 mg/ml ; 0.00472 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.

-6.08 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)

1.58

Application In Synthesis of [ 22245-83-6 ]

* 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 [ 22245-83-6 ]

[ 22245-83-6 ] Synthesis Path-Downstream   1~3

  • 1
  • [ 22245-83-6 ]
  • [ 99368-66-8 ]
YieldReaction ConditionsOperation in experiment
94% With sulfuric acid; nitric acid; at -10 - 40℃; for 6h; The HNO3 (24 mL, 0.55 mol) was dropped solwly at -10 C to a solution of 2-hydroxyl-3- (trifluoromethyl)pyridine 5 (20.00 g,0.12 mol) in H2SO4 (160 mL). The reaction mixture was stirred at 40 C for 6 h and TLC analysis indicated the reactionwas completed.The reaction mixture was added into ice water. Then the solutionwas adjusted pH being 4-5 with saturated aqueous NaOH andextracted with EtOAc. The organic phase was washed with saturatedbrine, dried over Na2SO4, filtered and concentrated underreduced pressure to give the corresponding product. It was obtainedas a light yellow solid in 94% yield. 6 was ready for the nextstep without the further purification. HRMS (ESI): m/z, calcd forC6H4F3N2O3 [M H], 209.0169; found: 209.0171.
78% With sulfuric acid; nitric acid; at 60℃; for 21.5h;Cooling with ice; To an ice-cooled solution of 3-(trifluoromethyl)pyridin-2-ol (5 g, 30.7 mmol) in H2SO4 (30 mL, 563 mmol) was added nitric acid (1.507 mL, 33.7 mmol) dropwise. After 30 min, the ice bath was removed and the reaction mixture was stirred at 25 C for 16 h. The reaction mixture was warmed to 60 C for 5 h, cooled, and added to 150 g of ice. The resulting precipitate was collected by filtration, rinsed with additional H20, and air-dried to afford the first batch of product. Another crop of product was obtained after evaporating the mother liquor to less than 100 mL, cooling on an ice bath, and adding NaOH to adjust to pH 8. The mixture was extracted by EA (100 mL). The organic layer was dried and concentrated to give the product, which was combined with the first batch to yield a yellow solid of 5-nitro-3-(trifluoromethyl)pyridin-2-ol (5 g, 24.03 mmol, 78.0% yield): NMR (400 MHz, CD3OD) delta 8.85 (d, J= 3.2 Hz, 1H), 8.58 (d, J= 2.8 Hz, 1H).
74.5% With sulfuric acid; nitric acid; at 20℃; for 4h;Cooling with ice; In an ice bath, 2-hydroxy-3-trifluoromethylpyridine (25 g, 0.15 mol) was added into cold concentrated sulthric acid (150 ml), followed by drop wise addition of concentrated nitric acid (58 ml). The reaction mixture was warmed to room temperature and was stirred at room temperature for 4 h, and the reaction mixture was poured into 1 liter of icy water to afford white solids. The solids were filtered off and washed with water twice and dried to afford the first batch of compound 2 (16.97 g). The filtrate was adjusted to weak acidic by 1 OM sodium hydroxide, and the solution was extracted by200 ml ethyl acetate for three times. The combined organic phases were dried over anhydrous sodium sulfate, and thesolvent was removed. The residue was purified by columnchromatography (mobile phase, DCMJMeOH) to give the second batch of compound 2 (6.81 g). Total yield was 74.5%.
74% With sulfuric acid; nitric acid; at 20℃; To a solution of compound 1 (25g, 0.15mol) in cocnH2SO4 (100ml) was added the mixture HNO3 and cocnH2SO4 (v/v=1/1)(100ml) drop-wise at room temperature. The reaction mixture was stirred for 4h. This reaction mixture was added into ice (1kg) portion-wise, stirred for 2h, filtrated, washed with water (50ml), then, dried to afford 5-nitro-3-(trifluoromethyl)pyridin-2-ol (2) (23.3g, 74%). 1H NMR (400 MHz, DMSO-d6) delta 13.49 (br, 1H), 8.97 (s, 1H), 8.47 (s, 1H). 13C NMR (101 MHz, DMSO-d6) delta 158.0, 142.4, 134.1 (q, J =5.1Hz), 128.7, 121.9 (q, J = 272.7 Hz), 116.8 (q, J = 30.3 Hz).
