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Structure of 1221171-88-5

Chemical Structure| 1221171-88-5

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Product Details of [ 1221171-88-5 ]

CAS No. :1221171-88-5
Formula : C6H5F3N2O
M.W : 178.11
SMILES Code : NC1=NC=C(OC(F)(F)F)C=C1
MDL No. :MFCD19690149
InChI Key :HCYQWUCBICRJGO-UHFFFAOYSA-N
Pubchem ID :49871146

Safety of [ 1221171-88-5 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P261-P280-P305+P351+P338

Computational Chemistry of [ 1221171-88-5 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 6
Fraction Csp3 0.17
Num. rotatable bonds 2
Num. H-bond acceptors 5.0
Num. H-bond donors 1.0
Molar Refractivity 35.32
TPSA ?

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

48.14 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

1.69
Log Po/w (WLOGP)?

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

2.83
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.

0.45
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

1.22
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.52

Water Solubility

Log S (ESOL):?

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

-2.25
Solubility 1.01 mg/ml ; 0.00566 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.

-2.32
Solubility 0.861 mg/ml ; 0.00483 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

-2.29
Solubility 0.911 mg/ml ; 0.00512 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.

-6.19 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)

1.9

Application In Synthesis of [ 1221171-88-5 ]

* 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 [ 1221171-88-5 ]

