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Chemical Structure| 1221171-96-5

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2-Chloro-4-iodo-6-(trifluoromethoxy)pyridine

CAS No.: 1221171-96-5

4.5 *For Research Use Only !

Cat. No.: A432709 Purity: 97%

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Product Details of [ 1221171-96-5 ]

CAS No. :1221171-96-5
Formula : C6H2ClF3INO
M.W : 323.44
SMILES Code : FC(F)(F)OC1=CC(I)=CC(Cl)=N1
MDL No. :MFCD22571776
Boiling Point : No data available
InChI Key :GBLAONUGHUCGKN-UHFFFAOYSA-N
Pubchem ID :49871804

Safety of [ 1221171-96-5 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P280-P305+P351+P338-P310

Calculated chemistry of [ 1221171-96-5 ] Show Less

Physicochemical Properties

Num. heavy atoms 13
Num. arom. heavy atoms 6
Fraction Csp3 0.17
Num. rotatable bonds 2
Num. H-bond acceptors 5.0
Num. H-bond donors 0.0
Molar Refractivity 48.65
TPSA ?

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

22.12 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.42
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

3.98
Log Po/w (WLOGP)?

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

4.5
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.

2.53
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

3.59
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.4

Water Solubility

Log S (ESOL):?

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

-4.56
Solubility 0.00886 mg/ml ; 0.0000274 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-4.15
Solubility 0.0231 mg/ml ; 0.0000715 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately 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

-4.2
Solubility 0.0206 mg/ml ; 0.0000638 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately 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

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.

-5.45 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

0.0
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

2.0 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)

2.29

Application In Synthesis [ 1221171-96-5 ]

* 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 [ 1221171-96-5 ]