73.3% With sulfuric acid; nitric acid; at 0 - 60℃; for 21h; To a mixture of 3- (trifluoromethyl) pyridin-2-ol (2 g 12.26 mmol) was added nitric acid (1.644 mL 36.8 mmol) and H2SO4(12.03 g 123 mmol) at 0 . Then the mixture was stirred at 25 for 16 h. The mixture was then warmed to 60 for 5 h cooled and added to 150 g of ice. The mixture was extracted with EA (2 x 100 mL) and washed with H2O (100 mL) to give the organic layer. The combined organic extract was washed with brine dried over Na2SO4 concentrated to yield a brown solid of 5-nitro-3- (trifluoromethyl) pyridin-2-ol (2.2 g 8.99 mmol 73.3yield) 1HNMR(400 MHz CD3OD) delta 8.91 (d J 2.43 Hz 1H) 9.42 (d J 2.43 Hz 1H) ES-LCMS m/z 209.0 (M+H)
69% Reference Example 117 5-nitro-3-(trifluoromethyl)pyridin-2-ol; 2-Hydroxy-3-(trifluoromethyl)pyridine (3.0 g) was added to conc. sulfuric acid (18 mL) under ice-cooling, and the mixture was stirred at the same temperature for 5 min. Fuming nitric acid (90-95%, 7 mL) was added dropwise over 5 min, and the mixture was allowed to return to room temperature over 2 hr, heated to 50 C. and stirred for 3 hr. After cooling to room temperature, the reaction mixture was poured into ice (200 g), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitate was washed with diisopropyl ether to give the title compound as a solid (yield 2.7 g, 69%). 1H-NMR (CDCl3) delta: 8.65-8.67 (1H, m), 8.80-8.81 (1H, m), 1H not detected.
51.5% With sulfuric acid; nitric acid; at 26℃; for 10.5h;Cooling with ice; To an ice-cooled solution of 3-(trifluoromethyl)pyridin-2-ol (4 g, 24.53 mmol) in H2SO4 (26.1 mL, 491 mmol) was added nitric acid (1.206 mL, 27.0 mmol) dropwise. After 30 min, the ice bath was removed and the reaction was stirred at 26 C. for 10 h. The reaction mixture was added to 120 g ice. The resulting precipitate was collected by filtration, rinsed with additional H2O and air-dried to afford the first batch of product. Another crop of product was obtained after evaporating the mother liquor to less than 100 mL, cooling on an ice bath, and adding NaOH to adjust to pH=8. The mixture was extracted by EA (100 mL). The organic layer was dried and concentrated to give the product, which was combined with the first batch to yield a yellow solid of 5-nitro-3-(trifluoromethyl)pyridin-2-ol (2.63 g, 12.64 mmol, 51.5% yield): 1H NMR (400 MHz, CD3OD) delta: 8.86 (d, J=3.1 Hz, 1H), 8.55 (d, J=2.6 Hz, 1H); ES-LCMS m/z 209.0 (M+H).
With sulfuric acid; nitric acid; In water; at 0 - 20℃; for 3h; 3. 5-Nitro-3-trifluoromethyl-pyridin-2-ol To 3-trifluoromethyl-pyridin-2-ol (1.63 g, 10 mmol) in concentrated sulfuric acid at O0C, add dropwise fuming nitric acid (2 mL). Stir the mixture at room temperature for 3 hours and pour onto ice. Collect the precipitate by filtration, air-dry and finally dry in a vacuum oven overnight to give the title compound as a white solid
EXAMPLE 26; 3-(4-tert-Butyl-phenyl)-N-(6-imidazol-1-yl-5-trifluoromethyl-pyridin-3-yl)-propionamide (Cpd 202) A. To an ice-cooled solution of compound 26a (5.93 g, 36.4 mmol) in 35 mL concentrated H2SO4 was added concentrated HNO3 (2.6 mL, 40.8 mmol) dropwise. After 30 minutes the ice bath was removed and the reaction was stirred at ambient temperature for 15 hours. The reaction mixture was then warmed to 60 C for 5 hours, cooled, and added to 150 g of ice. The resulting precipitate was collected by filtration, rinsed with additional water, and air-dried to afford the first batch of product. Another crop of product was obtained after evaporating the mother liquor to less than 100 mL volume, cooling on an ice bath, and adding NaOH (25.34 g). This solid was filtered off, rinsed with water, and air-dried to provide another batch of product of compound 26b. 1H NMR (d6-DMSO): delta 13.49 (br s, 1H), 8.96 (s, 1H), 8.47 (s, 1H).

  • 3
  • [ 22245-83-6 ]
  • [ 99368-67-9 ]
 

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