[ 1221171-88-5 ] Synthesis Path-Downstream   1~7

  • 1
  • C19H13F3N2O [ No CAS ]
  • [ 119-61-9 ]
  • [ 1221171-88-5 ]
YieldReaction ConditionsOperation in experiment
2-Amino-5-trifluoromethoxy pyridine (34); 2-Chloro-5-trifluoromethoxypyridine (6, 1.0 g, 5.0 mmol), benzophenone imine (1.09 g, 6.0 mmol, 1.2 eq), NaOtBu (0.72 g, 7.5 mmol, 1.5 eq), DPEphos (0.03 g, 0.05mmol, 0.01 eq), Pd2dba3 (0.07 g, 0.1 mmol, 0.02 eq) were introduced in dry toluene (15 mL) and the reaction mixture was heated at 80 0C and vigorously stirred for 2 h. GC monitoring indicated 100% conversion. The mixture was allowed to cool to ambient temperature before being filtrated on celite and washed with ethyl acetate. The filtrate was poured onto a 10% aqueous solution of citric acid (30 mL) and the reaction mixture was then vigorously stirred for 16 h at room temperature. GC of the organic phase indicated disappearance of starting reagent and formation of diphenylketone. The aqueous phase was adjusted to pH 9-10 with 5% sodium hydroxide (40 mL) and extracted with ethyl acetate (5 x 20 mL). The combined organic layers were dried over sodium sulfate before being evaporated to afford a crude yellow powder. Crystallization in hexane provided pure 2-amino-5-trifluoromethoxy pyridine (34, 0.36 g, 2.0 mmol, 40%) as colorless needles; m.p. 71 -73 0C.1H NMR (CDCl3, 300 MHz): delta = 7.91 (d, J = 2.7 Hz, 1 H), 7.23 (dd, J = 2.7, 8.9 Hz, 1 H), 6.39 (d, J= 8.9 Hz, 1 H), 4.49 (bs, 2 H). - 19F NMR (CDCl3, 282 MHz): delta = -58.9 - 13C NMR (CDCl3, 75 MHz): delta = 157.1, 141.4, 138.7, 131.6, 120.6 (q, J = 256 Hz), 108.7. - C6H5F3N2O (178): calcd. (%) C 40.46, H 2.83, N 15.73; found C 40.46, H 2.90, N 16.02.
  • 2
  • C19H13F3N2O [ No CAS ]
  • [ 1221171-88-5 ]
  • 3
  • N-(4-methoxybenzyl)-5-(trifluoromethoxy)pyridin-2-amine [ No CAS ]
  • [ 1221171-88-5 ]
YieldReaction ConditionsOperation in experiment
70% In water; trifluoroacetic acid; at 100℃; for 0.5h;Microwave irradiation; A mixture of N-(4-methoxybenzyl)-5-(trifluoromethoxy)pyridin-2-amine (Intermediate 16; 1.2 g, 4 mmol), TEA (12 mL) and H20 (1.2 mL) was stirred at 100 oC (microwave) for 0.5 hrs. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (100 mL) and H20 (25 mL). The organic layer was separated (phase separating cartridge) and the solvent was removed under reduced pressure. The crude product was purified by SPE (Isolute SCX-2 10 g column, 0 to 100% 7 M NH3 in MeOHDCM) to give the title compound as an off-white solid (0.46 g, 70%).1H NMR (ppm)(400 MHz, CDCI3): 4.52 - 4.51 (2H, m), 6.49 (1 H, d, J=9.6 Hz), 7.33 - 7.30 (1 H, m), 8.01 (IH, d, J=2.8 Hz)
  • 4
  • [ 1206972-45-3 ]
  • [ 1221171-88-5 ]
YieldReaction ConditionsOperation in experiment
With Benzophenone imine; tris-(dibenzylideneacetone)dipalladium(0); bis[2-(diphenylphosphino)phenyl] ether; sodium t-butanolate; In toluene; at 80℃; for 2h;Inert atmosphere; 2-Chloro-5-(trifluoromethoxy)pyridine (int-80) (1.0 g, 5.06 mmol), sodium tertbutoxide (0.97 g, 10.12 mmol) and benzophenone imine (int-81) (1.10 g, 6.07 mmol) were dissolved in toluene (15 mL). Then Pd2(dba)3 (92.60 mg, 0.10 mmol) and DPEPhos (109.0 mg, 0.20 mmol) were added under nitrogen atmosphere. The mixture was heated at 80 C for 2 h. Then it was filtered and washed with EtOAc (20 mL). The filtrate was treated with 3 M HC1 (50 mL) at 50 C for 4 h. The phases were separated and the aq. phase was basified with 10% NaOH to pH 10. The aq. phase was extracted with EtOAc (3 x 50 mL). The combined organic layers was dried over anhydrous Na2SO4 and concentrated in vacuo. Crude 5-(trifluoromethoxy)pyridin-2-amine (int-82) (400 mg, 44%) was used directly in the next step without further purification. MS (ESI): mlz 178.9 [M+H] .
  • 5
  • [ 1221171-88-5 ]
  • 3-bromo-5-(trifluoromethoxy)pyridin-2-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
200 mg With N-Bromosuccinimide; In dichloromethane; at 20℃; for 16h; Int-82 (200 mg, 1.12 mmol) was dissolved in DCM (10 mL) and a solution of Nbromosuccinimide (200 mg, 1.12 mmol) in DCM (5 mL) was added dropwise. The mixture was stined at rt for 16 h. The solvent was removed under reduced pressure and the residue was purified by colunm chromatography on silica gel using a mixture of petroleum ether and EtOAc (2:1) as eluent to give 3-bromo-<strong>[1221171-88-5]5-(trifluoromethoxy)pyridin-2-amine</strong> (int-83) (200 mg, 69%) as a yellow solid. MS (ESI): mlz 257.9 [M+Hj.
  • 6
  • [ 1221171-88-5 ]
  • (1r,4r)-4-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclohexanecarboxylic acid [ No CAS ]
  • (1r,4r)-4-[2-(4-chloro-3-fluorophenoxy)acetamido]-N-[5-(trifluoromethoxy)pyridin-2-yl]cyclohexane-1-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
22% One drop of N,N-dimethylformamide was added to a suspension of the product of Example 8A (40 mg, 0.12 mmol) in dichloromethane (2 mL). Oxalyl chloride (2.0 M in dichloromethane, 0.121 mL) was added in one portion. After stifling at ambient temperature for20 minutes, the resulting solution was concentrated under reduced pressure. The residue was then taken up in pyridine (1 mL) and transferred to a solution of 5-(trifluoromethoxy)pyridin-2- amine (24.9 mg, 0.14 mmol, Astatech) in a solvent mixture of N,N-dimethylformamide (1.0 mL) and pyridine (1.0 mL). The reaction mixture was stirred for 30 minutes, filtered through a glass microfiber fit, and purified by preparative HPLC [YMC TriArtTM Cl 8 Hybrid 5 jim column, 50 x 100 mm, flow rate 70 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (13 mg, 0.027 mmol, 22 % yield). 1H NMR (501 MHz, DMSO-d6) 5 ppm 10.67 (s, 1H), 8.40 (dt, J = 2.9, 0.7 Hz, 1H), 8.21 (dd, J = 9.1, 0.7 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.87(ddd, J = 9.2, 3.0, 1.1 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.07 (dd, J = 11.4, 2.8 Hz, 1H), 6.86 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.50 (s, 2H), 3.67 - 3.57 (m, 1H), 2.54 -2.43 (m, 1H), 1.91 - 1.77 (m, 4H), 1.53 - 1.42 (m, 2H), 1.39 - 1.24 (m, 2H); MS (ESf?) m/z 490 (M+H).
  • 7
  • [ 1221171-88-5 ]
  • 4-[2-(4-chloro-3-fluorophenoxy)acetamido]bicyclo[2.2.2]octane-1-carboxylic acid [ No CAS ]
  • 4-[2-(4-chloro-3-fluorophenoxy)acetamido]-N-[5-(trifluoromethoxy)pyridin-2-yl]bicyclo[2.2.2]octane-1-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
22% The product of Example 158B (62 mg, 0.11 mmol) and (1509) bis(tetramethylene)fluoroformamidinium hexafluorophosphate (50 mg, 0.16 mmol, Alfa) were charged to a sealed tube, and a solvent mixture of dichloromethane (0.26 mL) and N,N- diisopropylethylamine (0.083 mL, 0.47 mmol) was added in one portion. The resulting mixture was stirred at ambient temperature for 30 minutes and <strong>[1221171-88-5]5-(trifluoromethoxy)pyridin-2-amine</strong> (22.5 mg, 0.13 mmol, Astatech) was added. The tube was sealed and stirred at 75 C for 18 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The resulting residue was dissolved in N,N-dimethylformamide (3 mL), filtered through a glass microfiber frit and purified by preparative HPLC [YMC TriArt CI 8 Hybrid 5 mupiiota column, 50 x 100 mm, flow rate 70 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (12 mg, 0.023 mmol, 22% yield). JH NMR (400 MHz, DMSO-<) ppm 9.95 (s, 1H), 8.39 - 8.36 (m, 1H), 8.11 (dd, J = 9.2, 0.6 Hz, 1H), 7.83 (ddd, J = 9.2, 3.0, 1.0 Hz, 1H), 7.48 - 7.41 (m, 2H), 7.00 (dd, J = 11.4, 2.8 Hz, 1H), 6.78 (ddd, J = 9.0, 2.8, 1.2 Hz, 1H), 4.42 (s, 2H), 1.92 - 1.78 (m, 12H). MS (APCI+) m/z 516 (M+H)+.
 

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