[ 1221171-96-5 ] Synthesis Path-Downstream   1~5

  • 1
  • [ 124-38-9 ]
  • [ 1221171-96-5 ]
  • [ 1221171-97-6 ]
YieldReaction ConditionsOperation in experiment
71% 2-Chloro-6-trifluoromethoxy isonicotinic acid (43); At 0 0C, butyllithium (1.56 M in hexane, 4.0 mL, 6.2 mmol, 0.67 eq) was added dropwise to a solution of butylmagnesium chloride (2M in THF, 1.5 mL, 3.0 mmol, 0.33 eq) in THF (8 mL), followed after 10 min by a solution of 2-chloro-4-iodo-6- trifluoro?iepsilonthoxypyridinepsilon (42, 3.0 g, 9.3 mmol, 1 eq) in THF (5 mL). After 10 min the reaction mixture was poured onto an excess of freshly crushed dry ice before being treated with an aqueous solution of sodium hydroxide (5%, 15 mL). The resulting aqueous layer was collected, washed with diethylether (10 mL) and acidified to pH 4 by dropwise addition of hydrochloric acid (6 N, 5 mL). After extraction with ethyl acetate (3 x 10 mL), the combined organic layers were dried over sodium sulfate before being evaporated to afford pure 2-chloro-6-trifluoromethoxy isonicotinic acid (43, 1.6 g, 6.6 mmol, 71%) as a white powder; m.p. 65-68 0C.1H NMR (CDCl3, 300 MHz): delta = 10.12 (br s, 1 H), 7.88 (d, J = 0.9 Hz, 1 H), 7.56 (d, J = 0.9 Hz, 1 H). - 19F NMR (CDCl3, 282 MHz): delta = -57.3 - 13C NMR (CDCl3, 75 MHz): delta = 167.6, 156.3, 150.4, 143.0, 122.5, 120.2 (q, J = 260 Hz), 113.5. - C7H3ClF3NO3 (241): calcd. (%) C 34.81, H 1.25, N 5.80; found C 34.64, H 1.55, N 5.76.
  • 2
  • [ 1221171-95-4 ]
  • [ 1221171-96-5 ]
YieldReaction ConditionsOperation in experiment
80% 2-ChIoro-4-iodo-6-trifluoromethoxy pyridine (42); At 0 0C, diisopropylamine (1.4 g, 1.9 mL, 13.6 mmol, 1.1 eq) was added dropwise to a solution of butyllithium (1.56 M in hexane, 9.0 mL, 13.6 mmol, 1.1 eq) in THF (20 mL). At -78 0C, a solution of 2-chloro-5-iodo-6-trifluoromethoxypyridine (41, 4.0 g, 12.4 mmol, 1 eq) in THF (10 mL) was added dropwise and the reaction mixture was stirred for 1 h at this temperature. It was then neutralized with a solution of hydrochloric acid (2N, 10 mL), treated with a saturated aqueous solution sodium hydrogencarbonate (30 mL) and extracted with diethylether (3 x 20 mL). The combined organic layers were dried over sodium sulfate before being evaporated. The crude dark oil was distilled under vacuum (b.p. 104-107 0C / 16 mbar) to afford pure 2-chloro-4-iodo-6- trifluoromethoxypyridine (42, 3.2 g, 10.9 mmol, 80%) as a colorless oil; 1H NMR(CDCl3, 300 MHz): delta = 7.66 (d, J= 1.0 Hz, 1 H), 7.34 (d, J= 1.0 Hz, 1 H). - 19F NMR (CDCl3, 282 MHz): delta = -57.1 - 13C NMR (CDCl3, 75 MHz): delta = 155.1, 149.4, 130.7, 120.3, 119.1 (q, J= 262 Hz), 108.3.
  • 3
  • [ 1221171-96-5 ]
  • [ 1221172-00-4 ]
YieldReaction ConditionsOperation in experiment
4-Amino-2-chloro-6-trifluoromethoxypyridine (45); At -78 0C, butyllithium (1.56 M in hexane, 2.2 mL, 3.4 mmol, 1.1 eq) was added dropwise to a solution of <strong>[1221171-96-5]2-chloro-4-iodo-6-trifluoromethoxypyridine</strong> (42, 1.0 g, 3.1 mmol) in THF (8 mL) followed after 10 min by benzenesulfonyl azide (0.6 g, 3.4 mmol, 1.1 eq). The reaction mixture was was allowed to reach 25 0C before being treated with a saturated aqueous solution of ammonium chloride (10 mL) and extracted with diethylehter (3 x 8 mL). The combined organic layers were dried over sodium sulfate and evaporated to afford a crude red oil of 4-azido-2-chloro-6- trifluoromethoxypyridine. It was then dissolved in anhydrous diethylether (25 mL) and added dropwise to a suspension of lithium aluminium hydride (130 mg, 3.4 mmol, 1.1 eq) in diehtylether (25 mL). The reaction mixture was heated under reflux for 5 h before being treated with water (10 mL) and extracted with diethylether (3 x 10 mL). The combined organic layers were dried over sodium sulfate before being evaporated. The crude product was purified by chromatography on silica gel using ethyl acetate/cyclohexane (1:9) as eluent which afforded pure 4-amino-2-chloro-6- trifluoromethoxypyridine (45, 0.3 g, 1.4 mmol, 46%) as a yellow oil.1H NMR (CDCl3, 300 MHz): delta = 6.41 (d, J = 1.6 Hz, 1 H), 6.07 (d, J = 1.6 Hz, 1 H),4.30 (bs, 2 H). - 19F NMR (CDCl3, 282 MHz): delta = -56.8 - 13C NMR (CDCl3, 75 MHz): delta = 157.4, 156.7, 149.7, 119.9 (q, J = 260 Hz), 107.6, 96.0. - C6H4ClF3N2O (212): calcd. (%) C 33.90, H 1.90, N 13.18; found C 33.56, H 2.01, N 12.87.
  • 4
  • [ 1221171-96-5 ]
  • [ 55-21-0 ]
  • N-[2-chloro-6-(trifluoromethoxy)pyridin-4-yl]benzamide [ No CAS ]
  • 5
  • [ 1221171-96-5 ]
  • C11H20INO2Zn [ No CAS ]
  • C17H22ClF3N2O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With bis(tri-t-butylphosphine)palladium(0); In tetrahydrofuran; at 65℃; for 3.0h;Inert atmosphere; A 0.36 M solution of intermediate 6a in THF (42 mL, 15.12 mmol) was added to a stirred mixture of 4-bromo-2-methoxy-6-methylpyridine (CAS: 1083169-00-9; 2.98 g, 14.75 mmol) and Pd(/-Bu3P)2 (0.22 g, 0.31 mmol) at rt under N2. The mixture was stirred at reflux for 16 h. After cooling to rt a (1 : 1) mixture of a 32% solution of NFl·, (0369) (50 mL) and a saturated solution of NELCl (50 mL) was added. The mixture was extracted with EtOAc (200 mL). The organic layer was separated, dried (MgS04), filtered and the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography (silica, EtOAc in heptane, gradient from 0/100 to 50/50). The desired fractions were collected and concentrated in vacuo to yield intermediate 7b as a colorless oil (4.34 g, 91%).
 

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